[{"id":"adc-generations","kind":"roadmap","name":"ADC roadmap: from Mylotarg to bispecific and dual-payload ADCs","aka":[],"tldr":"Twenty-five years of trying to make chemotherapy hit only cancer cells, from the unstable first ADC to today's third-generation blockbusters and the fourth generation now in trials.","summary":"This roadmap traces antibody-drug conjugates from the first attempts with murine antibodies and the unstable first approved ADC, gemtuzumab ozogamicin, through the second generation that proved the class with brentuximab vedotin and T-DM1. The third generation brought TOP1 payloads and bystander killing with trastuzumab deruxtecan and sacituzumab govitecan, then moved into earlier lines, new targets and ADC plus PD-1 combinations. The emerging fourth generation arrives as bispecific ADCs led by izalontamab brengitecan, then dual-payload, degrader, immune-stimulating and masked ADCs, before a speculative era of imaging-guided therapy. Each generation fixed the previous one's weakness; the route is linked from TNBC, HR-positive and HER2-positive breast cancer, NSCLC and ovarian cancer.","asOf":"2026-09-04","links":[{"label":"ASCENT: sacituzumab govitecan doubles survival in heavily pretreated metastatic triple-negative breast cancer (New England Journal of Medicine 2021)","url":"https://doi.org/10.1056/NEJMoa2028485"},{"label":"DESTINY-Breast03: trastuzumab deruxtecan beats T-DM1 as second-line treatment of HER2-positive metastatic breast cancer (New England Journal of Medicine 2022)","url":"https://doi.org/10.1056/NEJMoa2115022"}],"tags":[],"related":["drug-discovery-roadmap"],"cancers":[],"sections":["adcs"],"technologies":["adc","bispecific-adc","dual-payload-adc","degrader-antibody-conjugate","immune-stimulating-adc","masked-adc","radioimmunotherapy","site-specific-conjugation"],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"steps":[{"era":"1980s-2000","title":"Concept and first attempt","description":"Murine antibodies with conventional chemotherapy payloads (doxorubicin) fail: immunogenic, too little drug delivered. Gemtuzumab ozogamicin (2000) becomes the first approved ADC with a calicheamicin payload and an unstable hydrazone linker; withdrawn in 2010 for toxicity, re-approved 2017 with fractionated dosing.","refs":["gemtuzumab-ozogamicin","cd33"],"status":"historic"},{"era":"2011-2013","title":"Second generation proves the class","description":"Brentuximab vedotin (2011, vc-MMAE, Hodgkin) and T-DM1 (2013, non-cleavable SMCC-DM1, HER2+ breast) succeed with humanised antibodies, ultra-potent tubulin payloads, and more stable linkers. Heterogeneous DAR, no bystander effect for T-DM1, and payload-driven neuropathy remain.","refs":["brentuximab-vedotin","trastuzumab-emtansine"],"status":"historic"},{"era":"2019-2022","title":"Third generation: TOP1 payloads and bystander killing","description":"Trastuzumab deruxtecan (DAR 8, cleavable GGFG linker, DXd) and sacituzumab govitecan (DAR ~7.6, SN-38) show that a permeable topoisomerase-I payload at high DAR works in low-antigen and heterogeneous tumours. Enfortumab vedotin (Nectin-4) transforms bladder cancer. HER2-low becomes a diagnosis. ADCs beat chemotherapy head-to-head and beat an older ADC (DESTINY-Breast03).","refs":["trastuzumab-deruxtecan","sacituzumab-govitecan","enfortumab-vedotin","destiny-breast03","destiny-breast04"],"status":"current"},{"era":"2023-2026","title":"Third generation matures: earlier lines, more targets, combinations","description":"Dato-DXd, mirvetuximab, telisotuzumab vedotin approved; T-DXd reaches early-stage breast cancer and tumour-agnostic HER2 IHC3+; ADC + PD-1 combinations become first-line standards (EV-302, ASCENT-04). New targets validated: FRα, TF, c-MET, B7-H3, CDH6, CLDN18.2. Problems surface: ILD, ocular toxicity, TOP1 cross-resistance, ADC sequencing.","refs":["datopotamab-deruxtecan","mirvetuximab-soravtansine","telisotuzumab-vedotin","ev-302","ascent-04","adc-sequencing"],"status":"current"},{"era":"2026-2028","title":"Fourth generation, wave 1: bispecific ADCs","description":"Izalontamab brengitecan (EGFR×HER3) posts the first positive phase 3 for a bispecific ADC (TNBC and ESCC, 2026). Eight bsADC phase 3 trials started in 2025; c-MET×EGFR (tilatamig samrotecan), Nectin-4×TROP2 (AK146D1, AVZO-103), HER2 biparatopic, PD-L1×B7-H3 follow. Bispecific ADCs offer better internalisation and tumour selectivity and address heterogeneity.","refs":["izalontamab-brengitecan","bl-b01d1-307","tilatamig-samrotecan","ak146d1","bispecific-adc"],"status":"emerging"},{"era":"2026-2030","title":"Fourth generation, wave 2: new payload logic","description":"The second wave brings dual-payload ADCs (TOP1 + orthogonal mechanism) to pre-empt cross-resistance; degrader-antibody conjugates (non-genotoxic payloads reaching intracellular targets); immune-stimulating conjugates (TLR/STING); masked/conditionally active ADCs unlocking EGFR, EpCAM, CD71; peptide-drug conjugates; radio-ADCs with 225Ac/177Lu. Homogeneous site-specific conjugation and hydrophilic linkers are the enabling chemistry.","refs":["dual-payload-adc","degrader-antibody-conjugate","immune-stimulating-adc","masked-adc","peptide-drug-conjugate","radioimmunotherapy","site-specific-conjugation"],"status":"emerging"},{"era":"2028+","title":"Speculative: imaging-guided, adaptive ADC therapy","description":"Antigen PET (TROP2, HER2, B7-H3) to select and sequence ADCs; ctDNA and payload-resistance biomarkers (SLFN11, TOP1) to switch payload class; AI-designed antibodies and linkers; personalised payload selection from ex vivo testing; ADCs as neoadjuvant chemotherapy replacements across common cancers.","refs":["trop2-pet","her2-pet","immuno-pet","ai-drug-design","functional-drug-testing"],"status":"speculative"}],"watch":[]},{"id":"ai-oncology-roadmap","kind":"roadmap","name":"AI in oncology roadmap: pattern readers → foundation models → agents in the workflow","aka":[],"tldr":"Artificial intelligence in cancer started as software that flagged spots on a mammogram. It now designs molecules, reads slides better than any single pathologist for some tasks, and is beginning to match patients to trials and draft the tumour board summary; the question is which of it will be proven to help.","summary":"Three strands of AI are converging on oncology. In discovery, structure prediction (AlphaFold 3, Boltz, Chai) and generative chemistry have produced the first AI-designed candidates in trials, and perturbation-scale single-cell datasets are training models that try to predict what a drug will do to a cell. In diagnosis, foundation models trained on millions of slides and scans (Virchow, Prov-GigaPath, UNI, TITAN, CT-FM) underpin the first AI tests cleared to predict treatment benefit (ArteraAI Prostate 2025, ArteraAI Breast 2026) and the first randomised evidence that AI reading improves screening (MASAI). In the clinic, language models are entering trial matching, documentation and tumour-board support, with radiotherapy auto-contouring as the most mature deployed use.\n\nThe gap between the thousands of published models and the handful in clinical use is the defining feature of the field. Prospective, ideally randomised, evidence that an AI-guided decision improves an outcome exists for a few tools; a regulatory route for models that keep updating, payment codes for AI-derived biomarkers, and data that can be shared or federated across hospitals are all unsettled.\n\nThis roadmap covers the whole stack from molecule to clinic; the companion roadmaps go deeper on the AI-assisted clinic and on the virtual cell.","asOf":"2026-09-10","links":[{"label":"MASAI randomised trial of AI-supported mammography screening (Lancet Digital Health 2025)","url":"https://doi.org/10.1016/S2589-7500(24)00267-X"},{"label":"FDA: Artificial intelligence-enabled medical devices list","url":"https://www.fda.gov/medical-devices/software-medical-device-samd/artificial-intelligence-enabled-medical-devices"}],"tags":[],"related":["ai-oncology-clinic","virtual-cell","idea-multimodal-foundation-model","idea-tr2-ai-external-validation-registry","idea-acc-ai-first-pathology-common-cases","idea-prev-opportunistic-ct-ai-registry","idea-tr1-ai-central-imaging-reads","idea-tr1-ehr-point-of-care-trial-alert","idea-bio1-in-silico-trials-dose","tahoe-100m","arc-virtual-cell-atlas","pathology-benchmarks","imaging-data-commons","flatiron-foundation-cgdb","multidisciplinary-tumour-board","drug-discovery-roadmap"],"cancers":[],"sections":["ai-computation"],"technologies":["radiology-ai-screening","digital-pathology-ai","pathology-foundation-model","ai-drug-design","ai-trial-matching","auto-contouring-ai","federated-learning-medical-ai","digital-twins-trials","ai-compute-platforms","whole-slide-scanners","virchow","prov-gigapath","uni-conch","titan","musk","chief","h-optimus","ct-fm","merlin-ct","aidoc-care","med-gemini","alphafold3","boltz","chai-1","rfdiffusion","esm3","chemistry42","phenom-2","geneformer","scgpt","state-arc","sybil","mirai","foresight-ehr","tempus-multimodal","bionemo"],"targets":[],"drugs":["artera-ai-prostate","artera-ai-breast","paige-prostate"],"companies":["paige","artera","pathai","owkin","tempus","aidoc","isomorphic-labs","insilico-medicine","recursion","xaira-therapeutics","google-deepmind","microsoft-research","nvidia","limbus-ai","therapanacea","trial-library","massive-bio","flatiron-health","pathos-ai","noetik"],"institutions":[],"pathways":[],"terms":[],"trials":["masai"],"people":[],"bottlenecks":["b-ai-validation","b-data-silos","b-real-world-evidence","b-workforce","b-reproducibility"],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"steps":[{"era":"1998-2016","title":"Computer-aided detection","description":"The first cleared cancer AI was computer-aided detection for mammography in 1998, which marked suspicious regions for the radiologist and, in large observational studies, did not improve accuracy. Rule-based decision support for treatment recommendations was tried and mostly abandoned. The lesson that survived: an algorithm has to be evaluated on the decision it changes, not on the pattern it finds.","refs":["radiology-ai-screening","mammography"],"status":"historic"},{"era":"2017-2022","title":"Deep learning reaches cleared devices","description":"Convolutional networks trained on labelled images matched specialists on narrow tasks. Paige Prostate (2021) became the first FDA-authorised AI for reading pathology slides; radiology triage tools for haemorrhage and embolism were cleared by the dozen; Sybil and Mirai predicted future lung and breast cancer from today's scan. Whole-slide scanning became routine in large centres, which made slide-level AI possible at all.","refs":["paige-prostate","paige","digital-pathology-ai","whole-slide-scanners","sybil","mirai","aidoc"],"status":"historic"},{"era":"2020-2026","title":"Structure prediction and generative design","description":"AlphaFold made protein structure a lookup rather than a two-year experiment; AlphaFold 3 (2024), Boltz and Chai extended it to drug-protein and antibody complexes, and RFdiffusion and ESM3 design proteins that never existed. Insilico's generative chemistry produced the first AI-discovered drug to reach phase 2, Isomorphic's first oncology candidate was cleared for trials, and Recursion and Xaira are betting that image and perturbation data can find targets no hypothesis would. None has yet produced an approved cancer drug, which is the honest benchmark.","refs":["alphafold3","boltz","chai-1","rfdiffusion","esm3","ai-drug-design","chemistry42","insilico-medicine","isomorphic-labs","recursion","phenom-2","xaira-therapeutics","google-deepmind"],"status":"current"},{"era":"2023-2026","title":"Foundation models and the first predictive tests","description":"Pathology models pretrained on millions of slides (Virchow, Prov-GigaPath, UNI and CONCH, H-optimus, TITAN) predict mutations, biomarkers and outcomes from a routine stain; MUSK adds clinical text. ArteraAI Prostate (2025) was the first AI test cleared to predict benefit from a treatment, and ArteraAI Breast followed in 2026. MASAI gave the first randomised evidence that AI-supported screening finds more cancers with less workload; Aidoc CARE (January 2026) was the first foundation-model triage platform cleared. Single-cell models (Geneformer, scGPT, State) and the Tahoe-100M dataset began the same arc for biology.","refs":["pathology-foundation-model","virchow","prov-gigapath","uni-conch","h-optimus","titan","musk","chief","artera-ai-prostate","artera-ai-breast","artera","masai","aidoc-care","ct-fm","merlin-ct","geneformer","scgpt","state-arc","tahoe-100m","pathology-benchmarks"],"status":"current"},{"era":"2025-2028","title":"Language models enter the workflow","description":"The first widely deployed AI in cancer care is not a diagnosis but a time-saver: auto-contouring of organs and tumours for radiotherapy planning now runs in hundreds of centres. Language models are being tested to match patients to trials from the record at the moment a treatment is chosen, to draft tumour-board summaries and pathology reports, and to answer patient questions under supervision. Federated learning lets models train across hospitals without moving data. The evidence standard for each is still being written.","refs":["auto-contouring-ai","limbus-ai","therapanacea","ai-trial-matching","trial-library","massive-bio","med-gemini","foresight-ehr","federated-learning-medical-ai","owkin","tempus","multidisciplinary-tumour-board","idea-tr1-ehr-point-of-care-trial-alert"],"status":"emerging"},{"era":"2027-2032","title":"From prediction to prospective proof","description":"The field has thousands of retrospective models and a handful of prospective trials. The infrastructure being proposed: a registry of external validation datasets with mandatory reporting, AI-first reading for high-volume common diagnoses with pathologists handling exceptions, every routine CT checked opportunistically for early cancer signs with a tracked pathway, AI central reads to cut trial endpoint cost, and digital twins as virtual control arms where a randomised control is unethical. Regulators are building predetermined change control plans so that models can update without re-clearance.","refs":["idea-tr2-ai-external-validation-registry","idea-acc-ai-first-pathology-common-cases","idea-prev-opportunistic-ct-ai-registry","idea-tr1-ai-central-imaging-reads","digital-twins-trials","imaging-data-commons","flatiron-foundation-cgdb","b-ai-validation"],"status":"emerging"},{"era":"2030+","title":"Patient-level models and the virtual cell","description":"The two long-range bets are a multimodal model that reads slides, scans, genomics and the record to recommend and monitor treatment, and a virtual cell accurate enough to run a drug experiment in silico before it is run in a dish. Both depend on data at a scale no single institution holds, on validation standards that do not yet exist, and on liability and consent questions that are open today. The companion roadmaps on the AI clinic and the virtual cell follow each in detail.","refs":["idea-multimodal-foundation-model","tempus-multimodal","pathos-ai","noetik","arc-virtual-cell-atlas","idea-bio1-in-silico-trials-dose","ai-oncology-clinic","virtual-cell"],"status":"speculative"},{"era":"What sets the pace","title":"Validation, data and compute","description":"The bottleneck is not model quality but the path from a published model to a deployed one: prospective evidence, external validation, regulatory status for updating models, payment, and data that can be shared. Records, scans and genomes sit in silos; real-world outcomes are weakly recorded, so there is little to learn from; and the workforce that would supervise AI is already short. Compute and model platforms are the one input that is not scarce.","refs":["b-ai-validation","b-data-silos","b-real-world-evidence","b-workforce","b-reproducibility","ai-compute-platforms","nvidia","bionemo"],"status":"current"}],"watch":[]},{"id":"ai-oncology-clinic","kind":"roadmap","name":"AI in the oncology clinic: from narrow cleared tools to multimodal decision support","aka":[],"tldr":"How AI is moving from single-task readers of scans and slides towards systems that weigh everything about a patient, and what regulators and evidence still require.","summary":"Hundreds of narrow AI devices are cleared, mostly in radiology triage and screening. The first predictive pathology tools (ArteraAI) prove that AI can change treatment decisions under regulation. Foundation models promise breadth, but the evidence base for deployment, the regulatory framework for updating models, and reimbursement are all unsettled.","asOf":"2026-09-08","links":[{"label":"MASAI: AI-supported mammography screening finds more cancers with half the radiologist workload (Lancet Oncology 2023)","url":"https://doi.org/10.1016/S1470-2045(23)00298-X"}],"tags":[],"related":[],"cancers":[],"sections":["ai-computation"],"technologies":["digital-pathology-ai","radiology-ai-screening","pathology-foundation-model","virchow","prov-gigapath","musk","med-gemini","ai-trial-matching","sybil","mirai"],"targets":[],"drugs":["artera-ai-prostate","artera-ai-breast"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"steps":[{"era":"2017-2021","title":"Narrow detection tools cleared","description":"FDA clears the first AI detection aids: mammography CAD successors, Paige Prostate (2021), radiology triage for haemorrhage and embolism. Evidence is mostly reader studies.","refs":["digital-pathology-ai","radiology-ai-screening","paige"],"status":"historic"},{"era":"2022-2024","title":"Screening at scale and risk models","description":"MASAI (Sweden) shows AI-supported mammography reading finds more cancers with less workload; Sybil and Mirai predict future cancer from today's scan; whole-slide imaging becomes routine, enabling slide-level AI.","refs":["mammography","sybil","mirai","digital-pathology-ai"],"status":"current"},{"era":"2025-2026","title":"First predictive AI and foundation models in products","description":"ArteraAI Prostate (de novo 2025) predicts treatment benefit; ArteraAI Breast cleared 2026. Pathology foundation models (Virchow2, Prov-GigaPath, TITAN, Atlas) move into commercial biomarker products; multimodal models (MUSK) predict immunotherapy response retrospectively.","refs":["artera-ai-prostate","artera-ai-breast","virchow","prov-gigapath","titan","atlas-aignostics","musk"],"status":"current"},{"era":"2026-2028","title":"Prospective evidence and regulatory frameworks","description":"Randomised or pragmatic trials of AI-guided decisions (screening intervals, treatment selection); FDA predetermined change control plans for model updates; EU AI Act high-risk obligations; payment codes for AI-derived biomarkers. LLM assistants (Med-Gemini class) enter tumour boards for documentation and trial matching under human review.","refs":["med-gemini","ai-trial-matching","tempus-multimodal","foresight-ehr"],"status":"emerging"},{"era":"2029+","title":"Speculative: multimodal decision support as standard of care","description":"A single model reads slides, scans, genomics and records to recommend and monitor therapy, audited against outcomes and updated continuously. Depends on data-sharing, liability and validation questions that are open today.","refs":["idea-multimodal-foundation-model","flatiron-foundation-cgdb","imaging-data-commons"],"status":"speculative"}],"watch":[]},{"id":"prevention-roadmap","kind":"roadmap","name":"Cancer prevention roadmap: tobacco control and vaccines → biomarker-guided chemoprevention → interception in carriers","aka":[],"tldr":"About four in ten cancers could be prevented with tools that already exist: vaccines against the viruses that cause them, tobacco and alcohol control, weight, aspirin for the right people, and finding the families who carry a high-risk gene. The roadmap is mostly about deployment, with interception vaccines as the long-range bet.","summary":"Prevention has the strongest evidence and the weakest deployment in oncology. Tobacco control has prevented more cancer deaths than any drug. Hepatitis B vaccination cut liver cancer in the countries that adopted it early, and HPV vaccination is eliminating cervical cancer where coverage is high; a single dose proved almost fully protective (KEN SHE, 2021) and the WHO endorsed one-dose schedules, which makes elimination affordable everywhere. Germline testing finds the BRCA and Lynch carriers who benefit from risk-reducing surgery, aspirin and intensive screening. Tamoxifen prevents breast cancer in high-risk women.\n\nThe present decade is adding precision to prevention: aspirin after bowel cancer surgery works in tumours with PIK3CA mutations (ALASCCA) and is being tested in four cancers in Add-Aspirin, while ASPREE showed it does not help everyone; low-dose tamoxifen keeps the benefit with fewer side-effects; salpingectomy during any pelvic operation prevents ovarian cancer; polygenic scores could set when screening starts; population germline screening would find the carriers who do not know. GLP-1 agonists and bariatric surgery may prevent obesity-related cancers and need a randomised trial to prove it.\n\nThe frontier is interception: vaccinating people who carry a high-risk gene against the cancers they are likely to develop, with the Lynch syndrome frameshift vaccine as the first candidate for a randomised trial. The pace is set by the adoption gap, by funding that follows treatment rather than prevention, and by the politics of alcohol, tobacco and food.","asOf":"2026-09-10","links":[{"label":"WHO cervical cancer elimination initiative","url":"https://www.who.int/initiatives/cervical-cancer-elimination-initiative"},{"label":"KEN SHE single-dose HPV vaccine trial (NEJM Evidence 2022)","url":"https://doi.org/10.1056/EVIDoa2100056"},{"label":"ALASCCA: aspirin in PIK3CA-mutated colorectal cancer (NEJM 2025)","url":"https://www.nejm.org/doi/full/10.1056/NEJMoa2504650"}],"tags":[],"related":["uk-biobank","cure-paths","early-detection-roadmap","nutrition-lifestyle-roadmap","idea-prev-hpv-single-dose-switch-catchup","idea-prev-hpv-self-sampling-mailed-default","idea-prev-hpv-male-catchup-oropharynx","idea-single-dose-hpv-self-sampling-elimination","idea-prev-hbv-treat-all-hcc","idea-prev-hpylori-family-test-and-treat","idea-moon-eliminate-infection-cancers","idea-prev-smokefree-generation-evaluation","idea-prev-cytisine-essential-medicine","idea-prev-alcohol-cancer-warning-labels","idea-prev-glp1-cancer-prevention-rct","idea-reg-aspirin-pik3ca-implementation","idea-prev-lynch-aspirin-implementation","idea-prev-low-dose-tamoxifen-uptake","idea-prev-opportunistic-salpingectomy-default","idea-moon-population-germline-screening","idea-prev-population-germline-screening-at-30","idea-prev-cascade-direct-contact-relatives","idea-prev-reflex-germline-testing","idea-prev-prs-screening-start-age","idea-prev-prs-ancestry-portability-standard","idea-interception-vaccines","idea-prev-lynch-frameshift-vaccine-rct","idea-moon-lynch-vaccine-phase3","idea-prev-brca1-denosumab-prevention","idea-prev-chemoprevention-master-protocol","idea-prev-precursor-endpoints-for-approval","idea-fund-social-impact-bonds-prevention","idea-prev-pharmacy-prevention-hub","idea-moon-hpv-vaccine-confidence","idea-prev-radon-testing-at-property-sale","lung-cancer-evidence-roadmap"],"cancers":["lung-cancer"],"sections":["prevention"],"technologies":["hpv-vaccine","hpv-testing","precancer-ablation","germline-testing","chemoprevention","aspirin-cancer-prevention","risk-reducing-salpingectomy","polygenic-risk-scores","interception-vaccination","shared-antigen-vaccine","alcohol-reduction-labelling","smoking-cessation-after-diagnosis","glp1-agonists-cancer-risk","bariatric-surgery-cancer-incidence","hcc-surveillance","colorectal-screening","low-dose-ct-screening"],"targets":[],"drugs":["gardasil-9","cervavac","tamoxifen"],"companies":["serum-institute-of-india","myriad-genetics"],"institutions":["who","iarc","icmr-nicpr"],"pathways":[],"terms":["risk-factor","obesity-related-cancers"],"trials":["ken-she","iarc-india-hpv-dose-study","osmanabad-hpv-screening","alascca","add-aspirin","aspree","nordicc","nlst-nelson"],"people":[],"bottlenecks":["b-prevention-adoption","b-hereditary-risk","b-funding-allocation","b-incentive-misalignment","b-global-access","b-overdiagnosis"],"keyPapers":["paper-barnabas-nejm-evid"],"journals":[],"dependsOn":[],"notes":[],"steps":[{"era":"1950-2000","title":"Tobacco, hepatitis B and the first chemoprevention","description":"The link between smoking and lung cancer, established in the 1950s, produced the taxes, advertising bans and smoke-free laws that have prevented more cancer deaths than any treatment. Universal infant hepatitis B vaccination, begun in Taiwan in the 1980s, cut liver cancer in the vaccinated generation. Helicobacter pylori was identified as the cause of most stomach cancer. Tamoxifen was shown to prevent breast cancer in high-risk women in 1998, the first drug proven to stop a cancer before it starts.","refs":["risk-factor","hpv-vaccine","chemoprevention","tamoxifen","iarc","smoking-cessation-after-diagnosis"],"status":"historic"},{"era":"2006-2020","title":"HPV vaccines, hereditary testing and the elimination goal","description":"The first HPV vaccine (2006) and the nine-valent version that prevents about nine in ten cervical cancers turned an infection into a preventable one; HPV DNA testing replaced the smear and one round of it in rural India cut cervical cancer deaths (Osmanabad). Germline testing made BRCA and Lynch carriers findable, and risk-reducing surgery, aspirin (CAPP2) and intensive surveillance gave them options. In 2020 the WHO adopted a strategy to eliminate cervical cancer as a public health problem: vaccinate, screen, treat.","refs":["gardasil-9","hpv-testing","osmanabad-hpv-screening","precancer-ablation","germline-testing","myriad-genetics","risk-reducing-salpingectomy","aspirin-cancer-prevention","who","hcc-surveillance","colorectal-screening","nordicc"],"status":"historic"},{"era":"2021-2026","title":"One dose, self-sampling and vaccines made where they are needed","description":"KEN SHE showed in 2021 that a single dose of HPV vaccine is almost fully protective against the two most dangerous types, confirming what an interrupted Indian trial had suggested; the WHO endorsed one-dose schedules in 2022, halving the cost of elimination. India's Serum Institute launched its own vaccine, Cervavac. Self-collected HPV swabs and same-day thermal ablation of precancer are letting nurses run cervical programmes without colposcopy. Catch-up vaccination for men, to prevent the throat cancers that now outnumber cervical cancers in some countries, is the next policy step.","refs":["ken-she","iarc-india-hpv-dose-study","cervavac","serum-institute-of-india","hpv-testing","precancer-ablation","idea-prev-hpv-single-dose-switch-catchup","idea-prev-hpv-self-sampling-mailed-default","idea-single-dose-hpv-self-sampling-elimination","idea-prev-hpv-male-catchup-oropharynx","idea-moon-hpv-vaccine-confidence"],"status":"current"},{"era":"2022-2027","title":"Aspirin and tamoxifen for the right people","description":"ASPREE showed that daily aspirin does not help healthy older people and can harm them; ALASCCA showed that three years of low-dose aspirin roughly halves recurrence in bowel cancers carrying PIK3CA mutations; Add-Aspirin is testing it in 11,000 patients across four cancers. The lesson is that chemoprevention needs a biomarker or a defined high-risk group. Low-dose tamoxifen keeps the preventive benefit with fewer side-effects and could be prescribed by pharmacists and nurses; removing the fallopian tubes during any pelvic operation, once childbearing is finished, prevents most ovarian cancers at no extra operation.","refs":["aspree","alascca","add-aspirin","aspirin-cancer-prevention","idea-reg-aspirin-pik3ca-implementation","idea-prev-lynch-aspirin-implementation","idea-prev-low-dose-tamoxifen-uptake","risk-reducing-salpingectomy","idea-prev-opportunistic-salpingectomy-default"],"status":"current"},{"era":"2025-2030","title":"Weight, alcohol, tobacco and infection at population scale","description":"People on GLP-1 agonists have lower rates of obesity-related cancers in observational data and bariatric surgery patients develop fewer cancers; a randomised trial with cancer as the primary outcome is the most important prevention study this decade could run. Smoke-free generation laws are being enacted and need built-in evaluation; cytisine, a cheap plant-based quit-smoking pill, belongs on every essential medicines list; cancer warning labels on alcohol are a natural experiment waiting to be measured. Treating everyone with chronic hepatitis B, curing hepatitis C and family-based H. pylori test-and-treat would remove most of the remaining infection-caused cancers.","refs":["glp1-agonists-cancer-risk","bariatric-surgery-cancer-incidence","obesity-related-cancers","idea-prev-glp1-cancer-prevention-rct","idea-prev-smokefree-generation-evaluation","idea-prev-cytisine-essential-medicine","alcohol-reduction-labelling","idea-prev-alcohol-cancer-warning-labels","idea-prev-hbv-treat-all-hcc","idea-prev-hpylori-family-test-and-treat","idea-moon-eliminate-infection-cancers","idea-prev-radon-testing-at-property-sale"],"status":"emerging"},{"era":"2026-2032","title":"Inherited risk found before the cancer","description":"Most people who carry a high-risk cancer gene find out when they or a relative get cancer. The proposals: reflex germline testing for every cancer where it changes care, letting clinics contact relatives directly when a gene is found, offering everyone at 30 a test for the genes that matter, and polygenic risk scores that set when screening starts, built to work in every ancestry before they are deployed anywhere. UK Biobank is the cohort where most of these scores are being validated.","refs":["germline-testing","b-hereditary-risk","idea-prev-reflex-germline-testing","idea-prev-cascade-direct-contact-relatives","idea-prev-population-germline-screening-at-30","idea-moon-population-germline-screening","polygenic-risk-scores","idea-prev-prs-screening-start-age","idea-prev-prs-ancestry-portability-standard","uk-biobank"],"status":"emerging"},{"era":"2030+","title":"Interception: vaccinating people who do not yet have cancer","description":"Lynch syndrome tumours share frameshift neoantigens, which makes a shared vaccine possible; a randomised prevention trial in carriers would be the first preventive cancer vaccine that is not against a virus. A bone drug (denosumab) may prevent BRCA1 breast cancers by hitting the cells they grow from. A master protocol for chemoprevention across many precancers, and regulators accepting shrinkage of precancer as an endpoint, would make prevention drugs developable at all. The bar is high: healthy people accept risk today for a probabilistic benefit years later.","refs":["interception-vaccination","shared-antigen-vaccine","idea-interception-vaccines","idea-prev-lynch-frameshift-vaccine-rct","idea-moon-lynch-vaccine-phase3","idea-prev-brca1-denosumab-prevention","idea-prev-chemoprevention-master-protocol","idea-prev-precursor-endpoints-for-approval","cure-paths"],"status":"speculative"},{"era":"What sets the pace","title":"Deployment, funding and politics","description":"Around four in ten cancers are preventable with tools we already own, and the gap is deployment, not discovery. Prevention has no product to sell, so funding follows treatment; the commercial determinants of alcohol, tobacco and food are politically defended; and screening brings overdiagnosis that has to be managed rather than ignored. Community pharmacies as prevention hubs and social impact bonds repaid from avoided treatment costs are two ways to pay for what is already proven.","refs":["b-prevention-adoption","b-funding-allocation","b-incentive-misalignment","b-global-access","b-overdiagnosis","idea-prev-pharmacy-prevention-hub","idea-fund-social-impact-bonds-prevention","icmr-nicpr"],"status":"current"}],"watch":[]},{"id":"cell-therapy-roadmap","kind":"roadmap","name":"Cell therapy roadmap: CD19 CAR-T → solid tumours → in vivo CAR","aka":[],"tldr":"From a cure for some leukaemias in 2017 to the first solid-tumour CAR-T and the prospect of making CAR-T inside the body with an injection.","summary":"This roadmap starts with the foundations of cell therapy, Rosenberg's TIL therapy in melanoma and the first-generation CARs, then the approvals of CD19 and BCMA CAR-T alongside T-cell engagers as off-the-shelf competitors. Blood cancers were the easy case with a clean antigen and accessible cells; the current step brings solid tumours within reach through lifileucel, afamitresgene autoleucel and CLDN18.2, GD2 and GPC3 CAR-T. The emerging manufacturing revolution covers gene-edited allogeneic products and in vivo CAR-T made inside the body by targeted LNPs or lentivirus, ending speculatively with in vivo CAR as an outpatient injection. The route links CAR-T, TIL, TCR-T, in vivo CAR-T, allogeneic cell therapy and CAR-NK, and is pointed to by glioblastoma and the manufacturing bottleneck.","asOf":"2026-09-04","links":[{"label":"ELIANA: the global trial that made tisagenlecleucel the first approved CAR-T therapy for children and young adults with relapsed ALL (New England Journal of Medicine 2018)","url":"https://doi.org/10.1056/NEJMoa1709866"},{"label":"CARTITUDE-4: cilta-cel CAR-T versus standard combinations after one to three prior lines of myeloma therapy (New England Journal of Medicine 2023)","url":"https://doi.org/10.1056/NEJMoa2303379"}],"tags":[],"related":[],"cancers":[],"sections":["cell-therapy"],"technologies":["car-t","til-therapy","tcr-t","in-vivo-car-t","allogeneic-cell-therapy","armored-car","car-nk-macrophage"],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"steps":[{"era":"1988-2016","title":"Foundations","description":"Rosenberg's TIL therapy in melanoma (1988); first-generation CARs (Eshhar, 1989); 4-1BB and CD28 costimulation (June, Sadelain, Campana); Emily Whitehead treated with CTL019 (2012).","refs":["til-therapy"],"status":"historic"},{"era":"2017-2022","title":"CD19 and BCMA CAR-T approved","description":"Tisagenlecleucel and axicabtagene (2017), then five more products; ZUMA-7 puts CAR-T ahead of transplant in second-line lymphoma; ide-cel and cilta-cel in myeloma; blinatumomab and teclistamab establish off-the-shelf T-cell engagers as competitors.","refs":["axicabtagene-ciloleucel","ciltacabtagene-autoleucel","blinatumomab","teclistamab"],"status":"historic"},{"era":"2024-2026","title":"Solid tumours: TIL, TCR-T, CAR-T","description":"Solid-tumour cell therapy arrives: lifileucel (melanoma TIL, 2024), afamitresgene autoleucel (MAGE-A4 TCR-T, synovial sarcoma, 2024; age ≥12 in 2026), satri-cel (CLDN18.2 CAR-T, gastric, China 2025), GD2 CAR-T in neuroblastoma and glioma, GPC3 CAR-T in HCC. CAR-T expands to autoimmune disease.","refs":["lifileucel","afamitresgene-autoleucel","satricabtagene-autoleucel","cldn18-2","gpc3","mage-a4"],"status":"current"},{"era":"2025-2028","title":"Manufacturing revolution: allogeneic and in vivo","description":"Gene-edited allogeneic products (cema-cel, ALLO-316) show feasibility with persistence limits. In vivo CAR-T via targeted LNPs (Capstan/AbbVie, Orna) and lentivirus (Umoja, Interius) enter first-in-human trials with B-cell depletion and no lymphodepletion. iPSC-derived CAR-NK. CAR-T cost and access become policy issues.","refs":["in-vivo-car-t","allogeneic-cell-therapy","car-nk-macrophage","abbvie"],"status":"emerging"},{"era":"2028+","title":"Speculative","description":"Logic-gated and armoured CARs for solid tumours; neoantigen-specific TCR-T at scale via AI-predicted TCRs; in vivo CAR as an outpatient injection for lymphoma and autoimmune disease; CAR-T against fibroblast and myeloid targets; regional delivery for glioma, mesothelioma, and pancreatic cancer.","refs":["armored-car","tcr-t","fap"],"status":"speculative"}],"watch":[]},{"id":"chemotherapy-roadmap","kind":"roadmap","name":"Chemotherapy roadmap: mustard gas → curative combinations → the warhead inside smarter drugs","aka":[],"tldr":"Chemotherapy went from a poison that sometimes worked to the backbone of most cures, and is now being given more precisely: to fewer people, at better doses, and increasingly delivered inside an antibody so that it reaches the tumour and not the whole body.","summary":"Cytotoxic drugs produced the first cures of disseminated cancer (childhood leukaemia, Hodgkin lymphoma, testicular cancer) by combining agents with different mechanisms so that no single resistance pathway could escape. Platinums, taxanes, anthracyclines, antimetabolites and topoisomerase inhibitors remain curative in several cancers and are the partner that immunotherapy and targeted drugs are added to in most first-line regimens.\n\nThe field is now doing three things at once. It is giving chemotherapy to fewer people, using gene-expression tests and residual-disease blood tests to identify who gains nothing from it (TAILORx, RxPONDER, DYNAMIC) and dropping components that add toxicity without benefit (RATHL, SCARLET). It is re-examining dose and schedule, with the FDA's Project Optimus guidance, metronomic oral regimens tested at Tata Memorial, and pharmacogenomic testing before the first dose. And it is moving the cytotoxic payload inside antibody-drug conjugates, which have already replaced chemotherapy as the standard in advanced bladder cancer and parts of breast cancer.\n\nThe pace is set by problems that are economic as much as scientific: generic shortages, the absence of any incentive to optimise the dose of an off-patent drug, and the under-measurement of toxicity and quality of life in trials.","asOf":"2026-09-10","links":[{"label":"FDA final guidance: Optimizing the Dosage of Human Prescription Drugs and Biological Products for the Treatment of Oncologic Diseases (August 2024)","url":"https://www.fda.gov/regulatory-information/search-fda-guidance-documents/optimizing-dosage-human-prescription-drugs-and-biological-products-treatment-oncologic-diseases"},{"label":"DeVita and Chu, A history of cancer chemotherapy (Cancer Research 2008)","url":"https://doi.org/10.1158/0008-5472.CAN-07-6611"}],"tags":[],"related":["idea-tr1-pre-emptive-pharmacogenomic-testing","idea-bio2-lean-mass-dosing","idea-reg-metronomic-lmic-phase3-to-label","idea-acc-metronomic-lmic-platform-trial","idea-reg-nonprofit-generic-chemo-manufacturer","idea-reg-generic-chemo-strategic-reserve","idea-moon-neuropathy-prevention-programme","idea-moon-olanzapine-antiemetic-everywhere","idea-moon-hearing-protection-cisplatin","idea-tr1-response-adapted-dose-reduction","adc-generations","cannabinoids-nausea"],"cancers":[],"sections":["chemotherapy"],"technologies":["cytotoxic-chemotherapy","adc","g-csf-growth-factors","scalp-cooling","cardio-oncology","pharmacy-automation","infusion-devices-vascular-access","generic-drug-shortage-response","mrd-testing"],"targets":[],"drugs":["methotrexate","vincristine","cyclophosphamide","doxorubicin","cisplatin","carboplatin","oxaliplatin","paclitaxel","docetaxel","capecitabine","gemcitabine","irinotecan","temozolomide","trastuzumab-deruxtecan","sacituzumab-govitecan","enfortumab-vedotin","sodium-thiosulfate","dexrazoxane","rolapitant"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["eortc-26981","keynote-024-189","checkmate-649","cross","napoli-3","prodige-24","interlace","echelon-1","polarix","tailorx","rxponder","dynamic","rathl","scarlet-s2212","apt-trial","ev-302","destiny-breast06","metronomic-vs-cisplatin-tmh","metro-plus-varanasi","low-dose-nivolumab-tmh","olanzapine-appetite-tmh"],"people":[],"bottlenecks":["b-dose-optimisation","b-generic-repurposing","b-toxicity-qol","b-global-access","b-cachexia-supportive"],"keyPapers":["paper-devita-cancer-res"],"journals":[],"dependsOn":[],"notes":[],"steps":[{"era":"1940s-1970s","title":"From poison to the first cures","description":"Nitrogen mustard, then methotrexate (1948), produced remissions that did not last. The insight that made cure possible was combination: several drugs with different mechanisms, given together at full dose, so that no single resistant clone survived. Childhood leukaemia, Hodgkin lymphoma and, with cisplatin, testicular cancer became curable diseases. Vincristine, cyclophosphamide, doxorubicin and dactinomycin from this era are still in most curative paediatric regimens.","refs":["methotrexate","vincristine","cyclophosphamide","doxorubicin","dactinomycin","cisplatin","mercaptopurine","cytotoxic-chemotherapy"],"status":"historic"},{"era":"1980s-2000s","title":"New classes, adjuvant cures and the supportive care that made them deliverable","description":"Taxanes, third-generation platinums, gemcitabine, irinotecan and oral capecitabine widened the arsenal. Adjuvant chemotherapy after surgery raised cure rates in breast and colon cancer, and temozolomide with radiation became the glioblastoma standard (EORTC 26981, 2005). None of it would have been tolerable without the supportive care built alongside: 5-HT3 antiemetics, G-CSF to prevent febrile neutropenia, implanted ports and ambulatory pumps.","refs":["paclitaxel","docetaxel","oxaliplatin","carboplatin","capecitabine","gemcitabine","irinotecan","temozolomide","eortc-26981","g-csf-growth-factors","infusion-devices-vascular-access"],"status":"historic"},{"era":"2010s-2026","title":"The backbone that immunotherapy and ADCs are built on","description":"Most first-line regimens still start with chemotherapy and add something to it: a PD-1 blocker in lung (KEYNOTE-189), stomach (CheckMate 649) and cervical cancer, chemoradiation before oesophageal surgery (CROSS), a four-drug regimen after pancreatic surgery (PRODIGE 24) or as first treatment (NAPOLI 3). INTERLACE showed that six weeks of cheap generic chemotherapy before cervical chemoradiation cuts deaths, an advance usable anywhere. ECHELON-1 and POLARIX swapped one component of a curative regimen for an antibody-drug conjugate and improved outcomes.","refs":["keynote-024-189","checkmate-649","cross","prodige-24","napoli-3","interlace","echelon-1","polarix"],"status":"current"},{"era":"2018-2026","title":"Giving it to fewer people","description":"The largest recent gains in chemotherapy have come from not giving it. TAILORx and RxPONDER showed that a gene-expression score identifies most women with hormone-positive breast cancer who can skip it; DYNAMIC halved adjuvant chemotherapy in stage II colon cancer by testing blood for residual disease; RATHL dropped bleomycin after a clear interim PET scan; SCARLET tests dropping the anthracycline from triple-negative breast regimens; and the APT regimen showed a gentle schedule is enough for small HER2-positive tumours.","refs":["tailorx","rxponder","dynamic","mrd-testing","rathl","scarlet-s2212","apt-trial"],"status":"current"},{"era":"2019-2026","title":"The warhead moves inside an antibody","description":"Antibody-drug conjugates carry a cytotoxic payload too potent to give on its own and release it inside or beside the tumour cell. EV-302 ended four decades of platinum chemotherapy as the first-line standard in advanced bladder cancer; DESTINY-Breast06 moved trastuzumab deruxtecan ahead of chemotherapy in hormone-positive breast cancer. The chemistry lessons of the ADC roadmap (linker stability, bystander killing, drug-to-antibody ratio) are what turned chemotherapy from a systemic exposure into a targeted one.","refs":["adc","trastuzumab-deruxtecan","sacituzumab-govitecan","enfortumab-vedotin","ev-302","destiny-breast06","adc-generations"],"status":"current"},{"era":"2024-2030","title":"The right dose, the right schedule, the right patient","description":"Most chemotherapy doses were set decades ago as the maximum tolerated, calculated from body surface area. The FDA's Project Optimus guidance (August 2024) requires randomised dose comparison for new drugs; the harder task is re-optimising old ones. Tata Memorial's trials showed oral metronomic regimens matching intravenous cisplatin and a fraction of a nivolumab dose improving survival when added to them. Pre-emptive DPYD and UGT1A1 testing, dosing by lean mass rather than surface area, and response-adapted reduction are the next steps, and none has a commercial sponsor.","refs":["b-dose-optimisation","metronomic-vs-cisplatin-tmh","metro-plus-varanasi","low-dose-nivolumab-tmh","idea-tr1-pre-emptive-pharmacogenomic-testing","idea-bio2-lean-mass-dosing","idea-tr1-response-adapted-dose-reduction","idea-reg-metronomic-lmic-phase3-to-label","idea-acc-metronomic-lmic-platform-trial"],"status":"emerging"},{"era":"2024-2030","title":"Fewer harms from the drugs we keep","description":"Scalp cooling preserves hair, sodium thiosulfate halves permanent hearing loss from cisplatin in children and is now being tested in adults, dexrazoxane protects the heart from anthracyclines, low-dose olanzapine controls nausea and restores appetite for pennies, and cardio-oncology has become a specialty. Chemotherapy-induced neuropathy still has no proven prevention; SARM1 inhibitors, limb cooling and compression are the candidates.","refs":["scalp-cooling","sodium-thiosulfate","idea-moon-hearing-protection-cisplatin","dexrazoxane","cardio-oncology","olanzapine-appetite-tmh","idea-moon-olanzapine-antiemetic-everywhere","rolapitant","cannabinoids-nausea","idea-moon-neuropathy-prevention-programme"],"status":"emerging"},{"era":"What sets the pace","title":"Generics, incentives and what trials measure","description":"Cisplatin and carboplatin have gone into shortage in the richest health systems because generic manufacturing has no margin; a non-profit manufacturer and a strategic reserve are the proposed fixes. Nobody is paid to find the lowest effective dose of an off-patent drug, so public funding has to do it. And trials still measure how long people live far better than how they live, which is why toxicity remains under-reported and under-treated.","refs":["b-generic-repurposing","generic-drug-shortage-response","idea-reg-nonprofit-generic-chemo-manufacturer","idea-reg-generic-chemo-strategic-reserve","b-toxicity-qol","b-global-access","b-cachexia-supportive"],"status":"current"}],"watch":[]},{"id":"colorectal-roadmap","kind":"roadmap","name":"Colorectal cancer roadmap: from the adenoma-carcinoma sequence and the first screening trials to total mesorectal excision, oxaliplatin, RAS testing, immunotherapy for mismatch repair-deficient disease, ctDNA-guided treatment and organ preservation","aka":["Colorectal cancer history","Bowel cancer roadmap","CRC evidence roadmap","Colon and rectal cancer roadmap"],"tldr":"Bowel cancer grows from a polyp over years, so removing the polyp prevents it. This roadmap follows the evidence from that discovery through the stool tests and scopes that built the screening programmes, the operation that changed rectal cancer, the chemotherapy and antibody era, immunotherapy that dissolves some tumours without surgery, and the unexplained rise in young adults, to 2032.","summary":"Colorectal cancer is the cancer with the best-understood natural history. Vogelstein and Fearon's 172 tumours (1988) showed that it accumulates mutations as an adenoma grows, and the National Polyp Study (2012) showed that cutting the adenoma out halves the death rate two decades later. That logic built the screening programmes: the Nottingham (1996), Funen (1996) and Minnesota (1993) stool-blood trials, the UK flexible sigmoidoscopy trial (2010, 17-year follow-up 2017) and finally NordICC (2022), the first randomised trial of colonoscopy itself, whose modest 18 percent reduction in incidence turned on the fact that only 42 percent of those invited came.\n\nTreatment moved on two tracks. In the rectum the change was surgical: Heald's total mesorectal excision (1982) cut pelvic recurrence from a quarter of patients to a few percent, and the Swedish (1997), Dutch TME (2001) and MRC CR07 (2009) trials settled that radiotherapy before the operation buys local control rather than survival. In the colon the change was chemical: fluorouracil with levamisole (1990), oxaliplatin added in MOSAIC (2004), then a long de-escalation as QUASAR (2007) measured how small the stage II benefit is, the IDEA collaboration (2018) halved the duration for lower-risk stage III disease and FOxTROT (2023) moved six weeks of it before the operation.\n\nThe metastatic era began with bevacizumab (2004) and cetuximab (CRYSTAL, 2009), and immediately produced the field's first negative predictive biomarker: the EGFR antibodies work only when RAS is normal (PRIME's extended testing, 2013) and, as the pooled analysis of six trials showed (2017), only when the primary tumour is on the left. Refractory lines arrived with regorafenib (2013), trifluridine-tipiracil (2015), the combination with bevacizumab (SUNLIGHT, 2023) and fruquintinib (2023), each measured in weeks.\n\nThen the disease split in two. Le's 41 patients (2015) showed that mismatch repair-deficient tumours respond to PD-1 blockade and proficient ones do not, KEYNOTE-177 (2020) made immunotherapy the first-line standard for that 5 percent, CheckMate 8HW (2024) added the CTLA-4 antibody, NICHE-2 (2024) produced 68 percent pathological complete responses before surgery and Cercek's dostarlimab series (2022, 2025) made surgery unnecessary in every mismatch repair-deficient rectal cancer treated. BRAF V600E disease got a targeted doublet (BEACON, 2019) and then a first-line triplet, HER2 got three regimens, KRAS G12C got sotorasib with panitumumab (2023). Circulating tumour DNA became the first reliable measure of residual disease in a solid tumour (Tie 2016), and DYNAMIC (2022) used it to halve chemotherapy in stage II without losing recurrence-free survival.\n\nWhat has not been solved: 95 percent of metastatic disease is microsatellite stable and still ignores immunotherapy, screening uptake rather than test performance sets what programmes achieve, and incidence in people under 50 is rising by about 3 percent a year in the United States and by 1.6 to 7.9 percent a year across Europe for reasons nobody can name, with colibactin-producing gut bacteria the strongest current lead.","asOf":"2026-09-24","links":[{"label":"NICE NG151: colorectal cancer (published 29 January 2020)","url":"https://www.nice.org.uk/guidance/ng151"},{"label":"NICE NG12: suspected cancer, recognition and referral","url":"https://www.nice.org.uk/guidance/ng12"},{"label":"ESMO clinical practice guidelines: gastrointestinal cancers","url":"https://www.esmo.org/guidelines/esmo-clinical-practice-guidelines-gastrointestinal-cancers"},{"label":"NCCN guidelines: colon cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1428"},{"label":"NCCN guidelines: rectal cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1461"},{"label":"National Bowel Cancer Audit (NATCAN)","url":"https://www.natcan.org.uk/audits/bowel/"},{"label":"ClinicalTrials.gov NCT05174169","url":"https://clinicaltrials.gov/study/NCT05174169"},{"label":"ClinicalTrials.gov NCT05253651","url":"https://clinicaltrials.gov/study/NCT05253651"}],"tags":["colorectal","gi","roadmap","colorectal-evidence"],"related":["early-detection-roadmap","surgery-roadmap","chemotherapy-roadmap","immunotherapy-roadmap","kras-roadmap","ctdna-tests","neoadjuvant-io-dmmr","anti-egfr-left-sided","idea-ctdna-guided-adjuvant-crc","idea-immunotherapy-mss-crc","idea-crc-early-onset-cause-hunt","idea-crc-screening-uptake-and-age-extension","idea-crc-ctdna-de-escalation-beyond-stage-ii","idea-crc-organ-preservation-randomised-in-pmmr-rectal","idea-crc-mss-immunotherapy-by-biomarker-not-by-line","idea-crc-peritoneal-disease-found-early-and-treated-in-networks","idea-crc-exercise-as-a-funded-treatment","idea-crc-uk-colonoscopy-capacity-and-fit-threshold","idea-crc-uk-young-patient-referral-and-diagnostic-interval"],"cancers":["colorectal","colon-cancer","rectal-cancer","msi-high-colorectal","braf-v600e-colorectal","her2-amplified-colorectal","kras-g12c-colorectal","early-onset-colorectal"],"sections":["early-detection","prevention","surgery","radiation","chemotherapy","targeted-therapy","immunotherapy","diagnostics"],"technologies":["colorectal-screening","colonoscopy","liquid-biopsy","mrd-testing","signatera","checkpoint-inhibitor","monoclonal-antibody","kras-inhibitors","cytotoxic-chemotherapy","radiotherapy","robotic-surgery","hipec","wes-wgs","exercise-oncology"],"targets":["apc","kras","braf","tp53","egfr","her2","pd1","ctla4"],"drugs":["fluorouracil","oxaliplatin","irinotecan","folfox","folfiri","capox","bevacizumab","cetuximab","panitumumab","trifluridine-tipiracil","encorafenib","pembrolizumab","dostarlimab","tucatinib","sotorasib","botensilimab"],"companies":["merck","bms","amgen","pfizer","servier","gsk","natera","unicancer","alliance-oncology"],"institutions":["esmo","nice","cruk","mskcc","nki","johns-hopkins","ncc-japan","iarc"],"pathways":["wnt","ras-mapk","microbiome-tumour"],"terms":["msi","mmr","sidedness","cms-subtypes","lynch-syndrome","fit-test","ctdna","mrd","total-mesorectal-excision","organ-preservation","clinical-complete-response","total-neoadjuvant-therapy","folfox-family","gut-microbiome-diversity"],"trials":["nordicc","keynote-177","checkmate-8hw","niche-2","atomic","azur-1","breakwater","paradigm","crystal-fire3","beacon-crc","mountaineer","codebreak-300","rapido","prodige-23","opra","dynamic","circulate-japan"],"people":["bert-vogelstein","thierry-andre","andrea-cercek","myriam-chalabi","julio-garcia-aguilar","scott-kopetz","eric-van-cutsem","jeanne-tie","michael-bretthauer","dung-le"],"bottlenecks":["b-early-detection","b-prevention-adoption","b-immunotherapy-response","b-dormancy-mrd","b-resistance","b-surgery-radiation-innovation","b-toxicity-qol","b-workforce","b-care-fragmentation","b-global-access"],"keyPapers":["paper-vogelstein-genetic-alterations-colorectal-tumor-development-nejm-1988","paper-tcga-colorectal-comprehensive-characterization-nature-2012","paper-cms-guinney-nat-med-2015","paper-zauber-national-polyp-study-colonoscopic-polypectomy-nejm-2012","paper-atkin-flexible-sigmoidoscopy-17-year-follow-up-lancet-2017","paper-nordicc-nejm-2022","paper-heald-mesorectum-rectal-cancer-surgery-br-j-surg-1982","paper-kapiteijn-dutch-tme-preoperative-radiotherapy-nejm-2001","paper-mosaic-oxaliplatin-adjuvant-colon-nejm-2004","paper-idea-duration-adjuvant-stage-iii-colon-nejm-2018","paper-van-cutsem-crystal-cetuximab-folfiri-nejm-2009","paper-arnold-primary-tumour-side-ras-wild-type-ann-oncol-2017","paper-le-mmr-deficiency-pd1-nejm-2015","paper-keynote-177-nejm-2020","paper-cercek-nonoperative-management-mismatch-repair-deficient-tumours-nejm-2025","paper-kopetz-beacon-encorafenib-braf-colorectal-nejm-2019","paper-dynamic-nejm-2022","paper-garcia-aguilar-opra-organ-preservation-jco-2022","paper-siegel-colorectal-incidence-birth-cohort-jnci-2017","paper-diaz-gay-colibactin-geographic-age-mutational-processes-nature-2025"],"journals":[],"dependsOn":[],"notes":["Dates in 'What to watch' are quoted from the registry as read on 2026-09-24 and are not predictions; estimated completion dates move.","Papers that already had a record here are linked rather than rewritten: Fearon and Vogelstein 1990, Guinney's consensus molecular subtypes, the Minnesota faecal occult blood trial, Sauer's German chemoradiotherapy trial, Hurwitz on bevacizumab, Amado and Van Cutsem on KRAS and anti-EGFR therapy, Galon's immune contexture, NICHE-2 and Cercek 2022.","A few trials and glossary entries named on this page have no record of their own yet and appear here as text only.","UK and NHS specifics (screening programme ages and uptake, the symptomatic FIT threshold in NG12, NICE NG151 positions, Cancer Drugs Fund status, endoscopy capacity, audit indicators and trial access) are on the UK and NHS page for colorectal cancer and are not restated here."],"steps":[{"era":"1975-1990","title":"A cancer with a visible precursor, and the first proof that finding it early saves lives","description":"Vogelstein, Fearon and colleagues looked for four genetic changes in 172 colorectal specimens spanning adenoma to carcinoma (1988) and found they accumulated in step with clinical progression: ras mutations in 58 percent of adenomas over 1 cm but 9 percent of those under 1 cm, chromosome 18 deletions in 73 percent of carcinomas against 11 to 13 percent of early adenomas, chromosome 17p loss almost only in carcinomas. Fearon and Vogelstein set the model out in Cell in 1990. If cancer grows out of a polyp over years, then screening can prevent it rather than merely bring diagnosis forward, and the Minnesota trial (1993) had already shown that annual stool-blood testing cut colorectal cancer deaths by a third.","refs":["paper-vogelstein-genetic-alterations-colorectal-tumor-development-nejm-1988","paper-fearon-cell","paper-minnesota-fobt-nejm-1993","apc","kras","tp53"],"status":"historic"},{"era":"1982-2009","title":"Total mesorectal excision, and radiotherapy before the operation","description":"Heald, Husband and Ryall found tumour deposits in the fatty envelope around the rectum centimetres below the tumour and began removing the whole envelope intact: 50 curative operations followed two years with no pelvic or staple-line recurrence (1982). The randomised trials then asked what radiotherapy adds on top. The Swedish Rectal Cancer Trial (1997, 1,168 patients) cut five-year local recurrence from 27 to 11 percent and improved survival from 48 to 58 percent, but against surgery that was not standardised. The Dutch TME trial (2001, 1,861 patients) repeated the question against quality-controlled total mesorectal excision: local recurrence fell from 8.2 to 2.4 percent at two years and survival did not change at all. MRC CR07 (2009, 1,350 patients) settled the timing, cutting local recurrence by 61 percent when everyone had short-course radiotherapy before surgery rather than selective chemoradiotherapy after it. Sauer's German trial (2004) made the same case for long-course chemoradiotherapy.","refs":["paper-heald-mesorectum-rectal-cancer-surgery-br-j-surg-1982","paper-swedish-rectal-cancer-trial-preoperative-radiotherapy-nejm-1997","paper-kapiteijn-dutch-tme-preoperative-radiotherapy-nejm-2001","paper-sebag-montefiore-cr07-preoperative-radiotherapy-lancet-2009","paper-sauer-preoperative-chemoradiotherapy-rectal-nejm-2004","total-mesorectal-excision","radiotherapy","cornelis-van-de-velde"],"status":"historic"},{"era":"1990-2007","title":"Chemotherapy after the operation, and how small the benefit is when the nodes are clear","description":"Moertel's 1,296 patients (1990) showed that a year of fluorouracil with levamisole cut recurrence by 41 percent and death by 33 percent in node-positive colon cancer, the first adjuvant standard in the disease. MOSAIC (2004, 2,246 patients) added oxaliplatin and raised three-year disease-free survival from 72.9 to 78.2 percent, at the price of grade 3 sensory neuropathy in 12.4 percent during treatment. QUASAR (2007, 3,239 patients, 91 percent node-negative) then measured what chemotherapy is worth when the nodes are clear: a relative risk of death of 0.82, which the authors translated into an absolute survival gain of 3.6 percent. That number is why stage II treatment has been a conversation rather than a rule ever since, and why a blood test that could pick out the 3.6 percent was worth building.","refs":["paper-moertel-levamisole-fluorouracil-adjuvant-colon-nejm-1990","paper-mosaic-oxaliplatin-adjuvant-colon-nejm-2004","paper-quasar-adjuvant-chemotherapy-vs-observation-lancet-2007","folfox","oxaliplatin","fluorouracil"],"status":"historic"},{"era":"1993-2022","title":"The screening programmes, and the discovery that uptake is the whole game","description":"Nottingham (1996, 152,850 people) and Funen (1996, 61,933) confirmed Minnesota in Europe: biennial stool-blood testing cut colorectal cancer mortality by 15 and 18 percent, with 40 percent of the Nottingham screening group never completing a single test. The National Polyp Study's 23-year follow-up (2012) showed that removing adenomas halved colorectal cancer deaths against the general population, and the UK flexible sigmoidoscopy trial showed one look at the left colon at 55 to 64 cut incidence 23 percent and mortality 31 percent (2010), still holding at 17 years (2017). Then NordICC (2022) randomised invitations to colonoscopy itself in 84,585 people and got an 18 percent reduction in ten-year incidence, because only 42 percent attended. Kaminski (2010) had already shown that who does the colonoscopy matters: endoscopists finding adenomas in under 20 percent of people left their patients around ten times more likely to develop an interval cancer. Multitarget stool DNA (2014) found 92 percent of cancers against 74 percent for the faecal immunochemical test, but only 42 percent of advanced precancerous lesions and with lower specificity.","refs":["paper-hardcastle-nottingham-faecal-occult-blood-lancet-1996","paper-kronborg-funen-faecal-occult-blood-lancet-1996","paper-zauber-national-polyp-study-colonoscopic-polypectomy-nejm-2012","paper-atkin-once-only-flexible-sigmoidoscopy-lancet-2010","paper-atkin-flexible-sigmoidoscopy-17-year-follow-up-lancet-2017","paper-nordicc-nejm-2022","nordicc","colorectal-screening","colonoscopy"],"status":"current"},{"era":"2004-2017","title":"Antibodies, and the two things that decide whether they work","description":"Hurwitz (2004) put bevacizumab into first-line chemotherapy and CRYSTAL (2009, 1,198 patients) put cetuximab into FOLFIRI, with a progression-free survival hazard ratio of 0.85 overall and 0.68 in KRAS wild-type tumours: the first negative predictive biomarker in the disease. PRIME's extended RAS analysis (2013) found that a further 17 percent of apparently eligible patients carried KRAS or NRAS mutations outside exon 2 and did worse on the antibody, so testing widened to all of KRAS and NRAS exons 2, 3 and 4. Then FIRE-3 (2014) and CALGB/SWOG 80405 (2017) compared the two antibodies head to head and disagreed: 28.7 against 25.0 months favouring cetuximab in Germany, 30.0 against 29.0 months and no difference in North America. Pooling 2,159 patients across six trials (Arnold 2017) reconciled them: the EGFR antibody helps on the left (overall survival hazard ratio 0.75) and not at all on the right (1.12), interaction p<0.001. PARADIGM confirmed it prospectively in 2022. For patients who need a response and cannot have an EGFR antibody, TRIBE (2015) showed the three-drug FOLFOXIRI backbone with bevacizumab reaches 29.8 months.","refs":["paper-hurwitz-bevacizumab-crc-nejm-2004","paper-van-cutsem-crystal-cetuximab-folfiri-nejm-2009","paper-kras-colorectal-j-clin-oncol-2008","paper-douillard-prime-panitumumab-ras-nejm-2013","paper-heinemann-fire-3-cetuximab-vs-bevacizumab-lancet-oncol-2014","paper-venook-calgb-80405-cetuximab-vs-bevacizumab-jama-2017","paradigm","crystal-fire3","cetuximab"],"status":"current"},{"era":"2012-2017","title":"The genome, the subtypes and the hypermutated sixth","description":"The Cancer Genome Atlas read 276 colorectal tumours (2012) and found colon and rectal cancers genomically alike once the hypermutated 16 percent were set aside: three-quarters of those were microsatellite unstable with MLH1 silencing and a quarter carried mismatch-repair or POLE mutations. Twenty-four genes were significantly mutated, and the network flagged amplifications of ERBB2, which is where every HER2 trial in this disease begins. Guinney's consensus molecular subtypes (2015) then sorted expression profiles into four groups, CMS1 immune, CMS2 canonical, CMS3 metabolic and CMS4 mesenchymal, giving the field a shared vocabulary for why right-sided and left-sided tumours behave differently and why stromal tumours resist.","refs":["paper-tcga-colorectal-comprehensive-characterization-nature-2012","paper-cms-guinney-nat-med-2015","cms-subtypes","msi","mmr"],"status":"historic"},{"era":"2013-2023","title":"Refractory lines measured in weeks, and de-escalation measured in months of chemotherapy avoided","description":"CORRECT (2013, 760 patients) gave regorafenib a median survival of 6.4 against 5.0 months with hand-foot skin reaction in 17 percent; RECOURSE (2015, 800 patients) gave trifluridine-tipiracil 7.1 against 5.3 months; SUNLIGHT (2023, 492 patients) added bevacizumab to the tablet and reached 10.8 against 7.5 months, the largest gain the refractory setting has seen; FRESCO-2 (2023, 691 patients) added fruquintinib at 7.4 against 4.8 months. In the curative setting the movement went the other way. The IDEA collaboration pooled six trials and 12,834 patients (2018): three months of CAPOX was non-inferior to six in T1-T3 N1 disease (83.1 against 83.3 percent three-year disease-free survival) while six months of FOLFOX stayed standard for T4 or N2 disease. FOxTROT (2023, 1,053 patients) moved six weeks of chemotherapy before the operation and cut two-year residual or recurrent disease from 21.5 to 16.9 percent with more complete resections.","refs":["paper-grothey-correct-regorafenib-lancet-2013","paper-mayer-recourse-tas-102-nejm-2015","paper-prager-sunlight-trifluridine-tipiracil-bevacizumab-nejm-2023","paper-dasari-fresco-2-fruquintinib-lancet-2023","paper-idea-duration-adjuvant-stage-iii-colon-nejm-2018","paper-foxtrot-preoperative-chemotherapy-colon-jco-2023","sunlight","fresco-2","regorafenib"],"status":"current"},{"era":"2015-2025","title":"Immunotherapy takes mismatch repair-deficient disease apart","description":"Le's 41 patients (2015) gave a 40 percent response in mismatch repair-deficient colorectal cancer and 0 percent in proficient disease, with 1,782 somatic mutations per tumour against 73; the 12-tumour expansion (2017) produced the first tumour-agnostic approval. KEYNOTE-177 (2020, 307 patients) made pembrolizumab the first-line standard for metastatic mismatch repair-deficient disease (16.5 against 8.2 months progression-free, grade 3 toxicity 22 against 66 percent) and reported 77.5 months median survival at five years. CheckMate 8HW (2024) took 24-month progression-free survival to 72 percent against 14 percent with chemotherapy. In curable disease NICHE-2 (2024) gave four weeks of nivolumab and one dose of ipilimumab before surgery and found 68 percent pathological complete responses with no relapses at three years, and ATOMIC (2025) halved recurrence by adding a year of atezolizumab to adjuvant FOLFOX. Then Cercek removed the operation altogether: every mismatch repair-deficient rectal cancer treated with six months of dostarlimab had a clinical complete response (2022, 2025), with 82 of 103 patients across both cohorts avoiding surgery and two-year recurrence-free survival of 92 percent.","refs":["paper-le-mmr-deficiency-pd1-nejm-2015","paper-le-mmr-deficiency-science-2017","paper-keynote-177-nejm-2020","paper-andre-checkmate-8hw-nivolumab-ipilimumab-nejm-2024","paper-niche-2-nejm-2024","paper-cercek-dostarlimab-rectal-nejm-2022","keynote-177","checkmate-8hw","niche-2"],"status":"current"},{"era":"2016-2024","title":"BRAF, HER2 and the first KRAS allele","description":"BRAF V600E disease had a median survival of 13.4 months in TRIBE's molecular analysis and four to six months after first-line failure. BEACON CRC (2019, 665 patients) blocked BRAF and EGFR together and reached 9.0 against 5.4 months with the triplet and 8.4 months with the doublet; BREAKWATER later moved encorafenib and cetuximab into first line with chemotherapy and doubled survival to 30.3 against 15.1 months. HER2 took a different route: HERACLES (2016) screened 914 patients to find 48 amplified and treated 27, with a 30 percent response to trastuzumab and lapatinib; DESTINY-CRC01 (2021) gave trastuzumab deruxtecan a 45.3 percent response with two deaths from interstitial lung disease; MOUNTAINEER (2023) gave tucatinib and trastuzumab a 38.1 percent response and the first United States approval of a HER2 regimen in this disease. CodeBreaK 300 (2023) showed that a KRAS G12C inhibitor needs an EGFR antibody beside it: 5.6 against 2.2 months progression-free with sotorasib plus panitumumab.","refs":["paper-kopetz-beacon-encorafenib-braf-colorectal-nejm-2019","paper-sartore-bianchi-heracles-trastuzumab-lapatinib-lancet-oncol-2016","paper-siena-destiny-crc01-trastuzumab-deruxtecan-lancet-oncol-2021","paper-strickler-mountaineer-tucatinib-trastuzumab-lancet-oncol-2023","paper-codebreak-300-nejm-2023","beacon-crc","breakwater","mountaineer"],"status":"current"},{"era":"2016-2026","title":"A blood test for the disease that is left behind","description":"Tie's 230 stage II patients (2016) showed circulating tumour DNA after surgery carried a hazard ratio of 18 for recurrence, the first reliable measure of minimal residual disease in a solid tumour. DYNAMIC (2022, 455 patients) turned it into a randomised strategy: chemotherapy fell from 28 to 15 percent of patients with two-year recurrence-free survival of 93.5 against 92.4 percent, non-inferior. GALAXY, the observational arm of CIRCULATE-Japan (2023, 1,039 patients), found a hazard ratio of 10.0 for recurrence at four weeks after surgery and showed the test picks out who benefits from adjuvant chemotherapy (hazard ratio 6.59). What no trial has shown is the other half: that escalating treatment for a positive result improves anything, which is what CIRCULATE-US and the European CIRCULATE trials are built to answer.","refs":["paper-tie-ctdna-minimal-residual-disease-stage-ii-colon-sci-transl-med-2016","paper-dynamic-nejm-2022","paper-galaxy-signatera-nat-med-2023","dynamic","circulate-japan","mrd-testing"],"status":"current"},{"era":"2004-2026","title":"Keeping the rectum, and what surgery still has to carry","description":"Habr-Gama simply watched the patients whose rectal cancers vanished after chemoradiotherapy: 71 of 265, with ten-year overall survival of 97.7 percent across the series (2004). Total neoadjuvant therapy made that outcome plannable. RAPIDO (2021, 920 patients) cut three-year disease-related treatment failure from 30.4 to 23.7 percent by moving all the chemotherapy in front of surgery after one week of radiotherapy; PRODIGE 23 (2021, 461 patients) raised three-year disease-free survival from 69 to 76 percent with FOLFIRINOX before chemoradiotherapy and halved the serious adverse events of adjuvant treatment; OPRA (2022, 324 patients) planned watch and wait from the start and kept the rectum in 53 percent of the consolidation-chemotherapy group with no apparent cost in disease-free survival. Elsewhere surgery held its ground the hard way: Verwaal (2003) established cytoreduction with heated intraperitoneal chemotherapy for peritoneal disease at 22.3 against 12.6 months, and PRODIGE 7 (2021) then removed the heated chemotherapy and found the survival unchanged at 41.7 against 41.2 months, so the benefit had always been the operation. CHALLENGE (2025, 889 patients) showed a three-year structured exercise programme after adjuvant chemotherapy improved disease-free survival with a hazard ratio of 0.72.","refs":["paper-habr-gama-nonoperative-stage-0-rectal-ann-surg-2004","paper-bahadoer-rapido-short-course-radiotherapy-lancet-oncol-2021","paper-conroy-prodige-23-neoadjuvant-folfirinox-rectal-lancet-oncol-2021","paper-garcia-aguilar-opra-organ-preservation-jco-2022","paper-verwaal-cytoreduction-hipec-peritoneal-colorectal-jco-2003","paper-quenet-prodige-7-hipec-peritoneal-colorectal-lancet-oncol-2021","rapido","prodige-23","opra"],"status":"current"},{"era":"2017-2026","title":"The disease is moving younger, and nobody can say why","description":"Siegel's age-period-cohort analysis of 490,305 United States cases (2017) showed the rise in young adults is a birth-cohort effect: someone born around 1990 has double the colon cancer risk and quadruple the rectal cancer risk of someone born around 1950, and the proportion of rectal cancers diagnosed under 55 doubled from 14.6 to 29.2 percent in 23 years. Vuik found the same pattern across 20 European countries and 143.7 million people (2019), with incidence rising 7.9 percent a year in 20 to 29-year-olds. By 2023 one in five new United States cases was in someone under 55, and 60 percent of cases were advanced at diagnosis against 52 percent in the mid-2000s, the stage shift screening had bought going into reverse. The United States lowered the screening start age to 45 in 2021. The strongest mechanistic lead came in 2025, when 981 genomes from 11 countries showed the colibactin signatures SBS88 and ID18 are 3.3 times more common in cancers diagnosed before 40 than after 70, are imprinted early in tumour development and account for about a quarter of APC driver indels where they are present.","refs":["paper-siegel-colorectal-incidence-birth-cohort-jnci-2017","paper-vuik-early-onset-colorectal-europe-gut-2019","paper-siegel-colorectal-cancer-statistics-ca-2023","paper-hur-sugar-sweetened-beverages-early-onset-colorectal-gut-2021","paper-diaz-gay-colibactin-geographic-age-mutational-processes-nature-2025","early-onset-colorectal","microbiome-tumour","idea-crc-early-onset-cause-hunt"],"status":"current"},{"era":"2026-2032","title":"What the registry says is coming","description":"The immunotherapy question moves into curable disease: AZUR-1 (dostarlimab alone for untreated mismatch repair-deficient rectal cancer, 154 participants, actual; active, not recruiting) has a primary completion date of 2 November 2026, and its randomised sibling in colon cancer (perioperative dostarlimab for T4N0 or stage III mismatch repair-deficient disease, 892 estimated participants; recruiting) of 19 March 2029; the NICHE platform runs to 1 March 2032. The ctDNA question moves from prognosis to strategy: CIRCULATE-US (NRG-GI008, 1,912 estimated participants; recruiting) has a primary completion date of 10 March 2029 and the French CIRCULATE (PRODIGE 70, 1,980 estimated participants; recruiting) of March 2032, while COBRA (NRG-GI005, 635 participants, actual) completes on 21 June 2026. HER2 moves first line with MOUNTAINEER-03 (400 estimated participants; recruiting), primary completion 31 December 2027, and BREAKWATER completes on 28 December 2027. Microsatellite stable disease has its first randomised test of Fc-enhanced CTLA-4 blockade (botensilimab and balstilimab, 234 participants, actual; active, not recruiting), primary completion September 2027. Screening's own long game continues: NordICC, with 95,000 participants actual, has a primary completion date of June 2026 and a study completion date of July 2036, which is when the 15-year mortality answer arrives.","refs":["azur-1","circulate-japan","nordicc","mountaineer","breakwater","dostarlimab","mrd-testing","idea-crc-ctdna-de-escalation-beyond-stage-ii","idea-crc-mss-immunotherapy-by-biomarker-not-by-line"],"status":"emerging"},{"era":"What sets the pace","title":"Uptake, capacity, the microsatellite stable majority and who gets to the operating table","description":"Four things no trial on this page has fixed. First, uptake: NordICC's 18 percent reduction in incidence is what a health system gets when 42 percent of invitations are accepted, and Nottingham's 40 percent who never returned a kit are the same problem thirty years earlier. Second, capacity and quality: every positive stool test needs a colonoscopy, and Kaminski showed a tenfold difference in interval cancer risk between endoscopists at either end of the adenoma detection distribution. Third, the microsatellite stable majority: 95 percent of metastatic colorectal cancer responds to none of the immunotherapy on this page, and the best signal so far is a 17 percent response rate in a single-arm phase 1. Fourth, who gets treated at all: organ preservation, peritoneal surgery and total neoadjuvant therapy each require an MRI service, a specialist multidisciplinary team and a high-volume centre, and the trials that established them enrolled fit patients under 75.","refs":["paper-nordicc-nejm-2022","paper-kaminski-adenoma-detection-rate-interval-cancer-nejm-2010","paper-bullock-botensilimab-balstilimab-mss-colorectal-nat-med-2024","paper-quenet-prodige-7-hipec-peritoneal-colorectal-lancet-oncol-2021","b-early-detection","b-workforce","idea-crc-screening-uptake-and-age-extension","idea-crc-uk-colonoscopy-capacity-and-fit-threshold","idea-crc-uk-young-patient-referral-and-diagnostic-interval"],"status":"current"}],"watch":[{"item":"NordICC primary completion on the registry (colonoscopy screening, 95,000 participants, actual; active, not recruiting); study completion is listed as July 2036, when the 15-year mortality answer is due","expected":"2026-06","source":"https://clinicaltrials.gov/study/NCT00883792","refs":["nordicc","colorectal-screening","idea-crc-screening-uptake-and-age-extension"]},{"item":"COBRA (NRG-GI005) study completion: circulating tumour DNA testing to direct treatment in stage IIA colon cancer (635 participants, actual; active, not recruiting)","expected":"2026-06-21","source":"https://clinicaltrials.gov/study/NCT04068103","refs":["mrd-testing","ctdna","idea-crc-ctdna-de-escalation-beyond-stage-ii"]},{"item":"JANUS primary completion: adding irinotecan to FOLFOX after long-course radiotherapy in locally advanced rectal cancer (760 participants, actual; active, not recruiting)","expected":"2026-09-30","source":"https://clinicaltrials.gov/study/NCT05610163","refs":["rectal-cancer","irinotecan","total-neoadjuvant-therapy","idea-crc-organ-preservation-randomised-in-pmmr-rectal"]},{"item":"AZUR-1 primary completion: dostarlimab monotherapy in untreated mismatch repair-deficient locally advanced rectal cancer (154 participants, actual; active, not recruiting)","expected":"2026-11-02","source":"https://clinicaltrials.gov/study/NCT05723562","refs":["azur-1","dostarlimab","organ-preservation","msi-high-colorectal"]},{"item":"ATOMIC (Alliance A021502) study completion: adjuvant FOLFOX with or without atezolizumab in stage III mismatch repair-deficient colon cancer (712 participants, actual; active, not recruiting)","expected":"2026-12-18","source":"https://clinicaltrials.gov/study/NCT02912559","refs":["atomic","atezolizumab","msi-high-colorectal"]},{"item":"Botensilimab and balstilimab in colorectal cancer, primary completion (234 participants, actual; active, not recruiting): the first randomised read on Fc-enhanced CTLA-4 blockade in microsatellite stable disease","expected":"2027-09","source":"https://clinicaltrials.gov/study/NCT05608044","refs":["botensilimab","balstilimab","idea-immunotherapy-mss-crc","idea-crc-mss-immunotherapy-by-biomarker-not-by-line"]},{"item":"MOUNTAINEER-03 primary completion: tucatinib with trastuzumab and mFOLFOX6 against standard of care in first-line HER2-positive metastatic colorectal cancer (400 estimated participants; recruiting)","expected":"2027-12-31","source":"https://clinicaltrials.gov/study/NCT05253651","refs":["mountaineer","tucatinib","trastuzumab","her2-amplified-colorectal"]},{"item":"BREAKWATER study completion: encorafenib and cetuximab with or without chemotherapy in previously untreated BRAF V600E metastatic disease (841 participants, actual; active, not recruiting)","expected":"2027-12-28","source":"https://clinicaltrials.gov/study/NCT04607421","refs":["breakwater","encorafenib","cetuximab","braf-v600e-colorectal"]},{"item":"CIRCULATE-US (NRG-GI008) primary completion: adjuvant chemotherapy directed by residual disease on circulating tumour DNA (1,912 estimated participants; recruiting)","expected":"2029-03-10","source":"https://clinicaltrials.gov/study/NCT05174169","refs":["mrd-testing","signatera","ctdna","idea-crc-ctdna-de-escalation-beyond-stage-ii"]},{"item":"Perioperative dostarlimab in untreated T4N0 or stage III mismatch repair-deficient resectable colon cancer, primary completion (892 estimated participants; phase 3; recruiting)","expected":"2029-03-19","source":"https://clinicaltrials.gov/study/NCT05855200","refs":["dostarlimab","niche-2","msi-high-colorectal","organ-preservation"]},{"item":"CIRCULATE (PRODIGE 70) primary completion: circulating tumour DNA-based adjuvant decision in stage II colon cancer (1,980 estimated participants; recruiting)","expected":"2032-03","source":"https://clinicaltrials.gov/study/NCT04120701","refs":["mrd-testing","ctdna","unicancer","idea-crc-ctdna-de-escalation-beyond-stage-ii"]},{"item":"NICHE platform primary completion: neoadjuvant checkpoint inhibition and novel combinations in early-stage colon cancer (353 estimated participants; recruiting)","expected":"2032-03-01","source":"https://clinicaltrials.gov/study/NCT03026140","refs":["niche-2","nivolumab","ipilimumab","nki","myriam-chalabi"]}]},{"id":"ctdna-tests","kind":"roadmap","name":"ctDNA tests roadmap: from a curiosity in plasma to blood tests that decide treatment","aka":["Liquid biopsy roadmap","MRD testing roadmap","Multi-cancer early detection roadmap"],"tldr":"Blood carries fragments of tumour DNA. This roadmap follows the tests that read them, from the first sighting in 1948 to blood tests that now choose a drug, spare chemotherapy, or screen for many cancers at once, and it lists the readouts to watch next.","summary":"Circulating tumour DNA (ctDNA) testing has three jobs, and each is at a different stage. Genotyping from blood is settled: the cobas EGFR plasma test became the first FDA-approved liquid biopsy in June 2016, and Guardant360 CDx and FoundationOne Liquid CDx followed in August 2020 as broad companion diagnostics. Residual disease testing after surgery has crossed from prognosis to action: DYNAMIC showed in 2022 that a ctDNA-guided approach halves chemotherapy in stage II colon cancer without harm, and in May 2026 the FDA approved adjuvant atezolizumab for ctDNA-positive muscle-invasive bladder cancer on IMvigor011, the first drug approval that depends on a ctDNA residual disease result. Escalation for a positive test is not yet proven: ALTAIR missed its endpoint and the MERMAID lung trials closed small.\n\nMulti-cancer early detection is the least settled. Shield won FDA approval for colorectal screening in July 2024 on a single-cancer claim. Galleri has one randomised trial behind it: NHS-Galleri did not reduce stage III and IV cancers combined, its primary endpoint, while reporting fewer stage IV diagnoses, and the FDA's advisory panel considers the test on 23 September 2026. The NCI's Vanguard study is the first randomised US test of the approach and runs to 2029.\n\nThe steps below are grouped by what the evidence allowed at the time. The 'What to watch' list carries registry completion dates and meeting dates as their sources state them. Tumour-informed assays (built from the patient's own tumour sequence) and tumour-naive assays (fixed panels, often methylation-based) compete on sensitivity, turnaround and cost; the roadmap treats that split as a running theme rather than an era.","asOf":"2026-09-21","links":[{"label":"Mandel and Metais: nucleic acids in human blood plasma (C R Seances Soc Biol Fil 1948)","url":"https://europepmc.org/article/MED/18875018"},{"label":"Leon et al.: free DNA in the serum of cancer patients and the effect of therapy (Cancer Research 1977)","url":"https://europepmc.org/article/MED/837366"},{"label":"Diehl et al.: circulating mutant DNA to assess tumour dynamics (Nature Medicine 2008)","url":"https://europepmc.org/article/MED/18670422"},{"label":"Dawson et al.: analysis of circulating tumour DNA to monitor metastatic breast cancer (NEJM 2013)","url":"https://europepmc.org/article/MED/23484797"},{"label":"Bettegowda et al.: detection of circulating tumour DNA in early- and late-stage human malignancies (Science Translational Medicine 2014)","url":"https://europepmc.org/article/MED/24553385"},{"label":"Tie et al.: ctDNA detects minimal residual disease and predicts recurrence in stage II colon cancer (Science Translational Medicine 2016)","url":"https://europepmc.org/article/MED/27384348"},{"label":"AACR: FDA approves first liquid biopsy test for lung cancer patients, 1 June 2016","url":"https://www.aacr.org/blog/2016/06/06/fda-approval-liquid-biopsy-test-lung-cancer/"},{"label":"FDA PMA P150044: cobas EGFR Mutation Test v2 (tissue and plasma)","url":"https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpma/pma.cfm?id=P150044"},{"label":"FDA PMA P200010: Guardant360 CDx, approved 7 August 2020","url":"https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpma/pma.cfm?id=P200010"},{"label":"FDA PMA P190032: FoundationOne Liquid CDx, approved 26 August 2020","url":"https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpma/pma.cfm?id=P190032"},{"label":"Natera: final Medicare coverage for Signatera in stage II-III colorectal cancer, 3 September 2020","url":"https://www.natera.com/company/news/natera-receives-final-medicare-coverage-for-its-signatera-mrd-test-in-stage-ii-iii-colorectal-cancer-2/"},{"label":"CMS article A58456: MolDX minimal residual disease testing for solid tumour cancers (revision effective 1 January 2026)","url":"https://www.cms.gov/medicare-coverage-database/view/article.aspx?articleId=58456"},{"label":"DYNAMIC: ctDNA analysis guiding adjuvant therapy in stage II colon cancer (NEJM, 16 June 2022)","url":"https://europepmc.org/article/MED/35657320"},{"label":"DYNAMIC five-year outcomes (Nature Medicine 2025)","url":"https://europepmc.org/article/MED/40055522"},{"label":"GALAXY: molecular residual disease and efficacy of adjuvant chemotherapy in colorectal cancer (Nature Medicine 2023)","url":"https://europepmc.org/article/MED/36646802"},{"label":"CIRCULATE-Japan: ctDNA-guided adaptive platform trials, design of GALAXY, VEGA and ALTAIR (Cancer Science 2021)","url":"https://europepmc.org/article/MED/33931919"},{"label":"ALTAIR: post-adjuvant trifluridine/tipiracil in ctDNA-positive resected colorectal cancer, primary endpoint not met (Nature Medicine 2026)","url":"https://europepmc.org/article/MED/42260101"},{"label":"IMvigor011: ctDNA-guided adjuvant atezolizumab in muscle-invasive bladder cancer (NEJM 2025)","url":"https://europepmc.org/article/MED/41124204"},{"label":"FDA approves atezolizumab for adjuvant treatment of muscle invasive bladder cancer with ctDNA molecular residual disease, 15 May 2026","url":"https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-atezolizumab-adjuvant-treatment-muscle-invasive-bladder-cancer-patients-molecular"},{"label":"PATHFINDER: blood-based tests for multicancer early detection (The Lancet 2023)","url":"https://europepmc.org/article/MED/37805216"},{"label":"FDA PMA P230009: Shield blood-based colorectal cancer screening test, approved 26 July 2024","url":"https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpma/pma.cfm?id=P230009"},{"label":"NHS-Galleri: performance of a multi-cancer early detection test across three annual rounds (Nature Medicine, 22 September 2026)","url":"https://europepmc.org/article/MED/42773209"},{"label":"GRAIL: full results from the NHS-Galleri trial, 30 May 2026","url":"https://grail.com/press-releases/grail-reports-full-results-from-nhs-galleri-trial-demonstrating-substantial-reduction-in-stage-iv-cancer-diagnoses-at-2026-asco-annual-meeting/"},{"label":"GRAIL: PATHFINDER 2 results in more than 35,000 participants, 31 May 2026","url":"https://grail.com/press-releases/grail-presents-pathfinder-2-results-of-more-than-35000-participants-showing-the-galleri-test-substantially-increased-cancer-detection-with-robust-performance-and-favorable-safety-at-2026-a/"},{"label":"GRAIL: FDA advisory committee meeting on the Galleri PMA set for 23 September 2026","url":"https://grail.com/press-releases/grail-announces-fda-advisory-committee-meeting-to-review-premarket-approval-application-for-the-galleri-multi-cancer-early-detection-test/"},{"label":"ClinicalTrials.gov NCT06995898","url":"https://clinicaltrials.gov/study/NCT06995898"},{"label":"ClinicalTrials.gov NCT05174169","url":"https://clinicaltrials.gov/study/NCT05174169"},{"label":"ClinicalTrials.gov NCT04050345","url":"https://clinicaltrials.gov/study/NCT04050345"},{"label":"ClinicalTrials.gov NCT04660344","url":"https://clinicaltrials.gov/study/NCT04660344"},{"label":"ClinicalTrials.gov NCT05155605","url":"https://clinicaltrials.gov/study/NCT05155605"}],"tags":["ctdna","liquid-biopsy","mrd","mced"],"related":["diagnostics-roadmap","early-detection-roadmap","cure-paths","ctdna-mrd-to-adjuvant","idea-ctdna-guided-adjuvant-crc","idea-tr2-ctdna-mrd-qualification","idea-bio2-mrd-coverage-with-evidence","idea-prev-mced-positive-resolution-pathway","colorectal-roadmap","lung-cancer-evidence-roadmap","idea-lung-resistance-directed-sequencing-at-every-progression","prostate-roadmap","idea-prostate-plasticity-surveillance-before-it-is-neuroendocrine"],"cancers":["tnbc","gallbladder"],"sections":["diagnostics","early-detection"],"technologies":["liquid-biopsy","mrd-testing","mced","cfdna-methylation-testing","fragmentomics","continuous-ctdna-monitoring","methylation-profiling","companion-diagnostic"],"targets":[],"drugs":["cobas-egfr-mutation-test","guardant360-cdx","foundationone-cdx","signatera","guardant-reveal","radar-mrd","galleri","shield"],"companies":["roche-genentech","guardant-health","foundation-medicine","natera","grail","exact-sciences","freenome","delfi-diagnostics"],"institutions":[],"pathways":[],"terms":["cfdna","ctdna","mrd","tumour-informed-assay","de-escalation","stage-shift","ppv","surrogate-validation"],"trials":["dynamic","circulate-japan","imvigor011","tracc","bespoke-crc","mermaid-1","mermaid-2","circulate-us","pathfinder-2","nhs-galleri","eclipse-shield","vanguard-study"],"people":["nitzan-rosenfeld","dawson-sarah-jane","nickolas-papadopoulos","alberto-bardelli","jeanne-tie","thomas-powles","deb-schrag","peter-sasieni","klaus-pantel"],"bottlenecks":["b-dormancy-mrd"],"keyPapers":["paper-dynamic-nejm-2022","paper-galaxy-signatera-nat-med-2023","paper-imvigor011-nejm-2025","paper-pathfinder-lancet-2023","paper-nhs-galleri-design-cancers-2022","paper-nhs-galleri-performance-nat-med-2026"],"journals":[],"dependsOn":[],"notes":["How this stays current: run `npm run ctdna:watch`. The script reads this roadmap, lists every trial it references with its corpus status, checks each NCT id against the ClinicalTrials.gov v2 API for overall status and completion dates, and searches Europe PMC for papers on the trial acronyms published since the roadmap's asOf date. Anything it prints that this page does not say is an edit to make; then move asOf forward.","Dates in 'What to watch' are quoted from registries and releases and are not predictions. Registry completion dates move, and a company release is used only for a meeting date or a readout date, never for a result the paper has not yet reported."],"steps":[{"era":"1948-1994","title":"A curiosity in plasma","description":"Mandel and Metais reported nucleic acids in human blood plasma in 1948, and in 1977 Leon and colleagues found that people with cancer carried more free DNA in their serum and that levels fell when treatment worked. Nobody could yet say which fragments came from the tumour, so for four decades this stayed an observation rather than a test.","refs":["cfdna","ctdna","liquid-biopsy","klaus-pantel"],"status":"historic"},{"era":"2008-2016","title":"Proof that blood tracks the tumour","description":"Digital PCR and deep sequencing made it possible to count tumour-specific mutations in plasma: Diehl and colleagues showed mutant DNA rising and falling with disease in 2008, Dawson and colleagues tracked metastatic breast cancer with it in 2013, and Bettegowda and colleagues detected ctDNA across early- and late-stage cancers in 2014. Tie and colleagues then showed in 2016 that ctDNA found after surgery for stage II colon cancer predicted recurrence, the observation the residual disease trials were built on.","refs":["ctdna","liquid-biopsy","nitzan-rosenfeld","dawson-sarah-jane","nickolas-papadopoulos","alberto-bardelli","jeanne-tie","clonal-evolution"],"status":"historic"},{"era":"2016-2020","title":"Regulators accept a blood genotype","description":"On 1 June 2016 the FDA approved the cobas EGFR Mutation Test v2 for plasma, the first liquid biopsy companion diagnostic, letting lung cancer patients start erlotinib on a blood result when tissue was unavailable. Two broad panels followed in August 2020: Guardant360 CDx on 7 August and FoundationOne Liquid CDx on 26 August, each a companion diagnostic for several drugs, with a negative blood result sent back to tissue testing.","refs":["cobas-egfr-mutation-test","guardant360-cdx","foundationone-cdx","companion-diagnostic","roche-genentech","guardant-health","foundation-medicine","erlotinib","osimertinib"],"status":"historic"},{"era":"2019-2021","title":"Tumour-informed residual disease tests reach the clinic and the payer","description":"Signatera sequences each patient's tumour, picks 16 mutations, and looks for them in plasma after surgery; in the GALAXY registry a positive test four weeks after colorectal surgery carried a tenfold higher recurrence risk. Medicare's MolDX programme finalised coverage for serial Signatera testing in stage II and III colorectal cancer on 3 September 2020, and its coverage article for residual disease tests now lists several tests and cancers, which is how tumour-informed testing became routine before any randomised trial had finished.","refs":["signatera","natera","mrd-testing","mrd","tumour-informed-assay","guardant-reveal","radar-mrd","paper-galaxy-signatera-nat-med-2023","circulate-japan","medicare-ced"],"status":"current"},{"era":"2022-2026","title":"Randomised trials: sparing treatment works, adding it is harder","description":"DYNAMIC, published in June 2022, randomised 455 people with stage II colon cancer and cut adjuvant chemotherapy from 28 percent to 15 percent with two-year recurrence-free survival of 93.5 against 92.4 percent; the five-year update in 2025 held at 88 against 87 percent. Escalation has been harder to prove: ALTAIR, which gave trifluridine/tipiracil to ctDNA-positive patients after colorectal surgery, did not meet its disease-free survival endpoint, the MERMAID lung trials closed with 89 and 30 participants, and TRACC, BESPOKE and CIRCULATE-Japan's VEGA de-escalation trial are still running.","refs":["dynamic","paper-dynamic-nejm-2022","circulate-japan","tracc","bespoke-crc","mermaid-1","mermaid-2","ctdna-mrd-to-adjuvant","de-escalation","trifluridine-tipiracil","colorectal"],"status":"current"},{"era":"2025-2026","title":"The first drug approval that depends on a ctDNA result","description":"IMvigor011 tested 761 people after cystectomy for muscle-invasive bladder cancer and randomised the 250 whose blood turned ctDNA-positive to atezolizumab or placebo: disease-free survival hazard ratio 0.64 and overall survival hazard ratio 0.59, published in NEJM in December 2025. On 15 May 2026 the FDA approved adjuvant atezolizumab for patients with ctDNA molecular residual disease after cystectomy, with Signatera CDx as the companion diagnostic, so a residual disease blood test now sits inside a drug label.","refs":["imvigor011","paper-imvigor011-nejm-2025","atezolizumab","signatera","thomas-powles","urothelial","companion-diagnostic"],"status":"current"},{"era":"2021-2026","title":"Screening from blood: one cancer approved, many cancers under review","description":"PATHFINDER, published in 2023, was the first prospective test of a multi-cancer blood test in 6,621 adults without symptoms: 1.4 percent had a signal, 38 percent of those had cancer, and resolving a positive took a median of 79 days. Shield became the first FDA-approved blood test for colorectal cancer screening on 26 July 2024, for average-risk adults aged 45 and over with colonoscopy after a positive. NHS-Galleri, the randomised trial of Galleri in 142,250 people in England, reported on 30 May 2026 that stage III and IV cancers combined were not reduced (the primary endpoint) while stage IV diagnoses fell by 14 percent; PATHFINDER 2 reported a positive predictive value of 60.3 percent in 35,878 people the next day, and GRAIL's premarket application, filed on 29 January 2026, goes to an FDA advisory panel on 23 September 2026. The trial's peer-reviewed test-performance paper appeared in Nature Medicine on 22 September 2026: positive results in 1.03, 0.80 and 0.90 percent of intervention-arm participants across three annual rounds, positive predictive values of 58.0, 50.4 and 45.8 percent, specificity of 99.50 to 99.60 percent and episode sensitivity of 26.7 to 37.2 percent for all cancers; it states the primary endpoint was not met and is reported elsewhere.","refs":["mced","galleri","shield","grail","guardant-health","pathfinder-2","nhs-galleri","eclipse-shield","paper-pathfinder-lancet-2023","paper-nhs-galleri-design-cancers-2022","paper-nhs-galleri-performance-nat-med-2026","cfdna-methylation-testing","stage-shift","ppv","deb-schrag","peter-sasieni"],"status":"current"},{"era":"2026-2029","title":"The randomised answers arrive","description":"The open questions each have a trial with a date on the registry. For screening, the NCI's Vanguard study randomises 24,000 people to multi-cancer detection tests or usual care, with primary completion listed for 31 January 2029, and NHS-Galleri's follow-up continues. For residual disease, CIRCULATE-US randomises stage III colon cancer patients by Signatera result to more or less chemotherapy (primary completion 10 March 2029), TRACC follows 1,000 people to 2029, and VEGA asks whether ctDNA-negative patients can skip chemotherapy altogether. If escalation trials keep missing, the field's case will rest on de-escalation and on ctDNA as a surrogate endpoint.","refs":["vanguard-study","circulate-us","tracc","circulate-japan","nci","nrg-oncology","idea-ctdna-guided-adjuvant-crc","idea-tr2-ctdna-mrd-qualification","surrogate-validation"],"status":"emerging"},{"era":"2026-2030","title":"Deeper, cheaper and tumour-naive","description":"Two technical routes are competing to make the tests more sensitive without a tumour sample: methylation, which reads chemical marks that also point to the tissue of origin, and fragmentomics, which reads the sizes and positions of the fragments themselves. Whole-genome approaches and repeated sampling aim to catch relapse earlier than a three-monthly draw. The gating question for all of them is utility rather than sensitivity: finding disease earlier has to change an outcome, and the clonal haematopoiesis of normal blood cells is the main source of false positives.","refs":["cfdna-methylation-testing","fragmentomics","methylation-profiling","continuous-ctdna-monitoring","delfi-diagnostics","freenome","guardant-reveal","clonal-haematopoiesis","mrd-kinetics-models","idea-bio2-whole-genome-mrd-depth","idea-bio1-methylation-clone-tracking"],"status":"emerging"},{"era":"What sets the pace","title":"Payment, standards and what to do with a positive","description":"In the United States, Medicare pays for residual disease tests through a MolDX coverage article that names tests and cancers one at a time (revision effective 1 January 2026); screening tests need their own coverage route, and most health systems outside the United States pay for none of this yet. Laboratories run different assays with no shared reference material, so a positive in one is not a positive in another, and a screening positive still needs a fast, agreed diagnostic pathway. Coverage with evidence, reference plasma standards and a national positive-result pathway are the proposals on the table.","refs":["medicare-ced","fda-ldt-rule","idea-bio2-mrd-coverage-with-evidence","idea-tr2-ctdna-reference-plasma","idea-bio2-mrd-reference-standards","idea-prev-mced-positive-resolution-pathway","b-dormancy-mrd"],"status":"current"}],"watch":[{"item":"FDA Molecular and Clinical Genetics Panel reviews the Galleri premarket approval application","expected":"2026-09-23","source":"https://grail.com/press-releases/grail-announces-fda-advisory-committee-meeting-to-review-premarket-approval-application-for-the-galleri-multi-cancer-early-detection-test/","refs":["galleri","grail","mced"]},{"item":"IMvigor011 study completion on the registry; longer follow-up of ctDNA-negative patients under surveillance","expected":"2026-10-01","source":"https://clinicaltrials.gov/study/NCT04660344","refs":["imvigor011","atezolizumab"]},{"item":"NHS-Galleri: peer-reviewed test-performance paper (reported: Nature Medicine, 22 September 2026, states the primary endpoint was not met and is reported elsewhere)","expected":"2026-09-22","source":"https://doi.org/10.1038/s41591-026-04652-8","refs":["nhs-galleri","galleri","stage-shift","paper-nhs-galleri-performance-nat-med-2026"]},{"item":"NHS-Galleri: primary-endpoint paper (stage III/IV incidence) not yet on Europe PMC; registry study completion, with cancer-specific mortality follow-up, listed as January 2031","expected":"2031-01","source":"https://clinicaltrials.gov/study/NCT05611632","refs":["nhs-galleri","galleri","stage-shift"]},{"item":"ECLIPSE (Shield) study completion on the registry","expected":"2027-08-05","source":"https://clinicaltrials.gov/study/NCT04136002","refs":["eclipse-shield","shield"]},{"item":"PATHFINDER 2 study completion (primary completion listed as 2026-02-11)","expected":"2028-04-30","source":"https://clinicaltrials.gov/study/NCT05155605","refs":["pathfinder-2","galleri"]},{"item":"Vanguard study primary completion: the NCI's randomised feasibility trial of multi-cancer detection tests in 24,000 people","expected":"2029-01-31","source":"https://clinicaltrials.gov/study/NCT06995898","refs":["vanguard-study","nci"]},{"item":"CIRCULATE-US primary completion: ctDNA-guided escalation and de-escalation of adjuvant chemotherapy in stage III colon cancer","expected":"2029-03-10","source":"https://clinicaltrials.gov/study/NCT05174169","refs":["circulate-us","signatera"]},{"item":"TRACC primary completion: 1,000 people with early colorectal cancer followed by ctDNA","expected":"2029-07-31","source":"https://clinicaltrials.gov/study/NCT04050345","refs":["tracc"]},{"item":"VEGA (CIRCULATE-Japan): non-inferiority of no chemotherapy in ctDNA-negative colon cancer; no readout date in the sources read","source":"https://europepmc.org/article/MED/33931919","refs":["circulate-japan"]},{"item":"BESPOKE CRC: registry status not updated since a listed completion of September 2025; watch for the primary publication","expected":"2025-09","source":"https://clinicaltrials.gov/study/NCT04264702","refs":["bespoke-crc","signatera"]}]},{"id":"devices-roadmap","kind":"roadmap","name":"Devices and physical therapies roadmap: heat and light → electric fields and focused sound → drug-releasing implants","aka":[],"tldr":"Devices treat cancer with physics rather than chemistry: heat, cold, light, electric fields and sound. After decades at the margins, several now have randomised proof and approvals, and the next generation aims to prime the immune system as it destroys the tumour.","summary":"Physical therapies were the original alternatives to the knife: brachytherapy placed radium inside tumours a century ago, hyperthermia and photodynamic therapy were tested through the 1980s and 1990s, and needle-based ablation with heat or cold became standard for small liver and kidney tumours. What held the field back was evidence: device trials are hard to blind, rarely funded at drug-trial scale, and reimbursed inconsistently.\n\nThat has changed. Tumour treating fields, alternating electric fields worn on the scalp or torso that disrupt cell division, extended survival in glioblastoma (EF-14) and in 2026 won approval in pancreatic cancer after PANOVA-3, the first device to do so. Photoimmunotherapy, an antibody carrying a light-activated dye, is approved in Japan for head and neck cancer. A pretzel-shaped implant that releases gemcitabine inside the bladder cleared carcinoma in situ in most patients in SunRISe-1 and reached the market. Histotripsy, which destroys tissue mechanically with focused sound, is approved in the liver and being studied as an immune primer, and focused ultrasound is opening the blood-brain barrier for drugs in trials.\n\nThe pace is set by the same problems as before: trial design and funding for interventions no pharma company owns, sham-controlled evidence, reimbursement, and access outside specialist centres.","asOf":"2026-09-10","links":[{"label":"EF-14: tumour treating fields plus temozolomide in glioblastoma (JAMA 2017)","url":"https://doi.org/10.1001/jama.2017.18718"},{"label":"PANOVA-3 (Journal of Clinical Oncology 2025)","url":"https://doi.org/10.1200/JCO-25-00746"}],"tags":[],"related":["idea-photoimmunotherapy-plus-pd1","idea-acc-hpv-self-sample-same-day-ablation","sunnybrook-odette","dna-origami-nanorobots","frontier-2035","surgery-roadmap","radiation-roadmap"],"cancers":[],"sections":["devices"],"technologies":["ttfields","hyperthermia","photoimmunotherapy","brachytherapy","thermal-ablation","irreversible-electroporation","hifu-histotripsy","litt","bbb-focused-ultrasound","histotripsy-immune-priming","electrochemotherapy","il12-electroporation","bcg-and-intravesical-therapy","scalp-cooling","photobiomodulation-mucositis","precancer-ablation","infusion-devices-vascular-access","pharmacy-automation","magnetic-nanoparticle-hyperthermia","photothermal-nanoparticles","sonodynamic-therapy","radiodynamic-therapy","partial-nephrectomy-active-surveillance"],"targets":[],"drugs":["optune","cetuximab-sarotalocan","tar-200","aminolevulinic-acid","nadofaragene-firadenovec"],"companies":["novocure","histosonics","insightec","biofrontera","biolitec","luminate-medical","isono-health","ananya-health","alpha-tau-medical","sonalasense","zap-surgical-systems","boston-scientific"],"institutions":[],"pathways":[],"terms":[],"trials":["ef-14","panova-3","stellar","sunrise-1"],"people":[],"bottlenecks":["b-surgery-radiation-innovation","b-trial-design","b-drug-pricing","b-global-access","b-brain-delivery"],"keyPapers":["paper-stupp-jama","paper-panova-3-ttfields-locally-advanced-pancreatic-jco-2025"],"journals":[],"dependsOn":[],"notes":[],"steps":[{"era":"1900s-1990s","title":"Radium, heat and light","description":"Brachytherapy placed radioactive sources inside tumours within a decade of radium's discovery and remains standard in cervical and prostate cancer. Hyperthermia, heating tumours to 40-43 degrees to sensitise them to radiation and chemotherapy, showed benefit in randomised trials for cervical cancer and sarcoma but never became routine. Photodynamic therapy, a light-activated drug for skin and superficial tumours, was approved in the 1990s. Each worked in a niche; none had the trial machinery to grow beyond it.","refs":["brachytherapy","hyperthermia","photoimmunotherapy","aminolevulinic-acid","biofrontera","biolitec"],"status":"historic"},{"era":"1990s-2015","title":"Ablation through a needle","description":"Radiofrequency, then microwave and cryoablation, destroyed small liver, kidney and lung tumours through a needle under imaging guidance and became guideline alternatives to surgery for patients who could not have an operation. Irreversible electroporation used high-voltage pulses to kill cells without heat, sparing vessels and ducts near the pancreas. Laser interstitial thermal therapy reached deep brain tumours through a small skull hole. High-intensity focused ultrasound treated prostate cancer from outside the body.","refs":["thermal-ablation","irreversible-electroporation","litt","hifu-histotripsy","partial-nephrectomy-active-surveillance"],"status":"historic"},{"era":"2011-2026","title":"Electric fields become a treatment","description":"Tumour treating fields, delivered through electrodes worn on the skin for most of the day, disrupt the mitotic spindle in dividing cells. EF-14 showed that adding the device to temozolomide extends survival in newly diagnosed glioblastoma; STELLAR supported approval in mesothelioma; and in 2026 PANOVA-3 made the device the first ever approved for pancreatic cancer, extending survival when added to chemotherapy. The mechanism is unusual enough that the field spent years arguing about it; the randomised data settled the practical question.","refs":["ttfields","optune","ef-14","stellar","panova-3","novocure"],"status":"current"},{"era":"2020-2026","title":"Light-activated drugs and drug-releasing implants","description":"Cetuximab sarotalocan, an EGFR antibody carrying a dye that bursts cells when near-infrared light is shone on them, is approved in Japan for recurrent head and neck cancer and is being paired with PD-1 blockade to turn the burst tumour into a vaccine. In the bladder, the TAR-200 pretzel implant releases gemcitabine for weeks and cleared carcinoma in situ in most patients in SunRISe-1; nadofaragene firadenovec became the first bladder gene therapy. Electrochemotherapy and IL-12 gene electrotransfer use electric pulses to get drugs or genes into a tumour directly.","refs":["cetuximab-sarotalocan","photoimmunotherapy","idea-photoimmunotherapy-plus-pd1","tar-200","sunrise-1","bcg-and-intravesical-therapy","nadofaragene-firadenovec","electrochemotherapy","il12-electroporation"],"status":"current"},{"era":"2024-2028","title":"Focused sound: destroy, prime, open","description":"Histotripsy destroys tissue with cavitation bubbles rather than heat, without incision or radiation; it is approved for liver tumours, its inventor was acquired for over two billion dollars, and trials are asking whether the debris it leaves primes an immune response that other ablations do not. Focused ultrasound with microbubbles briefly opens the blood-brain barrier so that chemotherapy or antibodies can reach brain tumours, in trials at Sunnybrook and elsewhere. Sonodynamic therapy activates a drug only where ultrasound hits it, in glioblastoma trials.","refs":["hifu-histotripsy","histosonics","histotripsy-immune-priming","bbb-focused-ultrasound","insightec","sunnybrook-odette","sonodynamic-therapy","sonalasense","b-brain-delivery"],"status":"emerging"},{"era":"2015-2028","title":"Devices that make treatment bearable and reachable","description":"Scalp cooling caps preserve hair through chemotherapy and are cleared and increasingly funded; a compression device aims to do the same more cheaply; low-level laser reduces the mouth ulcers of head and neck radiotherapy; a wearable ultrasound images the whole breast in minutes; and a portable freezing device lets a nurse treat cervical precancer in any clinic, which matters where colposcopy does not exist. Infusion pumps, ports and compounding robots are the devices every chemotherapy dose depends on.","refs":["scalp-cooling","luminate-medical","photobiomodulation-mucositis","isono-health","precancer-ablation","ananya-health","idea-acc-hpv-self-sample-same-day-ablation","infusion-devices-vascular-access","pharmacy-automation"],"status":"current"},{"era":"2030+","title":"Nanoparticles, alpha seeds and machines made of DNA","description":"Iron-oxide nanoparticles heated by an alternating magnetic field, gold nanoshells heated by light, and nanoparticles that amplify radiotherapy inside the tumour all have first-in-human data and no randomised proof. Radioactive seeds that emit short-range alpha particles from inside a tumour are in trials. DNA origami nanorobots that open only on contact with a tumour are mouse data. Each has a specific, known failure mode (delivery, clearance, toxicity) rather than a vague one, which is what keeps them on the map.","refs":["magnetic-nanoparticle-hyperthermia","photothermal-nanoparticles","radiodynamic-therapy","alpha-tau-medical","dna-origami-nanorobots","frontier-2035"],"status":"speculative"},{"era":"What sets the pace","title":"Trials nobody owns, evidence nobody blinds","description":"Devices are approved on less evidence than drugs, then struggle for guideline adoption and payment because the trials were small or unblinded. No pharma company funds a device trial, and device companies are small. Sham-controlled designs, standing platform trials for local therapies, and reimbursement tied to registries are the fixes; access outside specialist centres, and outside rich countries, is the larger gap.","refs":["b-surgery-radiation-innovation","b-trial-design","b-drug-pricing","b-global-access"],"status":"current"}],"watch":[]},{"id":"diagnostics-roadmap","kind":"roadmap","name":"Diagnostics roadmap: stains → gene panels → blood tests that decide treatment","aka":[],"tldr":"Cancer diagnosis moved from what a tumour looks like under a microscope to what is driving it, and now to reading it from a blood sample. The next step is tests that tell the doctor what to do, not only what is there.","summary":"Histopathology and immunohistochemistry remain the foundation of every cancer diagnosis, and the first companion diagnostic (HER2 testing paired with trastuzumab in 1998) set the pattern that every targeted drug since has followed: no test, no drug. Single-gene tests gave way to comprehensive genomic profiling of hundreds of genes, tumour-agnostic biomarkers (mismatch repair deficiency, tumour mutational burden, NTRK fusions), and gene-expression signatures that let most women with early hormone-positive breast cancer skip chemotherapy.\n\nThe current shift is from tissue to blood and from description to decision. Circulating tumour DNA now genotypes lung cancer without a biopsy, detects molecular residual disease after surgery months before a scan would, and has changed treatment in randomised trials: DYNAMIC halved adjuvant chemotherapy in stage II colon cancer, SERENA-6 switched endocrine therapy on an ESR1 mutation found in blood, and IMvigor011 produced the first ctDNA-guided drug approval in 2026. Digital pathology is following the same path, with the first AI tests that predict treatment benefit from a routine slide cleared in 2025 and 2026.\n\nWhat decides the pace is validation rather than invention: prospective evidence that acting on a test improves outcomes, standardisation across laboratories, reimbursement for tests that avoid treatment rather than add it, and data that flows between the sequencer, the slide scanner, the record and the registry.","asOf":"2026-09-10","links":[{"label":"FDA: list of cleared or approved companion diagnostic devices","url":"https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools"},{"label":"DYNAMIC trial (NEJM 2022)","url":"https://www.nejm.org/doi/full/10.1056/NEJMoa2200075"}],"tags":[],"related":["signatera","foundationone-cdx","guardant360-cdx","oncotype-dx","her2-testing-assays","cobas-egfr-mutation-test","dako-pd-l1-22c3-pharmdx","guardant-reveal","radar-mrd","artera-ai-prostate","artera-ai-breast","fda-ldt-rule","idea-bio2-national-mrd-platform","idea-bio2-mrd-coverage-with-evidence","idea-ctdna-guided-adjuvant-crc","idea-tr2-ctdna-mrd-qualification","idea-tr2-biomarker-study-registry","idea-tr2-marker-stratified-default","idea-moon-universal-sequencing-learning-system","early-detection-roadmap","ai-oncology-clinic","trial-modernisation-roadmap"],"cancers":[],"sections":["diagnostics"],"technologies":["histopathology-ihc","companion-diagnostic","cgp","liquid-biopsy","mrd-testing","single-cell-spatial","methylation-profiling","digital-pathology-ai","pathology-foundation-model","msi-mmr-testing","tmb-testing","hrd-testing","rna-seq","wes-wgs","proteomics","long-read-sequencing","spatial-omics-guided-therapy","continuous-ctdna-monitoring","fragmentomics","variant-knowledgebases","reference-laboratories"],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["tailorx","rxponder","dynamic","serena-6","imvigor011","circulate-japan","insight-gist","masai"],"people":[],"bottlenecks":["b-biomarker-validation","b-dormancy-mrd","b-data-silos","b-tumor-heterogeneity"],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"steps":[{"era":"1940s-1990s","title":"Morphology, stains and the first companion test","description":"Haematoxylin and eosin, then immunohistochemistry and FISH, defined cancer by appearance and a handful of proteins. HER2 testing approved alongside trastuzumab in 1998 created the companion diagnostic: a test whose result is the gate to a drug. Every targeted therapy since has been launched with one.","refs":["histopathology-ihc","cytogenetics-fish","her2-testing-assays","companion-diagnostic","core-needle-biopsy"],"status":"historic"},{"era":"2000s-2010s","title":"Single-gene tests and gene-expression signatures","description":"PCR kits for EGFR, KRAS and BRAF matched the first kinase inhibitors to the right patients; the cobas EGFR test became the first blood-based companion diagnostic. Gene-expression signatures did the opposite job, identifying who could safely skip treatment: TAILORx (2018) and RxPONDER showed that most women with early hormone-positive breast cancer and a low Oncotype DX score gain nothing from chemotherapy.","refs":["cobas-egfr-mutation-test","therascreen-cdx","oncotype-dx","tailorx","rxponder","mammaprint","prosigna"],"status":"historic"},{"era":"2017-2022","title":"Comprehensive profiling and tumour-agnostic biomarkers","description":"Sequencing hundreds of genes at once (FoundationOne CDx, TruSight Oncology, Tempus xT) replaced serial single-gene tests, and the biomarker began to matter more than the organ: pembrolizumab for any mismatch-repair-deficient tumour and larotrectinib for any NTRK fusion made the test the indication. Guardant360 CDx did the same from blood. Variant knowledgebases and molecular tumour boards turned raw variants into decisions.","refs":["cgp","foundationone-cdx","trusight-oncology-comprehensive","tempus-xt-cdx","guardant360-cdx","msi-mmr-testing","tmb-testing","hrd-testing","variant-knowledgebases","multidisciplinary-tumour-board","tumour-agnostic"],"status":"current"},{"era":"2022-2026","title":"Blood tests that change treatment in randomised trials","description":"Molecular residual disease testing crossed from prognosis to action. DYNAMIC (2022) halved adjuvant chemotherapy in stage II colon cancer with no loss of recurrence-free survival; CIRCULATE-Japan runs the same question at national scale; SERENA-6 switched endocrine therapy when an ESR1 mutation appeared in blood before a scan showed progression; and IMvigor011 delivered the first ctDNA-guided approval, in bladder cancer, in 2026. Tumour-informed (Signatera, RaDaR) and tumour-naive (Guardant Reveal) assays now compete on sensitivity and turnaround.","refs":["mrd-testing","liquid-biopsy","dynamic","circulate-japan","serena-6","imvigor011","signatera","radar-mrd","guardant-reveal","insight-gist"],"status":"current"},{"era":"2024-2028","title":"Slides become data","description":"Whole-slide scanning made the microscope image computable, and foundation models trained on millions of slides now predict biomarkers, recurrence risk and treatment benefit from a routine stain. ArteraAI Prostate (2025) was the first AI test cleared to predict benefit from a therapy; ArteraAI Breast followed in 2026. MASAI showed in a randomised screening trial that AI reading finds more cancers with less radiologist workload. The open question is prospective proof that AI-derived biomarkers should change treatment, and a regulatory route for models that keep learning.","refs":["digital-pathology-ai","pathology-foundation-model","whole-slide-scanners","virchow","prov-gigapath","artera-ai-prostate","artera-ai-breast","masai","musk"],"status":"emerging"},{"era":"2027-2032","title":"Spatial, single-cell and protein layers guide the choice","description":"Genotype explains which drug could work; architecture and phenotype may explain which one will. Spatial and single-cell profiling map where immune cells sit relative to tumour cells, proteomics measures the drug's actual target, long-read sequencing resolves rearrangements and methylation together, and near-continuous ctDNA sampling turns monitoring into a running signal. Each is a research tool today; the work of this era is showing that any of them changes an outcome when used to choose treatment.","refs":["single-cell-spatial","spatial-omics-guided-therapy","spatial-biology-instruments","proteomics","long-read-sequencing","continuous-ctdna-monitoring","fragmentomics","methylation-profiling"],"status":"emerging"},{"era":"What sets the pace","title":"Validation, standardisation and payment","description":"Tests that decide who gets a drug are still often validated retrospectively, run differently in different laboratories, and paid for only when they add treatment rather than remove it. The fixes on the table: pre-registration of biomarker studies, a national platform every ctDNA-positive patient can join, coverage-with-evidence for residual disease tests, universal sequencing that feeds a shared learning system, and a clear regulatory status for laboratory-developed tests.","refs":["b-biomarker-validation","b-dormancy-mrd","b-data-silos","b-tumor-heterogeneity","idea-tr2-biomarker-study-registry","idea-bio2-national-mrd-platform","idea-bio2-mrd-coverage-with-evidence","idea-moon-universal-sequencing-learning-system","fda-ldt-rule","reference-laboratories"],"status":"current"}],"watch":[]},{"id":"nutrition-lifestyle-roadmap","kind":"roadmap","name":"Diet, exercise and lifestyle roadmap: causes established → interventions that disappointed → exercise proven as treatment","aka":[],"tldr":"What people eat, weigh and do shapes who gets cancer and how treatment goes. Decades of trials separated what is established (obesity, alcohol and inactivity cause cancer; exercise after treatment reduces recurrence) from what is hype, and the next questions are being asked with the rigour of a drug trial.","summary":"Epidemiology established the causes: tobacco, then excess body fat (now linked to at least thirteen cancers), alcohol, processed meat and physical inactivity. The first generation of intervention trials mostly disappointed. A vegetable-rich diet did not reduce breast cancer recurrence (WHEL), vitamin D and fish oil did not prevent cancer (VITAL), fish oil did not slow cachexia, and high-dose vitamin C did not treat anything. Those null results are as valuable as positive ones: they are why this front can tell evidence from marketing.\n\nThe breakthrough came from exercise. In 2025 the CHALLENGE trial showed that a coached, structured exercise programme after colon cancer treatment reduces recurrence and improves survival, the first randomised proof that a lifestyle intervention changes a hard cancer outcome. Nutrition care during treatment has its own evidence base: malnutrition screening, dietitian-led therapy, enhanced recovery around surgery and prehabilitation are all in guidelines. The live scientific questions are the gut microbiome's effect on immunotherapy, whether GLP-1 agonists and bariatric surgery prevent cancer, whether fasting or ketogenic diets help around treatment, and how to treat cachexia as a disease.\n\nThe pace is set by the absence of a commercial sponsor for anything that cannot be patented, by misinformation that fills the gap, and by health systems that do not pay for exercise or dietetics the way they pay for drugs.","asOf":"2026-09-10","links":[{"label":"CHALLENGE trial (NEJM 2025)","url":"https://www.nejm.org/doi/full/10.1056/NEJMoa2502760"},{"label":"IARC: body fatness and cancer (NEJM 2016)","url":"https://www.nejm.org/doi/full/10.1056/NEJMsr1606602"}],"tags":[],"related":["idea-exercise-as-adjuvant","idea-bio2-exercise-reimbursement","idea-nl-exercise-dose-finding","idea-bio2-prehabilitation-standard","idea-prev-glp1-cancer-prevention-rct","idea-prev-glp1-endometrial-hyperplasia","idea-bio2-gdf15-plus-exercise","idea-cachexia-gdf15-prevention","idea-nl-sleep-circadian-survivorship-rct","idea-moon-integrative-oncology-bridge","idea-prev-alcohol-cancer-warning-labels","idea-prev-minimum-unit-pricing-cancer-endpoints","maat-pharma","survivorship-roadmap","prevention-roadmap"],"cancers":[],"sections":["nutrition-lifestyle"],"technologies":["exercise-oncology","structured-exercise-survivorship","exercise-during-chemotherapy","prehabilitation","eras-perioperative-nutrition","oncology-nutrition","nutrition-screening-mnt","enteral-parenteral-nutrition","immunonutrition-perioperative","dietitian-led-weight-loss-breast","mediterranean-plant-forward-diet","dietary-fibre-microbiome-io","fmt-checkpoint-nonresponders","probiotics-antibiotic-stewardship-io","microbiome-modulation-io","glp1-agonists-cancer-risk","bariatric-surgery-cancer-incidence","fasting-mimicking-diet","ketogenic-diet-glioblastoma","time-restricted-eating","cachexia-therapy","cachexia-appetite-pharmacotherapy","resistance-training-cachexia","sleep-circadian-interventions","vitamin-d-omega3-supplementation","omega3-epa-cachexia","high-dose-vitamin-c","dietary-supplements-treatment-interactions","alcohol-reduction-labelling","red-processed-meat-reduction","ultra-processed-food-ssb","smoking-cessation-after-diagnosis","integrative-oncology","yoga-cancer"],"targets":[],"drugs":[],"companies":["cctg"],"institutions":["espen","iarc"],"pathways":[],"terms":["obesity-related-cancers","risk-factor","cachexia","sarcopenia","gut-microbiome-diversity","metabolic-syndrome","malnutrition-screening","warburg-effect-diet-claims","unproven-diet-claims","dietary-pattern-scores"],"trials":["challenge","bwel","whel","vital","ergo2","fmt-pd1-refractory-melanoma-pitt","mimic-01","ponsegromab-phase-2","olanzapine-appetite-tmh","prehab-trial"],"people":[],"bottlenecks":["b-cachexia-supportive","b-prevention-adoption","b-misinformation","b-generic-repurposing","b-funding-allocation"],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"steps":[{"era":"1950s-2016","title":"The causes are established","description":"Cohort studies and IARC's monographs built the list that is no longer in dispute: tobacco, alcohol (a group 1 carcinogen for at least seven cancers), processed meat, and excess body fat, which IARC linked to thirteen cancers in 2016. Physical inactivity and sugary drinks joined through the same evidence. The World Cancer Research Fund's Continuous Update Project keeps the grading current, which is why this front can say 'convincing', 'probable' or 'insufficient' rather than 'linked to'.","refs":["risk-factor","obesity-related-cancers","alcohol-reduction-labelling","red-processed-meat-reduction","ultra-processed-food-ssb","metabolic-syndrome","iarc","dietary-pattern-scores"],"status":"historic"},{"era":"1990s-2020","title":"The intervention trials that disappointed, and taught","description":"Three thousand breast cancer survivors coached for years to eat far more vegetables had no fewer recurrences (WHEL). Vitamin D and fish oil did not prevent cancer in 25,000 people (VITAL). Fish oil did not slow cancer wasting. High-dose vitamin C failed twice in randomised trials at the Mayo Clinic. Each null result closed a question that supplements marketing keeps open, and together they set the standard: a diet claim needs a randomised trial with a cancer endpoint.","refs":["whel","vital","vitamin-d-omega3-supplementation","omega3-epa-cachexia","high-dose-vitamin-c","dietary-supplements-treatment-interactions","unproven-diet-claims","warburg-effect-diet-claims"],"status":"historic"},{"era":"2020-2026","title":"Exercise becomes a treatment","description":"CHALLENGE randomised nearly 900 people after colon cancer treatment to a three-year coached exercise programme or health education and, in 2025, reported fewer recurrences and fewer deaths in the exercise arm: the first randomised proof that a lifestyle intervention changes a hard cancer outcome. Exercise during chemotherapy is safe and reduces fatigue; four weeks of prehabilitation before major surgery cuts complications (PREHAB); enhanced recovery protocols replaced pre-operative fasting. The question is no longer whether but how to prescribe, deliver and pay for it.","refs":["challenge","cctg","exercise-oncology","structured-exercise-survivorship","exercise-during-chemotherapy","prehabilitation","prehab-trial","eras-perioperative-nutrition","idea-exercise-as-adjuvant","idea-bio2-exercise-reimbursement","idea-bio2-prehabilitation-standard"],"status":"current"},{"era":"2015-2026","title":"Nutrition care as a standard of care","description":"Weighing every patient, screening for malnutrition, dietitian-led counselling and, when needed, tube or intravenous feeding are in ESPEN and ASCO guidelines because malnutrition predicts toxicity, complications and death. Immunonutrition before major surgery, a Mediterranean pattern for survivors, and dietitian-led weight loss in hormone-positive breast cancer (the 3,000-patient BWEL trial is awaited) are the evidence-based options. Soy is safe; most supplements are unnecessary and some interact with treatment.","refs":["oncology-nutrition","nutrition-screening-mnt","malnutrition-screening","enteral-parenteral-nutrition","immunonutrition-perioperative","mediterranean-plant-forward-diet","dietitian-led-weight-loss-breast","bwel","espen","sarcopenia"],"status":"current"},{"era":"2024-2028","title":"The microbiome and immunotherapy","description":"Patients who eat plenty of fibre and avoid unnecessary antibiotics respond better to checkpoint inhibitors in observational studies, and small trials of faecal microbiota transplantation from responders or healthy donors converted some non-responders into responders (Pittsburgh, MIMic-01). Defined bacterial consortia and stewardship of antibiotics around immunotherapy are the next tests. This is the one area of nutrition where a mechanism, the gut's training of the immune system, is being tested in randomised trials with response as the endpoint.","refs":["dietary-fibre-microbiome-io","fmt-checkpoint-nonresponders","fmt-pd1-refractory-melanoma-pitt","mimic-01","probiotics-antibiotic-stewardship-io","microbiome-modulation-io","gut-microbiome-diversity","maat-pharma"],"status":"emerging"},{"era":"2025-2030","title":"Metabolic interventions under randomised test","description":"People taking GLP-1 agonists for obesity have lower rates of obesity-related cancers in observational data, and bariatric surgery patients develop fewer cancers, but neither has a randomised trial with cancer as the primary outcome; that trial is the most important one this front could run. Fasting-mimicking diets around chemotherapy, ketogenic diets in glioblastoma (ERGO2 is the only randomised test) and time-restricted eating have plausible mechanisms and small trials. GLP-1 drugs to reverse endometrial precancer in women with obesity is the nearest practical application.","refs":["glp1-agonists-cancer-risk","bariatric-surgery-cancer-incidence","idea-prev-glp1-cancer-prevention-rct","idea-prev-glp1-endometrial-hyperplasia","fasting-mimicking-diet","ketogenic-diet-glioblastoma","ergo2","time-restricted-eating"],"status":"emerging"},{"era":"2026-2030","title":"Cachexia as a treatable disease","description":"Cancer wasting is driven in part by the hormone GDF-15, and the first antibody against it (ponsegromab) improved weight and physical activity in phase 2. Low-dose olanzapine restored appetite in a Tata Memorial trial for pennies; resistance training and protein remain the foundation. The proposal is to treat cachexia like sepsis, with a trigger, a bundle and an audit, and to combine the new antibody with exercise and nutrition rather than test it alone.","refs":["cachexia","cachexia-therapy","ponsegromab-phase-2","cachexia-appetite-pharmacotherapy","olanzapine-appetite-tmh","resistance-training-cachexia","idea-bio2-gdf15-plus-exercise","idea-cachexia-gdf15-prevention"],"status":"emerging"},{"era":"2030+","title":"Exercise dosed like a drug, and sleep as a target","description":"CHALLENGE proved exercise works in one cancer at one dose; dose-finding trials across cancers, reimbursement of supervised programmes as treatment, and delivery at population scale are the next decade's work. Half of people with cancer sleep badly, and trials are asking whether treating insomnia and restoring circadian rhythm changes outcomes. Evidence-based integrative oncology in every centre is the proposed bridge that meets patient demand without ceding ground to unproven regimens.","refs":["idea-nl-exercise-dose-finding","idea-exercise-as-adjuvant","sleep-circadian-interventions","idea-nl-sleep-circadian-survivorship-rct","integrative-oncology","yoga-cancer","idea-moon-integrative-oncology-bridge"],"status":"speculative"},{"era":"What sets the pace","title":"No patent, no sponsor, plenty of noise","description":"Nothing on this front can be patented, so trials depend on public and charitable funders and are rare; misinformation fills the space with alkaline diets and juice cures; health systems pay for drugs but not for dietitians or exercise physiologists; and the prevention measures already proven (alcohol pricing and labelling, sugar taxes, active travel) are politically harder than any drug approval. Cancer warning labels on alcohol, evaluated as a natural experiment, would be a start.","refs":["b-cachexia-supportive","b-prevention-adoption","b-misinformation","b-generic-repurposing","b-funding-allocation","idea-prev-alcohol-cancer-warning-labels","idea-prev-minimum-unit-pricing-cancer-endpoints","smoking-cessation-after-diagnosis"],"status":"current"}],"watch":[]},{"id":"drug-discovery-roadmap","kind":"roadmap","name":"Drug discovery roadmap: screening in mice → maps of dependency → designing in silico","aka":[],"tldr":"Finding the next cancer drug used to mean testing compounds on mice and cell lines and hoping. It now means mapping which genes each cancer cannot live without, growing a patient's tumour in a dish, and designing molecules on a computer; the job is making those tools predict what happens in people.","summary":"Nine in ten cancer drugs that work in mice fail in humans, and most of the history of drug discovery is the attempt to close that gap. Natural-product screening found vincristine and paclitaxel; target-based discovery, structural biology and high-throughput screening produced the kinase inhibitors. What they could not do was predict which patients a drug would help or which combination would hold.\n\nThe present toolkit attacks that directly. Genome-wide CRISPR screens (DepMap) map the dependencies of a thousand cancer cell lines and expose synthetic-lethal targets; patient-derived organoids and xenografts keep a tumour's biology closer to the patient's; functional testing of drugs on a patient's own cells is being run alongside trials. Structure prediction (AlphaFold 3, Boltz, Chai) and generative design have put the first AI-designed molecules into oncology trials, and perturbation datasets of a hundred million cells are training models that try to predict a drug's effect before the experiment.\n\nThe pace is set by the predictive validity of models, by the half of landmark findings that do not reproduce, by the valley between an academic discovery and a funded programme, and by the secrecy that keeps compound libraries and negative results locked up.","asOf":"2026-09-10","links":[{"label":"DepMap portal","url":"https://depmap.org/portal/"},{"label":"AlphaFold 3 (Nature 2024)","url":"https://doi.org/10.1038/s41586-024-07487-w"},{"label":"Tahoe-100M single-cell perturbation atlas","url":"https://www.tahoebio.ai/"}],"tags":[],"related":["depmap","cancer-models","tcga-gdc","genie","cptac","tahoe-100m","arc-virtual-cell-atlas","virtual-cell","ai-oncology-roadmap","adc-generations","idea-tr2-organoid-coclinical-arms","idea-tr2-reference-model-panels","idea-bio1-in-silico-trials-dose","idea-bio1-multi-organ-chip-tox","idea-tr2-phd-replication-year","idea-tr2-preclinical-negative-registry","idea-bio2-shared-compound-access-pool","idea-bio1-undruggable-market-commitment"],"cancers":[],"sections":["drug-discovery"],"technologies":["crispr-screens","organoids","pdx-models","functional-drug-testing","organoid-guided-therapy-scale","pdac-organoid-pharmacotyping","bh3-profiling","high-throughput-screening-libraries","structural-biology-infrastructure","ai-drug-design","de-novo-protein-design","alphafold3","boltz","chai-1","rfdiffusion","esm3","chemistry42","phenom-2","protac-degrader","molecular-glue-platforms","peptide-drug-conjugate","antisense-sirna","degrader-antibody-conjugate","synthetic-lethality-approaches","proteomics","geneformer","scgpt","state-arc","digital-twins-trials"],"targets":[],"drugs":["vincristine","paclitaxel","dactinomycin","imatinib","sotorasib"],"companies":["isomorphic-labs","insilico-medicine","recursion","exscientia","xaira-therapeutics","generate-biomedicines","chai-discovery","hub-organoids","champions-oncology","sengine","curesponse","araris","bicycle-therapeutics","frontier-medicines","vevo-therapeutics","google-deepmind"],"institutions":["nci","arc-institute"],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":["b-preclinical-models","b-reproducibility","b-translational-valley","b-undruggable-targets","b-ip-collaboration","b-negative-results"],"keyPapers":["paper-abramson-nature"],"journals":[],"dependsOn":[],"notes":[],"steps":[{"era":"1950s-1990s","title":"Screening nature and hoping","description":"The NCI screened tens of thousands of compounds in mouse leukaemias and, from 1990, in a panel of sixty human cell lines. It found the periwinkle alkaloid vincristine, the yew-bark taxane paclitaxel and the antibiotic dactinomycin, and it established the pipeline everyone still uses: cells, then mice, then people. What it could not do was say which people.","refs":["nci","vincristine","paclitaxel","dactinomycin","pdx-models"],"status":"historic"},{"era":"1990s-2015","title":"Targets, structures and high-throughput screens","description":"Cloning the oncogenes gave discovery a target; crystal structures gave it a shape to fit; robotic screening of millions of compounds and later DNA-encoded libraries gave it throughput. Imatinib was the proof. The cost was a generation of drugs that hit their target and did nothing for patients, because the cell-line and xenograft models that selected them did not represent human tumours. Nine in ten oncology drugs entering trials still fail.","refs":["imatinib","high-throughput-screening-libraries","structural-biology-infrastructure","b-preclinical-models","pdx-models"],"status":"historic"},{"era":"2015-2024","title":"Maps of dependency and models closer to the patient","description":"Genome-wide CRISPR knockout screens across a thousand cell lines (DepMap) list which genes each cancer cannot live without, and expose synthetic-lethal pairs such as PRMT5 in MTAP-deleted tumours and WRN in mismatch-repair-deficient ones. Patient-derived organoids keep a tumour's architecture and drug response in a dish; xenograft banks keep it in a mouse; TCGA, GENIE and CPTAC supply the genomes and proteomes to interpret them. The first drugs found this way are now in trials.","refs":["crispr-screens","depmap","synthetic-lethality-approaches","organoids","hub-organoids","pdx-models","champions-oncology","cancer-models","tcga-gdc","genie","cptac","proteomics"],"status":"current"},{"era":"2020-2026","title":"Structure prediction and generative design","description":"AlphaFold turned protein structure into a lookup, and AlphaFold 3 (2024), Boltz and Chai extended it to drug and antibody complexes; RFdiffusion and ESM3 design proteins from scratch. Insilico's generative chemistry produced the first AI-discovered drug to reach phase 2; Isomorphic's first oncology candidate entered trials; Recursion merged with Exscientia to pair image-based biology with design; Xaira launched with over a billion dollars to build discovery around these models. The honest scorecard: faster hit-to-candidate, no approved cancer drug yet.","refs":["alphafold3","boltz","chai-1","chai-discovery","rfdiffusion","esm3","ai-drug-design","chemistry42","insilico-medicine","isomorphic-labs","google-deepmind","recursion","exscientia","phenom-2","xaira-therapeutics","generate-biomedicines"],"status":"current"},{"era":"2015-2026","title":"New modalities as platforms","description":"Discovery is no longer only about small molecules. Degrader and molecular glue platforms remove proteins that cannot be inhibited; ADC linker chemistry (Araris) and bicyclic peptide conjugates (Bicycle) turn a payload into a targeted drug; oligonucleotides silence genes; chemoproteomics finds covalent handles on KRAS. Each platform generates candidates faster than trials can test them, which moves the constraint downstream.","refs":["protac-degrader","molecular-glue-platforms","degrader-antibody-conjugate","araris","bicycle-therapeutics","peptide-drug-conjugate","antisense-sirna","frontier-medicines","sotorasib","adc-generations"],"status":"current"},{"era":"2026-2030","title":"Functional precision medicine","description":"Instead of inferring drug response from genotype, test the drug on the patient's own cells: organoid pharmacotyping in pancreatic cancer, the PARIS organoid screen, tumour fragments kept alive with their vessels, BH3 profiling in leukaemia. The proposal that would make it a field is to grow each trial patient's tumour as organoids and let the results decide which platform arm opens next, with shared reference organoid and xenograft panels so every laboratory tests against the same models.","refs":["functional-drug-testing","organoid-guided-therapy-scale","pdac-organoid-pharmacotyping","sengine","curesponse","bh3-profiling","idea-tr2-organoid-coclinical-arms","idea-tr2-reference-model-panels"],"status":"emerging"},{"era":"2026-2030","title":"Perturbation data at the scale the problem needs","description":"Tahoe-100M measured a hundred million single cells across 1,100 drugs and fifty cancer lines; Arc's Virtual Cell Atlas and State model, Geneformer and scGPT are the attempts to learn from that scale how a cell will respond to a perturbation it has never seen. Rigorous benchmarks show current models barely beat simple baselines on unseen contexts, which is the right kind of bad news: the problem is now measurable. The virtual cell roadmap follows this in detail.","refs":["tahoe-100m","vevo-therapeutics","arc-virtual-cell-atlas","arc-institute","state-arc","geneformer","scgpt","virtual-cell"],"status":"emerging"},{"era":"2030+","title":"In silico first","description":"The long-range bet is that a candidate is designed, its dose chosen and its toxicity screened in silico and on linked human organ chips before the first mouse, and that digital twins reduce the size of the trials that follow. That requires models that generalise, which requires data that reproduce. A funded replication in every cancer biology PhD and a registry for preclinical experiments that did not work are the unglamorous prerequisites.","refs":["idea-bio1-in-silico-trials-dose","idea-bio1-multi-organ-chip-tox","digital-twins-trials","de-novo-protein-design","idea-tr2-phd-replication-year","idea-tr2-preclinical-negative-registry","ai-oncology-roadmap"],"status":"speculative"},{"era":"What sets the pace","title":"Models, reproducibility and the valley of death","description":"Preclinical models still do not predict people, fewer than half of landmark findings reproduce, and most academic discoveries die before anyone tests them in humans because no one funds the step between. Companies hold compound libraries and negative results that would save others years. A shared compound pool for rare cancer researchers and a guaranteed purchase prize for the first drug against a named hard target are two proposals that attack the incentive problem directly.","refs":["b-preclinical-models","b-reproducibility","b-translational-valley","b-ip-collaboration","b-negative-results","b-undruggable-targets","idea-bio2-shared-compound-access-pool","idea-bio1-undruggable-market-commitment"],"status":"current"}],"watch":[]},{"id":"early-detection-roadmap","kind":"roadmap","name":"Early detection roadmap: organ screening → blood tests for many cancers","aka":[],"tldr":"From mammograms and colonoscopies to a single blood draw that might screen for dozens of cancers, with the FDA's first decision imminent.","summary":"Starting from organ-specific screening proven over decades, the Pap smear, mammography, colonoscopy and FIT, PSA and low-dose CT after NLST, this roadmap follows the cfDNA and methylation science behind the CCGA study, Galleri, Cologuard and Epi proColon. The current step covers pivotal trials and first approvals, with NHS-Galleri, PATHFINDER 2, Shield as the first FDA-approved blood test for colorectal screening and GRAIL's PMA filing, leading to FDA and NHS decisions and Medicare coverage. The speculative end is annual multi-analyte blood screening with tissue-of-origin-directed imaging. The route links mammography, MCED, liquid biopsy, methylation profiling, AI in radiology and whole-body MRI, and is pointed to by pancreatic and cervical cancer and the late-detection bottleneck.","asOf":"2026-09-04","links":[{"label":"PATHFINDER: the first prospective test of a multi-cancer blood test in people without symptoms (The Lancet 2023)","url":"https://doi.org/10.1016/S0140-6736(23)01700-2"},{"label":"DETECT-A: a blood test plus PET-CT found treatable cancers in 10,000 women with no symptoms (Science 2020)","url":"https://doi.org/10.1126/science.abb9601"}],"tags":[],"related":["pancreatic-roadmap","colorectal-roadmap","lung-cancer-evidence-roadmap","prostate-roadmap","idea-prostate-metastatic-presentation-as-the-screening-endpoint"],"cancers":["pancreatic","colorectal","lung-cancer","prostate"],"sections":["early-detection"],"technologies":["mammography","mced","liquid-biopsy","methylation-profiling","radiology-ai-screening","whole-body-mri"],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"steps":[{"era":"1943-2011","title":"Organ-specific screening proven","description":"Pap smear (1943), mammography (1970s-80s RCTs), colonoscopy/FIT, PSA (contested), low-dose CT for lung (NLST 2011). Each reduces mortality in its cancer; together they cover under half of cancer deaths.","refs":["mammography","ct"],"status":"historic"},{"era":"2014-2021","title":"cfDNA and methylation science","description":"CCGA study (GRAIL) shows methylation classifiers detect >50 cancers with ~0.5% false positives and predict tissue of origin; Galleri launched as an LDT (2021); Cologuard and Epi proColon establish stool and blood DNA screening.","refs":["methylation-profiling","galleri"],"status":"historic"},{"era":"2021-2026","title":"Pivotal trials and first approvals","description":"NHS-Galleri randomises 140,000; PATHFINDER 2 enrols 35,000; Shield becomes the first FDA-approved blood test for CRC screening (2024) and Medicare covers it; Exact launches Cancerguard as an LDT (2025); GRAIL files PMA (Jan 2026), advisory committee 23 Sep 2026. AI mammography reading validated at scale (MASAI).","refs":["nhs-galleri","pathfinder-2","shield","galleri","radiology-ai-screening","exact-sciences"],"status":"current"},{"era":"2026-2030","title":"Decision and integration","description":"FDA decision on Galleri; NHS decision on rollout; Medicare MCED coverage legislation; integration with risk-based screening (Mirai, polygenic scores); management pathways for positive signals with no imaging correlate; cost-effectiveness and overdiagnosis debates.","refs":["mced","ppv","stage-shift"],"status":"emerging"},{"era":"2030+","title":"Speculative","description":"Annual multi-analyte blood screening for adults over 50 with tissue-of-origin-directed imaging; MCED-detected pancreatic and ovarian cancers at resectable stages; risk-adapted intervals from AI; proteomic and fragmentomic layers improving stage I sensitivity.","refs":["proteomics","whole-body-mri"],"status":"speculative"}],"watch":[]},{"id":"epigenetics-roadmap","kind":"roadmap","name":"Epigenetic therapy roadmap: loosening silenced genes → mutation-specific enzymes → editing the epigenome","aka":[],"tldr":"Epigenetic drugs change how genes are read rather than the genes themselves. They started as gentle chemotherapy for blood cancers and are becoming precise drugs against the enzymes and scaffolds that particular cancers depend on.","summary":"The first epigenetic drugs were blunt: hypomethylating agents (azacitidine, decitabine) that strip chemical off-switches from DNA and HDAC inhibitors that loosen its packaging. They earned their place in myelodysplastic syndromes, acute myeloid leukaemia and T-cell lymphomas, and azacitidine plus venetoclax became the standard for older patients with AML (VIALE-A). The second generation is mutation-specific: IDH1 and IDH2 inhibitors for leukaemia, bile duct cancer and low-grade glioma (vorasidenib), the EZH2 inhibitor tazemetostat for epithelioid sarcoma and follicular lymphoma, and the menin inhibitors revumenib (2024) and ziftomenib (2025) for leukaemias driven by KMT2A rearrangements or NPM1 mutations.\n\nThe frontier is solid tumours and the transcriptional machinery itself: EZH2 inhibition to re-sensitise prostate cancer to hormone therapy (MEVPRO-1), PRMT5 inhibitors for the tenth of tumours lacking MTAP, degraders that remove transcription factors previously thought undruggable, and epigenetic editing that silences a gene durably without cutting DNA.\n\nThe pace is set by the undruggable nature of many epigenetic targets, by resistance that emerges through the same plasticity the drugs exploit, and by the difficulty of finding a biomarker for a mechanism that is not a mutation.","asOf":"2026-09-10","links":[{"label":"Baylin and Jones, Epigenetic determinants of cancer (Cold Spring Harbor Perspectives 2016)","url":"https://doi.org/10.1101/cshperspect.a019505"},{"label":"AUGMENT-101: revumenib (Nature 2023)","url":"https://doi.org/10.1038/s41586-023-05812-3"}],"tags":[],"related":["idea-bio1-fusion-tf-degraders","k36-therapeutics","arpeggio-bio","morphosys","chipscreen","paper-indigo-nejm-2023","paper-viale-a-venetoclax-azacitidine-nejm-2020","paper-augment-101-revumenib-menin-nature-2023","paper-hallmarks-new-dimensions-cancer-discov-2022","targeted-therapy-roadmap"],"cancers":[],"sections":["epigenetics"],"technologies":["epigenetic-drugs","epigenetic-editing","protac-degrader","methylation-profiling"],"targets":["menin","ezh2","idh","hdac","prmt5-mtap"],"drugs":["azacitidine","decitabine","decitabine-cedazuridine","vorinostat","romidepsin","belinostat","panobinostat","tucidinostat","ivosidenib","enasidenib","olutasidenib","vorasidenib","tazemetostat","revumenib","ziftomenib","venetoclax","mevrometostat","golcadomide","eprenetapopt"],"companies":[],"institutions":[],"pathways":["epigenetic-reprogramming","transcription-addiction","menin-kmt2a","idh-2hg","swi-snf-chromatin","myc"],"terms":["hma","nonmutational-epigenetic-reprogramming"],"trials":["viale-a","agile","augment-101","komet-001","mevpro-1","claridhy","golseek-1"],"people":["stephen-baylin","pierre-fenaux","courtney-dinardo","eytan-stein","ghayas-issa","ingo-mellinghoff","christopher-vakoc"],"bottlenecks":["b-undruggable-targets","b-resistance","b-tumor-heterogeneity","b-biomarker-validation"],"keyPapers":["paper-baylin-cold-spring-harb-perspect-biol"],"journals":[],"dependsOn":[],"notes":[],"steps":[{"era":"1980s-2006","title":"Silenced genes and the drugs that loosen them","description":"Baylin and others showed that abnormal DNA methylation silences tumour-suppressor genes as effectively as a mutation, and that the silencing can be reversed. Azacitidine, an old chemotherapy given at low dose, was approved for myelodysplastic syndromes in 2004 and shown to extend survival (AZA-001); decitabine followed. Vorinostat (2006) was the first HDAC inhibitor, loosening the packaging of DNA in cutaneous T-cell lymphoma.","refs":["stephen-baylin","epigenetic-reprogramming","azacitidine","decitabine","hma","pierre-fenaux","vorinostat","hdac"],"status":"historic"},{"era":"2009-2016","title":"The HDAC class finds its niche, and its limits","description":"Romidepsin and belinostat joined vorinostat in T-cell lymphomas, tucidinostat became China's first original epigenetic drug, and panobinostat was approved in myeloma in 2015 then withdrawn in 2021 when its confirmatory trial was not done. Broad HDAC inhibition proved too toxic and too unselective for solid tumours, which pushed the field towards enzymes that particular cancers depend on.","refs":["romidepsin","belinostat","tucidinostat","chipscreen","panobinostat","epigenetic-drugs"],"status":"historic"},{"era":"2017-2020","title":"Mutation-specific epigenetic drugs","description":"Mutant IDH1 and IDH2 produce a metabolite that scrambles how genes are read; enasidenib (2017) and ivosidenib (2018) block the mutant enzymes, and AGILE showed ivosidenib plus azacitidine sharply extends survival in newly diagnosed IDH1-mutant AML. ClarIDHy brought ivosidenib to bile duct cancer. Tazemetostat (2020) was the first EZH2 inhibitor, for epithelioid sarcoma and follicular lymphoma, until Ipsen withdrew it worldwide in March 2026 over secondary blood cancers. For the first time an epigenetic drug had a molecular biomarker.","refs":["ivosidenib","enasidenib","olutasidenib","agile","claridhy","idh","idh-2hg","tazemetostat","ezh2"],"status":"current"},{"era":"2020-2026","title":"Hypomethylating agents as the backbone","description":"VIALE-A made azacitidine plus venetoclax the standard for older patients with AML who cannot have intensive chemotherapy, doubling remission rates; the hypomethylating agent primes the leukaemia for the BCL-2 inhibitor. Oral azacitidine maintenance and oral decitabine-cedazuridine took the class out of the infusion chair. Every new AML drug is now tested on top of this backbone.","refs":["viale-a","venetoclax","azacitidine","decitabine-cedazuridine","courtney-dinardo","paper-viale-a-venetoclax-azacitidine-nejm-2020"],"status":"current"},{"era":"2023-2026","title":"Menin inhibitors and the first brain tumour epigenetic drug","description":"Certain leukaemias keep their genes switched on through a scaffold protein, menin. Revumenib (2024, AUGMENT-101) created the class for KMT2A-rearranged and NPM1-mutant acute leukaemias and ziftomenib (November 2025, KOMET-001) followed, both as once-daily pills; the resistance mutations in menin itself appeared within the first trials. Vorasidenib (INDIGO, 2023) became the first targeted therapy for IDH-mutant low-grade glioma, delaying radiation and chemotherapy by years.","refs":["revumenib","ziftomenib","augment-101","komet-001","menin","menin-kmt2a","eytan-stein","ghayas-issa","vorasidenib","ingo-mellinghoff","paper-indigo-nejm-2023","paper-augment-101-revumenib-menin-nature-2023"],"status":"current"},{"era":"2026-2030","title":"Solid tumours and the transcriptional machinery","description":"Mevrometostat pairs EZH2 inhibition with enzalutamide in three phase 3 prostate trials (MEVPRO-1). PRMT5 inhibitors exploit the loss of MTAP in about a tenth of all tumours. Golcadomide degrades two lymphoma transcription factors and is in a first-line phase 3 (GOLSEEK-1). Degraders for the fusion transcription factors that drive childhood sarcomas, drugs for broken SWI/SNF complexes, NSD2 inhibitors and BET inhibitors are all in the clinic. Eprenetapopt's failure to refold mutant p53 is the reminder that a compelling mechanism is not a drug.","refs":["mevrometostat","mevpro-1","prmt5-mtap","golcadomide","golseek-1","idea-bio1-fusion-tf-degraders","swi-snf-chromatin","k36-therapeutics","morphosys","eprenetapopt","transcription-addiction","myc","christopher-vakoc"],"status":"emerging"},{"era":"2030+","title":"Writing to the epigenome","description":"Epigenetic editing uses a targeting protein fused to a methylation writer to switch a chosen gene off durably without cutting DNA; it is in first human trials outside oncology and its cancer use depends on solving tumour delivery. In the other direction, hypomethylating agents make tumours more visible to the immune system by re-expressing silenced antigens, an idea being tested in combination with checkpoint blockade. AI models trained on RNA data are hunting drugs against transcription factors directly.","refs":["epigenetic-editing","nonmutational-epigenetic-reprogramming","arpeggio-bio","paper-hallmarks-new-dimensions-cancer-discov-2022","frontier-2035"],"status":"speculative"},{"era":"What sets the pace","title":"Undruggable targets, plasticity and biomarkers","description":"Many epigenetic regulators have no pocket for a small molecule, which is why degraders and glues matter here more than anywhere. The same plasticity the drugs exploit lets tumours change state to escape them. And because the mechanism is not a mutation, finding the patients who will respond is harder: methylation profiling and expression signatures, not gene panels, are the likely biomarkers.","refs":["b-undruggable-targets","b-resistance","b-tumor-heterogeneity","b-biomarker-validation","protac-degrader","methylation-profiling"],"status":"current"}],"watch":[]},{"id":"gallbladder-cancer-roadmap","kind":"roadmap","name":"Gallbladder cancer roadmap: from a chance finding at gallstone surgery to a disease with its own trials","aka":["Gallbladder carcinoma roadmap","Biliary tract cancer roadmap (gallbladder)"],"tldr":"Gallbladder cancer is usually found by accident when a gallbladder is removed for stones, and for most of its history the only treatment was a bigger operation. This roadmap follows the disease from the first cholecystectomy in 1882, through staging by depth and the borrowed chemotherapy standards of 2010 and 2019, to immunotherapy and HER2 drugs, and lists the trial readouts to watch to 2030.","summary":"Gallbladder cancer is the most common biliary tract cancer worldwide but rare in the countries that fund most trials, so its evidence has been borrowed: gemcitabine-cisplatin from ABC-02 (2010), adjuvant capecitabine from BILCAP (2019), durvalumab and pembrolizumab from TOPAZ-1 and KEYNOTE-966 (2022 to 2023) all came from mixed biliary populations in which gallbladder cancer was a subgroup. Its own evidence is surgical and observational: Nevin's staging by depth of invasion (1976), the residual disease series that justify re-resection of incidental cancer (Pawlik 2007), the timing window (Ethun 2017) and the T2a/T2b split that entered AJCC staging in 2017 (Shindoh 2015).\n\nTwo things are changing. HER2 is the first target where gallbladder cancer leads: about one in ten to one in five tumours are HER2-positive, HERIZON-BTC-01 produced a 41 percent response rate and zanidatamab was approved in 2024 (US), 2025 (EU, conditional) and 2026 (UK: MHRA in February, NICE TA1153 in May), with HERIZON-BTC-302 testing it first line. And the disease now has randomised trials of its own: OPT-IN and GAIN for chemotherapy before re-resection of incidental cancer, POLCAGB for radiotherapy before surgery in locally advanced disease, and adjuvant trials (ACTICCA-1, ARTEMIDE-Biliary01) large enough to report gallbladder subgroups.\n\nPrevention is the other half of the story. Chile's 2006 national prophylactic cholecystectomy programme, India's regional burden and the fourfold risk from chronic typhoid carriage are the levers in high-incidence regions, and the 2022 European polyp guideline is the closest thing to screening elsewhere; the Kaiser Permanente cohort suggests polyp surveillance finds little. The UK sits in the low-incidence world, with the CAPBIL study (2026) as its first national picture of practice; the NHS-specific gaps are named on the UK and NHS page for gallbladder cancer.","asOf":"2026-09-24","links":[{"label":"Hardy: Carl Langenbuch and the Lazarus Hospital, the first cholecystectomy in July 1882 (Aust N Z J Surg 1993)","url":"https://europepmc.org/article/MED/8466463"},{"label":"Traverso: Carl Langenbuch and the first cholecystectomy (Am J Surg 1976)","url":"https://europepmc.org/article/MED/782269"},{"label":"Glenn and Hays: the scope of radical surgery in malignant tumours of the extrahepatic biliary tract (Surg Gynecol Obstet 1954)","url":"https://europepmc.org/article/MED/13205425"},{"label":"Nevin et al.: carcinoma of the gallbladder, staging, treatment and prognosis (Cancer 1976)","url":"https://europepmc.org/article/MED/1247951"},{"label":"Piehler and Crichlow: primary carcinoma of the gallbladder, 6,222 reported patients (Surg Gynecol Obstet 1978)","url":"https://europepmc.org/article/MED/362580"},{"label":"Pawlik et al.: residual disease at re-resection for incidental gallbladder carcinoma (J Gastrointest Surg 2007)","url":"https://europepmc.org/article/MED/17846848"},{"label":"ABC-02: cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer (NEJM 2010)","url":"https://europepmc.org/article/MED/20375404"},{"label":"Shindoh et al.: tumour location predicts survival in T2 gallbladder cancer (Ann Surg 2015)","url":"https://europepmc.org/article/MED/24854451"},{"label":"Chun, Pawlik, Vauthey: AJCC 8th edition, pancreas and hepatobiliary cancers (Ann Surg Oncol 2018)","url":"https://europepmc.org/article/MED/28752469"},{"label":"Soreide et al.: systematic review of incidental gallbladder cancer management (Br J Surg 2019)","url":"https://europepmc.org/article/MED/30582640"},{"label":"ABC-06: second-line FOLFOX versus active symptom control (Lancet Oncol 2021)","url":"https://europepmc.org/article/MED/33798493"},{"label":"HERIZON-BTC-01: zanidatamab in HER2-amplified biliary tract cancer (Lancet Oncol 2023)","url":"https://europepmc.org/article/MED/37276871"},{"label":"TOPAZ-1 three-year overall survival update (J Hepatol 2025)","url":"https://europepmc.org/article/MED/40381735"},{"label":"ESMO Clinical Practice Guideline: biliary tract cancer (Ann Oncol 2023)","url":"https://europepmc.org/article/MED/36372281"},{"label":"Joint European guideline on gallbladder polyps (Eur Radiol 2022)","url":"https://europepmc.org/article/MED/34918177"},{"label":"Samaniego et al.: is it time to modify Chile's GES preventive cholecystectomy programme (Rev Med Chile 2024)","url":"https://europepmc.org/article/MED/40052976"},{"label":"CAPBIL: management of incidental gallbladder cancer in the UK (Br J Surg 2026)","url":"https://europepmc.org/article/MED/42013358"},{"label":"ClinicalTrials.gov NCT02170090","url":"https://clinicaltrials.gov/study/NCT02170090"},{"label":"ClinicalTrials.gov NCT04559139","url":"https://clinicaltrials.gov/study/NCT04559139"},{"label":"ClinicalTrials.gov NCT03673072","url":"https://clinicaltrials.gov/study/NCT03673072"},{"label":"ClinicalTrials.gov NCT02867865","url":"https://clinicaltrials.gov/study/NCT02867865"},{"label":"ClinicalTrials.gov NCT06109779","url":"https://clinicaltrials.gov/study/NCT06109779"},{"label":"ClinicalTrials.gov NCT06282575","url":"https://clinicaltrials.gov/study/NCT06282575"},{"label":"ClinicalTrials.gov NCT03875235","url":"https://clinicaltrials.gov/study/NCT03875235"},{"label":"ClinicalTrials.gov NCT04482309","url":"https://clinicaltrials.gov/study/NCT04482309"}],"tags":["gallbladder","biliary","roadmap"],"related":["immunotherapy-roadmap","chemotherapy-roadmap","surgery-roadmap","prevention-roadmap","early-detection-roadmap","ctdna-tests","gemcis-plus-io-btc","idea-gbc-report-gallbladder-separately-in-biliary-trials","idea-gbc-national-incidental-cancer-pathway","idea-gbc-t1b-simple-cholecystectomy-prospective-study","idea-gbc-t2a-spare-liver-resection-trial","idea-gbc-reflex-her2-testing-advanced-biliary","idea-gbc-risk-targeted-ultrasound-in-high-incidence-regions","idea-gbc-prophylactic-cholecystectomy-targeted-and-evaluated","idea-gbc-typhoid-carrier-cholecystectomy-or-surveillance","idea-gbc-ctdna-residual-disease-guided-adjuvant-trial","idea-gbc-neoadjuvant-for-high-risk-incidental-cancer","idea-gbc-randomised-adjuvant-chemoradiation-r1-node-positive","idea-gbc-burden-to-funding-audit-and-dedicated-call"],"cancers":["gallbladder","biliary-tract-cancer","cholangiocarcinoma","extrahepatic-cholangiocarcinoma"],"sections":["surgery","chemotherapy","immunotherapy","targeted-therapy","prevention","early-detection"],"technologies":["checkpoint-inhibitor","bispecific-antibody","cytotoxic-chemotherapy","liquid-biopsy","mrd-testing","ultrasound"],"targets":["her2"],"drugs":["gemcitabine-cisplatin","capecitabine","durvalumab","pembrolizumab","folfox","zanidatamab","trastuzumab-deruxtecan","rilvegostomig","signatera"],"companies":["astrazeneca","merck","jazz","zymeworks","ecog-acrin","swog"],"institutions":["cruk","the-christie","tata-memorial","esmo","nci"],"pathways":[],"terms":["incidental-gallbladder-cancer","radical-cholecystectomy","t2a-versus-t2b","gallbladder-polyp","prophylactic-cholecystectomy","tnm-staging","neoadjuvant-adjuvant","chemoradiation","ctdna","mrd","her2-positive"],"trials":["abc-02","bilcap","abc-06","topaz-1","keynote-966","herizon-btc-01","herizon-btc-302","destiny-pantumor02","nifty","naliricc","swog-s0809","opt-in","gain-igbc","polcagb","acticca-1","nct06109779"],"people":["juan-valle","john-primrose","angela-lamarca"],"bottlenecks":["b-rare-cancers","b-early-detection","b-prevention-adoption","b-trial-enrolment","b-biomarker-validation","b-dormancy-mrd","b-care-fragmentation","b-funding-allocation"],"keyPapers":["paper-abc-02-gemcitabine-cisplatin-nejm-2010","paper-bilcap-lancet-oncol-2019","paper-topaz-1-nejm-evidence-2022","paper-keynote-966-lancet-2023","paper-harding-lancet-oncol","paper-destiny-pantumor02-jco-2024","paper-abc-06-folfox-second-line-lancet-oncol-2021","paper-esmo-biliary-tract-cancer-guideline-ann-oncol-2023","paper-shindoh-t2-gallbladder-cancer-tumour-location-ann-surg-2015","paper-pawlik-incidental-gallbladder-cancer-residual-disease-jgs-2007","paper-roa-gallbladder-cancer-primer-nat-rev-dis-primers-2022","paper-mcclements-capbil-incidental-gallbladder-cancer-bjs-2026","paper-who-2019-digestive-system-tumours-nagtegaal-histopathology-2020"],"journals":[],"dependsOn":[],"notes":["How this stays current: scripts/roadmap-watch.ts (npm run roadmap:watch) checks each trial here against ClinicalTrials.gov and searches Europe PMC for new papers on the acronyms since asOf. Anything it prints that this page does not say is an edit to make; then move asOf forward.","Dates in 'What to watch' are quoted from the registry as read on 2026-09-24 and are not predictions; estimated completion dates move.","UK and NHS specifics (referral routes, NICE positions, Cancer Drugs Fund status, cholecystectomy histology policy) are held on the UK and NHS page for gallbladder cancer and are not restated here."],"steps":[{"era":"1882-1954","title":"Surgery arrives, and the cancer is found by accident","description":"Carl Langenbuch performed the first cholecystectomy at the Lazarus Hospital in Berlin in July 1882, an operation for gallstones that would become one of the commonest in the world and the way most gallbladder cancers come to light. In 1954 Glenn and Hays set out the scope of radical surgery for cancers of the extrahepatic biliary tract, the origin of the radical cholecystectomy: gallbladder, liver bed and regional lymph nodes removed together. For the next half century that operation was the whole of treatment.","refs":["radical-cholecystectomy","incidental-gallbladder-cancer","surgery","gallbladder"],"status":"historic"},{"era":"1976-2017","title":"Staging by depth, then by side","description":"Nevin and colleagues staged 66 cases by depth of invasion in 1976 and noted that essentially all had been found incidentally at gallstone surgery; Piehler and Crichlow's 1978 review of 6,222 reported patients described an elderly, mostly female population presenting either as stone disease or as incurable cancer. Depth of invasion became the T category of TNM. In 2015 Shindoh and colleagues showed in 437 patients that T2 tumours on the hepatic side did far worse than those on the peritoneal side (five-year survival 42.6 versus 64.7 percent), and the AJCC eighth edition of 2017 split T2 into T2a and T2b, the one staging change that came from gallbladder cancer's own anatomy.","refs":["paper-nevin-gallbladder-carcinoma-staging-cancer-1976","paper-shindoh-t2-gallbladder-cancer-tumour-location-ann-surg-2015","paper-chun-ajcc-8th-edition-hepatobiliary-aso-2018","paper-giannis-ajcc8-gallbladder-staging-validation-cancers-2021","t2a-versus-t2b","tnm-staging"],"status":"historic"},{"era":"2007-2026","title":"The incidental cancer pathway: re-resect from T1b, but who, when and how much","description":"Pawlik and colleagues found residual disease in 46 percent of 115 re-resection specimens in 2007, and the rule that T1b or deeper incidental cancers go back to theatre followed. Ethun's ten-centre analysis (2017) put the best interval at four to eight weeks; a 2026 individual patient data meta-analysis found timing made no measurable difference. The Dutch registry showed only 24 percent of eligible patients were re-resected (2020); the UK CAPBIL study (2026) found 67.7 percent had liver resection across 24 centres. Whether T1b tumours need the second operation at all (Kim 2018: five-year disease-specific survival 93.7 versus 95.5 percent) and whether peritoneal-side T2a tumours need the liver resected are the surgical questions still open.","refs":["paper-pawlik-incidental-gallbladder-cancer-residual-disease-jgs-2007","paper-ethun-re-resection-timing-incidental-gallbladder-cancer-jama-surg-2017","paper-selvakumar-revision-surgery-timing-ipd-meta-analysis-hpb-2026","paper-de-savornin-lohman-re-resection-incidental-gallbladder-cancer-aso-2020","paper-mcclements-capbil-incidental-gallbladder-cancer-bjs-2026","paper-kim-t1b-gallbladder-cancer-international-jhbps-2018","paper-kang-t2-gallbladder-cancer-location-meta-analysis-jcm-2021","paper-soreide-incidental-gallbladder-cancer-review-bjs-2019","incidental-gallbladder-cancer","radical-cholecystectomy","idea-gbc-national-incidental-cancer-pathway","idea-gbc-t1b-simple-cholecystectomy-prospective-study","idea-gbc-t2a-spare-liver-resection-trial"],"status":"current"},{"era":"2010","title":"A borrowed chemotherapy standard","description":"ABC-02, a Cancer Research UK trial of 410 patients with advanced biliary tract cancer including gallbladder cancer, showed in 2010 that gemcitabine plus cisplatin lengthened survival from 8.1 to 11.7 months (hazard ratio 0.64). It gave gallbladder cancer its first drug standard and the control arm for every first-line trial since, but the gallbladder subgroup has never had a trial of its own in this setting.","refs":["abc-02","paper-abc-02-gemcitabine-cisplatin-nejm-2010","gemcitabine-cisplatin","cruk","juan-valle","chemotherapy"],"status":"historic"},{"era":"2017-2021","title":"Adjuvant capecitabine and second-line FOLFOX, from UK trials","description":"BILCAP (reported 2017, published 2019) randomised 447 resected biliary cancers to six months of capecitabine or observation; the intention-to-treat result missed significance (hazard ratio 0.81, p=0.097) yet capecitabine became the adjuvant standard in the UK, Europe and the United States. ABC-06 (2019, published 2021) showed second-line FOLFOX added about a month of median survival and doubled one-year survival (25.9 versus 11.4 percent). NIFTY (2021) added liposomal irinotecan as a Korean option that the German NALIRICC trial later failed to reproduce. The UK CAPBIL surgical cohort (2026) saw no adjuvant benefit in matched analysis, so ACTICCA-1's readout matters.","refs":["bilcap","paper-bilcap-lancet-oncol-2019","abc-06","paper-abc-06-folfox-second-line-lancet-oncol-2021","nifty","paper-nifty-liposomal-irinotecan-lancet-oncol-2021","naliricc","paper-mcclements-capbil-surgical-outcomes-gallbladder-cancer-hpb-2026","capecitabine","folfox","john-primrose","angela-lamarca","the-christie"],"status":"current"},{"era":"2008-2015","title":"Radiotherapy: one single-arm trial and a nomogram","description":"SWOG S0809 (accrued 2008 to 2014, published 2015) gave 79 patients with resected gallbladder or extrahepatic bile duct cancer gemcitabine-capecitabine then chemoradiation: two-year survival was 65 percent and, unusually, no worse after a positive margin (60 percent) than a clear one (67 percent). With Wang's 2011 SEER-Medicare nomogram it is the basis of the US option of chemoradiation after node-positive or margin-positive resection. No randomised trial followed and UK practice rarely uses it; POLCAGB in Mumbai is testing radiotherapy before surgery in locally advanced disease instead.","refs":["swog-s0809","paper-swog-s0809-adjuvant-chemoradiation-jco-2015","paper-wang-adjuvant-chemoradiotherapy-nomogram-gallbladder-cancer-jco-2011","polcagb","chemoradiation","radiotherapy","swog","idea-gbc-randomised-adjuvant-chemoradiation-r1-node-positive"],"status":"historic"},{"era":"2022-2025","title":"Immunotherapy joins chemotherapy","description":"TOPAZ-1 (2022) added durvalumab to gemcitabine-cisplatin and KEYNOTE-966 (2023) added pembrolizumab; both trials were positive with small median gains and a growing tail of long survivors. The TOPAZ-1 three-year update (2025) reported 36-month survival of 14.6 versus 6.9 percent and extended long-term survivors in 17.0 versus 8.7 percent. Gallbladder cancer was a subgroup in both trials; US and Chilean immunogenomic profiling (2025) shows its immune environment differs by population even where mutations do not.","refs":["topaz-1","paper-topaz-1-nejm-evidence-2022","paper-topaz-1-three-year-survival-j-hepatol-2025","keynote-966","paper-keynote-966-lancet-2023","gemcis-plus-io-btc","durvalumab","pembrolizumab","paper-zhu-population-specific-immunogenomics-gallbladder-cancer-mod-pathol-2025","checkpoint-inhibitor","immunotherapy","idea-gbc-report-gallbladder-separately-in-biliary-trials"],"status":"current"},{"era":"2017-2025","title":"HER2: the first target where gallbladder cancer leads","description":"The 2017 Manchester meta-analysis put HER2 overexpression at about 20 percent in extrahepatic biliary cancers against 5 percent in intrahepatic tumours; a 2026 resected series using the trial definition found 9.4 percent of gallbladder cancers positive, often heterogeneous. HERIZON-BTC-01 (2023) gave zanidatamab to 80 HER2-positive patients after chemotherapy with a 41.3 percent confirmed response rate, and the FDA granted accelerated approval in November 2024, the European Commission conditional approval in June 2025, the MHRA approval in February 2026 and NICE a recommendation in May 2026 (TA1153); DESTINY-PanTumor02 gave trastuzumab deruxtecan a tumour-agnostic HER2 3+ route. HERIZON-BTC-302 is testing zanidatamab first line with an estimated primary completion of December 2028. Testing uptake, not drug supply, is now the limiting step.","refs":["paper-galdy-her2-biliary-tract-meta-analysis-cancer-metastasis-rev-2017","paper-angerilli-her2-ihc-cish-biliary-hum-pathol-2026","herizon-btc-01","paper-harding-lancet-oncol","herizon-btc-302","destiny-pantumor02","paper-destiny-pantumor02-jco-2024","zanidatamab","trastuzumab-deruxtecan","her2","her2-positive","jazz","idea-gbc-reflex-her2-testing-advanced-biliary"],"status":"current"},{"era":"2006-2026","title":"Prevention where the burden is: Chile, India and typhoid","description":"Chile's Explicit Health Guarantees programme has guaranteed cholecystectomy for gallstones at ages 35 to 49 since 2006, issuing 284,139 notifications by 2024; mortality has fallen, but it was falling before the programme and uptake does not follow incidence. India carries about a tenth of world cases, concentrated in the Gangetic belt, and Tata Memorial's registry saw 60 percent of 1,950 patients arrive with metastases. Chronic Salmonella Typhi carriage carries a roughly fourfold risk in two meta-analyses. Elsewhere the 2022 European polyp guideline is the only screening-like pathway, and the Kaiser Permanente cohort (2020) found people with polyps no more likely to develop the cancer than people without.","refs":["prophylactic-cholecystectomy","paper-samaniego-chile-ges-programme-evaluation-rev-med-chile-2024","paper-mardones-frenz-chile-ges-mortality-rev-med-chile-2019","paper-cid-chile-programme-gallbladder-cancer-mortality-am-j-epidemiol-2024","paper-dutta-gallbladder-cancer-epidemiology-india-chin-clin-oncol-2019","paper-patkar-tata-memorial-gallbladder-cancer-registry-cancer-epidemiol-2025","paper-koshiol-salmonella-typhi-gallbladder-cancer-cancer-med-2016","paper-nagaraja-eslick-typhi-carrier-gallbladder-cancer-meta-analysis-apt-2014","paper-gallbladder-polyp-joint-guideline-eur-radiol-2022","paper-szpakowski-gallbladder-polyps-20-year-cohort-jama-netw-open-2020","gallbladder-polyp","tata-memorial","prevention","idea-gbc-risk-targeted-ultrasound-in-high-incidence-regions","idea-gbc-prophylactic-cholecystectomy-targeted-and-evaluated","idea-gbc-typhoid-carrier-cholecystectomy-or-surveillance"],"status":"current"},{"era":"2026-2030","title":"What the registry says is coming","description":"For the first time gallbladder cancer has randomised trials that ask its own questions. OPT-IN (ECOG-ACRIN, phase 2/3, estimated primary completion July 2028) tests chemotherapy before re-resection of incidental cancer; GAIN closed in October 2024 with 68 of 333 planned patients and awaits publication; POLCAGB (Tata Memorial) compares chemoradiation with chemotherapy before surgery in locally advanced disease. ACTICCA-1 (789 patients, estimated primary completion December 2025) and ARTEMIDE-Biliary01 (760, January 2029) will say whether gemcitabine-cisplatin or added immunotherapy beats capecitabine after surgery, and HERIZON-BTC-302 whether HER2-positive patients should get zanidatamab from the start. Residual disease blood tests are prognostic after biliary resection (hazard ratios of 16 and 26 in two 2025 to 2026 cohorts) but no trial yet acts on them.","refs":["opt-in","gain-igbc","polcagb","acticca-1","nct06109779","herizon-btc-302","paper-malla-ctdna-resected-biliary-tract-cancer-esmo-gi-onc-2026","paper-yu-ctdna-early-recurrence-biliary-tract-cancer-jco-po-2025","mrd-testing","liquid-biopsy","idea-gbc-ctdna-residual-disease-guided-adjuvant-trial","idea-gbc-neoadjuvant-for-high-risk-incidental-cancer"],"status":"emerging"},{"era":"What sets the pace","title":"Under-studied relative to burden","description":"Gallbladder cancer has been called a rare tumour about which knowledge is scant (2004) and an understudied disease (2025) by successive generations of researchers. The reasons are structural: it is rare where trials are funded and common where they are not; most cases are found incidentally and treated by surgeons rather than oncologists; and it is pooled with bile duct cancer in every drug trial, so its results are subgroups. Whole-exome work across five countries (2026) shows the biology itself differs by population. Separate reporting, a burden-to-funding audit and national incidental cancer pathways are the levers this page proposes; the UK-specific gaps are set out on the UK and NHS page for gallbladder cancer.","refs":["paper-wistuba-gazdar-gallbladder-cancer-lessons-nat-rev-cancer-2004","paper-roa-gallbladder-cancer-primer-nat-rev-dis-primers-2022","paper-garate-calderon-gallbladder-cancer-worldwide-exome-ebiomedicine-2026","b-rare-cancers","b-funding-allocation","b-trial-enrolment","idea-gbc-burden-to-funding-audit-and-dedicated-call","idea-gbc-report-gallbladder-separately-in-biliary-trials","idea-gbc-national-incidental-cancer-pathway"],"status":"current"}],"watch":[{"item":"ACTICCA-1 primary completion: adjuvant gemcitabine-cisplatin vs capecitabine after resection of cholangiocarcinoma and muscle-invasive gallbladder cancer (789 patients; status active, not recruiting)","expected":"2025-12","source":"https://clinicaltrials.gov/study/NCT02170090","refs":["acticca-1","bilcap","capecitabine","gemcitabine-cisplatin"]},{"item":"GAIN: primary publication of the closed German trial of neoadjuvant gemcitabine-cisplatin before re-resection of incidental gallbladder cancer (completed 10 October 2024 with 68 participants)","expected":"2024-10-10","source":"https://clinicaltrials.gov/study/NCT03673072","refs":["gain-igbc","incidental-gallbladder-cancer"]},{"item":"POLCAGB primary completion: neoadjuvant chemoradiation vs chemotherapy in locally advanced gallbladder cancer (124 participants; study completion listed as 10 September 2027)","expected":"2025-09-10","source":"https://clinicaltrials.gov/study/NCT02867865","refs":["polcagb","chemoradiation"]},{"item":"TOPAZ-1 study completion on the registry (durvalumab plus gemcitabine-cisplatin, first line)","expected":"2027-05-16","source":"https://clinicaltrials.gov/study/NCT03875235","refs":["topaz-1","durvalumab"]},{"item":"DESTINY-PanTumor02 study completion (trastuzumab deruxtecan in HER2-expressing tumours including biliary)","expected":"2027-03-23","source":"https://clinicaltrials.gov/study/NCT04482309","refs":["destiny-pantumor02","trastuzumab-deruxtecan"]},{"item":"OPT-IN (EA2197) primary completion: perioperative vs adjuvant chemotherapy for incidental gallbladder cancer (186 estimated participants)","expected":"2028-07-01","source":"https://clinicaltrials.gov/study/NCT04559139","refs":["opt-in","incidental-gallbladder-cancer"]},{"item":"HERIZON-BTC-302 primary completion: first-line zanidatamab with standard of care in HER2-positive biliary tract cancer (286 estimated participants)","expected":"2028-12-01","source":"https://clinicaltrials.gov/study/NCT06282575","refs":["herizon-btc-302","zanidatamab","her2"]},{"item":"ARTEMIDE-Biliary01 primary completion: adjuvant rilvegostomig plus chemotherapy after resection of biliary tract cancer (760 participants)","expected":"2029-01-02","source":"https://clinicaltrials.gov/study/NCT06109779","refs":["nct06109779","rilvegostomig"]},{"item":"Chile: a redesign or formal evaluation of the GES preventive cholecystectomy programme, as its 2024 evaluation recommends; no date in the sources read","source":"https://europepmc.org/article/MED/40052976","refs":["prophylactic-cholecystectomy"]},{"item":"A trial that acts on a positive residual disease blood test after biliary resection; none found on ClinicalTrials.gov or Europe PMC on 24 September 2026","source":"https://europepmc.org/article/MED/42583118","refs":["mrd-testing","idea-gbc-ctdna-residual-disease-guided-adjuvant-trial"]}]},{"id":"global-access-roadmap","kind":"roadmap","name":"Global access and affordability roadmap: essential medicines and generics → biosimilars and frugal trials → reliance, pooling and homegrown innovation","aka":[],"tldr":"Seven in ten cancer deaths happen in countries with almost no cancer care, and even rich systems cannot afford every new drug. The roadmap is the set of levers that already work, from generics and biosimilars to trials that cut the dose, and the ones being built: regulators trusting each other's reviews, pooled purchasing, and drugs and cell therapies made where patients live.","summary":"The first levers were policy: the WHO Essential Medicines List, generic manufacturing in India, and compulsory licensing when a patent priced a drug out of reach (Natco v Bayer, 2012). Biosimilars of trastuzumab and rituximab, on the market since 2017, cut the price of HER2 and lymphoma treatment by large fractions, and India's National Cancer Grid showed that pooled procurement across hundreds of hospitals lowers prices further.\n\nThe second lever is frugal evidence. Tata Memorial's trials showed that a twentieth of a nivolumab dose added to cheap metronomic chemotherapy improves survival in head and neck cancer, that oral metronomic tablets match intravenous cisplatin, and that a single cheap progesterone injection before breast surgery helps; INTERLACE, PERSEPHONE and FAST-Forward showed that cheaper schedules of existing treatments are as good. India and China now develop their own: India's first CAR-T (NexCAR19) at a fraction of the Western price, an Indian HPV vaccine, and Chinese PD-1 antibodies and ADCs that have gone from domestic approval to beating Western standards head to head.\n\nThe next levers are institutional: regulators accepting each other's reviews (Project Orbis, reliance pathways), WHO prequalification and pooled demand for biosimilars, patent pools for essential cancer drugs, public cell-therapy manufacturing, pooled procurement of radiotherapy, and prices anchored to measured clinical benefit. The pace is set by pricing power, regulatory divergence, workforce, and the near-absence of pain relief where most people die of cancer.","asOf":"2026-09-10","links":[{"label":"OnCo: getting the cost of cancer care down","url":"https://onco.cc/costs/"},{"label":"WHO Model Lists of Essential Medicines","url":"https://www.who.int/groups/expert-committee-on-selection-and-use-of-essential-medicines/essential-medicines-lists"},{"label":"Lancet Oncology Commission: cancer care in India (Pramesh et al.)","url":"https://doi.org/10.1016/S1470-2045(14)70117-2"},{"label":"Patil et al., low-dose nivolumab with triple metronomic chemotherapy (JCO 2023)","url":"https://doi.org/10.1200/JCO.22.01015"}],"tags":[],"related":["nice-guidance","paper-pramesh-ncg-pooled-procurement-2023","paper-patil-low-dose-nivolumab-jco-2023","csco-guidelines","esmo-guidelines","src-nice-ta","idea-reg-orbis-work-sharing","idea-reg-reliance-90-day-lmic","idea-acc-biosimilar-prequalification-pool","idea-reg-pd1-biosimilar-advance-commitment","idea-reg-biosimilar-no-efficacy-trial","idea-reg-patent-pool-oncology-eml","idea-acc-eml-listing-price-commitments","idea-reg-tiered-pricing-for-exclusivity","idea-acc-pooled-procurement-radiotherapy","idea-acc-linac-uptime-contracts","idea-acc-frugal-hdr-brachytherapy","idea-acc-hypofractionation-default-lmic","idea-reg-lmic-public-cart-manufacturing","idea-fund-public-car-t-manufacturing","idea-fund-global-cancer-fund","idea-tr1-low-dose-immunotherapy-for-lmic","idea-reg-metronomic-lmic-phase3-to-label","idea-acc-metronomic-lmic-platform-trial","idea-reg-price-anchored-to-mcbs","idea-reg-indication-specific-pricing","idea-reg-public-deescalation-trials-for-cost","idea-reg-biosimilar-first-default-switching","idea-reg-nonprofit-generic-chemo-manufacturer","idea-reg-financial-toxicity-vital-sign","idea-cost-shorter-course-trials","idea-reg-middle-income-negotiation-bloc","idea-acc-community-health-workers-oncology","idea-acc-echo-tele-mentoring-oncology","idea-acc-remote-planning-hubs","idea-acc-balanced-opioid-policy-reform","idea-acc-registries-as-aid-condition","idea-prev-lmic-five-cancer-methylation-test","idea-fund-lmic-burden-match","idea-tr1-lmic-sites-in-pivotal-trials","idea-acc-hpv-self-sample-same-day-ablation","prevention-roadmap","chemotherapy-roadmap","radiation-roadmap","trial-modernisation-roadmap"],"cancers":[],"sections":[],"technologies":["global-oncology-access","generic-drug-shortage-response","palliative-radiotherapy","hpv-testing","precancer-ablation","telemedicine-teleoncology","oral-visual-screening"],"targets":[],"drugs":["trastuzumab-biosimilars","talicabtagene-autoleucel","varnimcabtagene-autoleucel","cervavac","sintilimab","camrelizumab","relmacabtagene-autoleucel","trastuzumab-rezetecan"],"companies":["cipla","natco","dr-reddys","sun-pharma","biocon","biocon-biologics","intas","zydus","immunoact","immuneel","serum-institute-of-india","hengrui","innovent","junshi"],"institutions":["who","uicc","tata-memorial","national-cancer-grid","tata-trusts","nhsa","fda-oce","ema","iarc"],"pathways":[],"terms":["biosimilar","who-essential-medicines","project-orbis","hta","hypofractionation"],"trials":["low-dose-nivolumab-tmh","metronomic-vs-cisplatin-tmh","metro-plus-varanasi","progesterone-preop-tmh","elective-neck-dissection-tmh","interlace","persephone","talicel-phase-1-2","imagine-varnimcabtagene","orient-11","harmoni-2","reliance","osmanabad-hpv-screening","kerala-oral-screening","mumbai-via-screening","iarc-india-hpv-dose-study","ken-she"],"people":[],"bottlenecks":["b-global-access","b-drug-pricing","b-regulatory-fragmentation","b-workforce","b-palliative","b-generic-repurposing","b-trial-diversity"],"keyPapers":["paper-pramesh-lancet-oncol"],"journals":[],"dependsOn":[],"notes":[],"steps":[{"era":"1977-2012","title":"Essential medicines, generics and the compulsory licence","description":"The WHO Essential Medicines List, first published in 1977, told health systems what to buy first; India's process-patent regime and companies such as Cipla, Natco and Dr Reddy's supplied the generics; and when a patented liver cancer drug was priced beyond reach, India issued its first compulsory licence (Natco v Bayer, 2012). Tobacco control, hepatitis B vaccination and cheap curative chemotherapy for childhood leukaemia and testicular cancer were the interventions that travelled.","refs":["who-essential-medicines","who","cipla","natco","dr-reddys","sun-pharma","global-oncology-access","b-global-access"],"status":"historic"},{"era":"2012-2020","title":"Biosimilars and pooled procurement","description":"Trastuzumab biosimilars, approved from 2017 with Biocon and Mylan's first, and rituximab biosimilars cut the price of two of the most important cancer antibodies by large fractions where they were adopted; in Europe, biosimilar-first defaults did most of the work. India's National Cancer Grid, run from Tata Memorial and linking more than 360 centres, showed that pooled procurement across hospitals lowers prices further and standardises what is bought.","refs":["trastuzumab-biosimilars","biosimilar","biocon","biocon-biologics","intas","zydus","national-cancer-grid","tata-memorial","tata-trusts","paper-pramesh-ncg-pooled-procurement-2023","idea-reg-biosimilar-first-default-switching"],"status":"historic"},{"era":"2015-2026","title":"Frugal evidence: less drug, cheaper schedules, same result","description":"Tata Memorial randomised the questions no company would fund: about a twentieth of a nivolumab dose added to cheap oral metronomic chemotherapy improved survival in head and neck cancer, oral metronomic tablets matched intravenous cisplatin, a single depot progesterone injection before breast surgery helped, and elective neck dissection was proven over watchful waiting. In the UK, PERSEPHONE showed six months of trastuzumab is nearly as good as twelve with half the heart toxicity, FAST-Forward cut breast radiotherapy to one week, and INTERLACE cut cervical cancer deaths with six weeks of generic chemotherapy. Each is usable anywhere; the task is getting them into labels and guidelines.","refs":["low-dose-nivolumab-tmh","paper-patil-low-dose-nivolumab-jco-2023","metronomic-vs-cisplatin-tmh","metro-plus-varanasi","progesterone-preop-tmh","elective-neck-dissection-tmh","persephone","hypofractionation","interlace","idea-tr1-low-dose-immunotherapy-for-lmic","idea-reg-metronomic-lmic-phase3-to-label","idea-acc-metronomic-lmic-platform-trial","idea-cost-shorter-course-trials","idea-reg-public-deescalation-trials-for-cost"],"status":"current"},{"era":"2018-2026","title":"Homegrown innovation in India and China","description":"India approved its first CAR-T, NexCAR19, developed at IIT Bombay and Tata Memorial and priced at a fraction of Western products; Immuneel ran the first industry CAR-T trial in India; the Serum Institute launched an Indian HPV vaccine. China's PD-1 antibodies (sintilimab, camrelizumab, toripalimab) were approved domestically at prices set by national negotiation and then taken global; its CAR-Ts and HER2 ADCs followed; and ivonescimab became the first drug to beat pembrolizumab head to head (HARMONi-2). The centre of gravity of affordable innovation is moving.","refs":["talicabtagene-autoleucel","talicel-phase-1-2","immunoact","varnimcabtagene-autoleucel","imagine-varnimcabtagene","immuneel","cervavac","serum-institute-of-india","sintilimab","innovent","orient-11","camrelizumab","hengrui","junshi","relmacabtagene-autoleucel","reliance","trastuzumab-rezetecan","harmoni-2","nhsa","csco-guidelines"],"status":"current"},{"era":"2000s-2026","title":"Screening and prevention that fit the budget","description":"One round of HPV testing in rural Indian villages cut cervical cancer deaths (Osmanabad); trained health workers with a torch found mouth cancers early in tobacco users (Kerala); vinegar and a lamp screened women in Mumbai slums. A single HPV vaccine dose proved almost fully protective (an interrupted Indian trial, then KEN SHE), and self-collected swabs with same-day thermal ablation let nurses run cervical programmes without colposcopy. These are the interventions with the highest return per dollar in oncology.","refs":["osmanabad-hpv-screening","kerala-oral-screening","oral-visual-screening","mumbai-via-screening","iarc-india-hpv-dose-study","ken-she","hpv-testing","precancer-ablation","idea-acc-hpv-self-sample-same-day-ablation","iarc","prevention-roadmap"],"status":"current"},{"era":"2026-2030","title":"Reliance, pooling and public manufacturing","description":"Project Orbis lets the FDA and partner regulators review together; the proposals extend it to a shared assessment report and a 90-day reliance approval for drugs cleared by two stringent regulators. WHO prequalification plus pooled demand could push biosimilar prices below a tenth of the originator; an advance market commitment could do the same for PD-1 biosimilars; Medicines Patent Pool licences for every patented drug on the essential list and tiered-price pledges tied to listing would formalise it. Public-sector CAR-T manufacturing in India, Brazil and South Africa, pooled procurement of radiotherapy machines with uptime contracts, and a Global Fund for cancer are the capital-intensive versions.","refs":["project-orbis","idea-reg-orbis-work-sharing","idea-reg-reliance-90-day-lmic","idea-acc-biosimilar-prequalification-pool","idea-reg-pd1-biosimilar-advance-commitment","idea-reg-biosimilar-no-efficacy-trial","idea-reg-patent-pool-oncology-eml","idea-acc-eml-listing-price-commitments","idea-reg-tiered-pricing-for-exclusivity","idea-reg-lmic-public-cart-manufacturing","idea-fund-public-car-t-manufacturing","idea-acc-pooled-procurement-radiotherapy","idea-acc-linac-uptime-contracts","idea-acc-frugal-hdr-brachytherapy","idea-acc-hypofractionation-default-lmic","idea-fund-global-cancer-fund","idea-reg-middle-income-negotiation-bloc"],"status":"emerging"},{"era":"2026-2030","title":"Paying for value in rich countries too","description":"New cancer drugs routinely cost more than a house per year, often for months of benefit, and systems cannot afford them without rationing. The levers: prices anchored to the ESMO and ASCO benefit scales and revisited when survival data mature, a different price for the same drug in different indications, publicly funded de-escalation trials of expensive drugs, biosimilar-first defaults, a non-profit manufacturer for generics in shortage, and screening every patient for financial toxicity as a vital sign. The costs page on this site pairs each driver with what is already being done.","refs":["b-drug-pricing","hta","nice-guidance","src-nice-ta","esmo-guidelines","idea-reg-price-anchored-to-mcbs","idea-reg-indication-specific-pricing","generic-drug-shortage-response","idea-reg-nonprofit-generic-chemo-manufacturer","idea-reg-financial-toxicity-vital-sign","chemotherapy-roadmap"],"status":"emerging"},{"era":"2030+","title":"Workforce, pain relief and the data to steer by","description":"Drugs do not treat patients; people do, and most of the world has too few oncologists, pathologists, physicists and nurses. Community health workers trained in triage, navigation and home palliative care, Project ECHO tele-mentoring for district clinicians, remote radiotherapy planning hubs, diaspora tumour boards, and opioid quota reform so morphine reaches people dying of cancer are the workforce answers. A population registry as a condition of every aid programme, burden-matched trial funding and pivotal-trial sites in Africa, South Asia and Latin America would make progress measurable. A ten-dollar blood test for the five cancers that kill most people in poorer countries is the diagnostic bet.","refs":["b-workforce","b-palliative","idea-acc-community-health-workers-oncology","idea-acc-echo-tele-mentoring-oncology","idea-acc-remote-planning-hubs","telemedicine-teleoncology","idea-acc-balanced-opioid-policy-reform","idea-acc-registries-as-aid-condition","idea-fund-lmic-burden-match","idea-tr1-lmic-sites-in-pivotal-trials","idea-prev-lmic-five-cancer-methylation-test","uicc","radiation-roadmap"],"status":"speculative"},{"era":"What sets the pace","title":"Pricing power, divergence and the absence of care","description":"Seven in ten cancer deaths happen where radiotherapy, pathology and essential drugs are scarce or absent. Prices are set by what the richest payer will bear, regulators duplicate each other's reviews so approvals lag by years, old cheap drugs have no sponsor to test them, trials rarely include the populations that carry the burden, and most people who die of cancer worldwide do so without adequate pain relief. Every lever above attacks one of these.","refs":["b-global-access","b-drug-pricing","b-regulatory-fragmentation","b-generic-repurposing","b-trial-diversity","b-palliative","b-workforce"],"status":"current"}],"watch":[]},{"id":"hormonal-therapy-roadmap","kind":"roadmap","name":"Hormonal therapy roadmap: removing the ovaries → tamoxifen → oral degraders switched by a blood test","aka":[],"tldr":"Cutting off the hormones that breast and prostate cancers feed on has kept people alive for decades. The therapy is now moving from blocking the hormone to destroying its receptor, and from waiting for a scan to switching drugs when a blood test sees resistance coming.","summary":"Endocrine therapy is the oldest targeted treatment in oncology: removal of the ovaries for breast cancer in 1896 and castration for prostate cancer in 1941 predate every drug. Tamoxifen (1977) made it a pill, aromatase inhibitors and GnRH analogues refined it, and for two decades the field advanced by combination: CDK4/6 inhibitors with endocrine therapy in breast cancer, and abiraterone, enzalutamide and docetaxel layered onto androgen deprivation in prostate cancer, each adding survival in randomised trials.\n\nThe current generation attacks resistance directly. Oral oestrogen-receptor degraders (elacestrant 2023, imlunestrant 2025, camizestrant 2026) and the first approved PROTAC (vepdegestrant 2026) remove the receptor rather than block it and work in tumours with ESR1 mutations; SERENA-6 was the first trial to change treatment on a blood test rather than a scan. PI3K, AKT and mTOR inhibitors address the parallel escape route. In prostate cancer, PARP inhibitors and AKT inhibitors are being matched to the tumours whose biology predicts benefit, and PSMA radioligands are moving earlier.\n\nThe pace is set by resistance biology, by the cost of multi-year combination therapy, and by tolerability: the side-effects that make people stop a drug they should take for five or ten years.","asOf":"2026-09-10","links":[{"label":"SERENA-6 (NEJM 2025)","url":"https://www.nejm.org/doi/full/10.1056/NEJMoa2502929"},{"label":"STAMPEDE platform trial","url":"https://www.stampedetrial.org/"}],"tags":[],"related":["idea-prev-low-dose-tamoxifen-uptake","idea-acc-cardiometabolic-clinic-hormone-therapy","idea-tr1-response-adapted-dose-reduction","idea-cost-shorter-course-trials","idea-bio1-ctdna-adaptive-tki","radiopharma-roadmap","cure-paths","targeted-therapy-roadmap","prostate-roadmap"],"cancers":["prostate"],"sections":["hormonal"],"technologies":["endocrine-therapy","androgen-deprivation","cdk46-inhibitor","protac-degrader","liquid-biopsy","acupuncture-hot-flushes","acupuncture-aromatase-inhibitor-arthralgia","cardio-oncology"],"targets":[],"drugs":["tamoxifen","letrozole","exemestane","fulvestrant","goserelin","palbociclib","ribociclib","abemaciclib","dalpiciclib","atirmociclib","alpelisib","capivasertib","inavolisib","gedatolisib","everolimus","elacestrant","imlunestrant","camizestrant","giredestrant","vepdegestrant","abiraterone","enzalutamide","apalutamide","darolutamide","relugolix","leuprolide","degarelix","bicalutamide","mevrometostat","breast-cancer-index","fluoroestradiol-f18"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["soft-text","paloma-2","monaleesa-2","monarch-3","monarche","natalee","pallas-penelope-b","solar-1","capitello-291","emerald","ember-3","serena-6","veritac-2","lidera","cambria","persevera","evera","postmonarch","fourlight-1","chaarted","stampede","latitude","arches","arasens","peace-1","embark","propel","talapro-2","magnitude","capitello-281","mevpro-1","psmafore"],"people":[],"bottlenecks":["b-resistance","b-toxicity-qol","b-drug-pricing","b-biomarker-validation"],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"steps":[{"era":"1896-1980s","title":"Removing the hormone","description":"Beatson removed the ovaries of a woman with advanced breast cancer in 1896 and watched the tumour regress; Huggins showed in 1941 that castration controlled metastatic prostate cancer. Tamoxifen (1977), a receptor blocker taken as a pill, halved recurrence after breast surgery and became the first targeted cancer drug. GnRH analogues made castration reversible and chemical.","refs":["tamoxifen","endocrine-therapy","androgen-deprivation","goserelin","leuprolide","bicalutamide"],"status":"historic"},{"era":"1990s-2010s","title":"Aromatase inhibitors, fulvestrant and ovarian suppression","description":"Aromatase inhibitors stopped oestrogen production in postmenopausal women and edged out tamoxifen in adjuvant trials; fulvestrant destroyed the receptor by injection. SOFT and TEXT showed that suppressing the ovaries and adding an aromatase inhibitor prevents more recurrences in young women than tamoxifen alone. Five to ten years of daily therapy became the norm, and adherence and side-effects became the limiting factor.","refs":["letrozole","exemestane","fulvestrant","soft-text","acupuncture-hot-flushes","acupuncture-aromatase-inhibitor-arthralgia"],"status":"historic"},{"era":"2011-2024","title":"Prostate cancer: earlier, deeper, combined","description":"Abiraterone and enzalutamide, then apalutamide and darolutamide, blocked the androgen pathway inside the tumour after castration stopped working, and were then moved to first metastatic diagnosis (LATITUDE, ARCHES). CHAARTED and STAMPEDE added docetaxel; ARASENS and PEACE-1 proved triplet therapy. EMBARK treated rising PSA after local therapy, and relugolix made testosterone suppression an oral pill. PSMAfore moved the PSMA radioligand ahead of chemotherapy.","refs":["abiraterone","enzalutamide","apalutamide","darolutamide","relugolix","degarelix","chaarted","stampede","latitude","arches","arasens","peace-1","embark","psmafore"],"status":"current"},{"era":"2015-2026","title":"Breast cancer: CDK4/6 inhibitors and the pathway partners","description":"Palbociclib (2015), ribociclib and abemaciclib roughly doubled progression-free time when added to endocrine therapy, and ribociclib extended survival (MONALEESA-2). monarchE and NATALEE brought the class into the adjuvant setting; PALLAS and PENELOPE-B showed it does not work for every drug. Alpelisib (SOLAR-1), capivasertib (CAPItello-291), inavolisib and gedatolisib target the PI3K-AKT-mTOR escape pathway in tumours that carry the mutations, at the cost of high blood sugar and rash.","refs":["cdk46-inhibitor","palbociclib","ribociclib","abemaciclib","dalpiciclib","paloma-2","monaleesa-2","monarch-3","monarche","natalee","pallas-penelope-b","alpelisib","solar-1","capivasertib","capitello-291","inavolisib","gedatolisib","everolimus"],"status":"current"},{"era":"2023-2026","title":"Degrading the receptor, switching on a blood test","description":"ESR1 mutations let the receptor work without oestrogen, defeating aromatase inhibitors. Oral degraders remove the receptor itself: elacestrant (2023, EMERALD), imlunestrant (2025, EMBER-3) and camizestrant (September 2026). Vepdegestrant, approved in 2026 after VERITAC-2, is the first PROTAC in any disease. SERENA-6 changed the rules of engagement: it switched to camizestrant when an ESR1 mutation appeared in blood, before the scan showed progression, and delayed progression by doing so. FES PET shows which deposits still carry the receptor.","refs":["elacestrant","emerald","imlunestrant","ember-3","camizestrant","serena-6","vepdegestrant","veritac-2","protac-degrader","liquid-biopsy","fluoroestradiol-f18"],"status":"current"},{"era":"2026-2030","title":"Into the adjuvant setting and around the next resistance","description":"lidERA is the first oral degrader to reduce recurrence after surgery; CAMBRIA-1 and CAMBRIA-2 test whether degraders should replace today's adjuvant pills outright, while persevERA showed they do not automatically win first-line. postMONARCH and evERA map what to do after CDK4/6 failure. Atirmociclib blocks CDK4 only, to keep the benefit without the low blood counts. In prostate cancer, PARP inhibitors (PROpel, TALAPRO-2, MAGNITUDE) work in tumours with DNA-repair defects, capivasertib in PTEN-deficient disease (CAPItello-281), and the EZH2 inhibitor mevrometostat aims to re-sensitise tumours to enzalutamide (MEVPRO-1).","refs":["lidera","giredestrant","cambria","persevera","postmonarch","evera","atirmociclib","fourlight-1","propel","talapro-2","magnitude","capitello-281","mevrometostat","mevpro-1"],"status":"emerging"},{"era":"2030+","title":"Living well through a decade of therapy","description":"If resistance can be anticipated from blood, therapy could be sequenced or given intermittently to keep the sensitive clone dominant, an approach being tested in lung cancer and proposed for hormone-driven disease. The Breast Cancer Index already asks who benefits from extending therapy beyond five years. The bigger gains may be in staying on treatment: acupuncture for hot flushes and joint pain, cardiometabolic screening for men on long-term androgen deprivation, and low-dose tamoxifen for prevention prescribed outside the oncology clinic.","refs":["breast-cancer-index","idea-bio1-ctdna-adaptive-tki","idea-tr1-response-adapted-dose-reduction","idea-acc-cardiometabolic-clinic-hormone-therapy","cardio-oncology","idea-prev-low-dose-tamoxifen-uptake"],"status":"speculative"},{"era":"What sets the pace","title":"Resistance, price and tolerability","description":"Every hormonal agent eventually meets resistance, and the biology of the next escape (ESR1, PI3K, AR splice variants) decides which drug comes next. Multi-year combination therapy is priced per month, so cost compounds; shorter-course and de-escalation trials exist only when public funders run them. And the side-effects that make people stop a drug they should take for years are still measured less carefully than the effects on the tumour.","refs":["b-resistance","b-drug-pricing","idea-cost-shorter-course-trials","b-toxicity-qol","b-biomarker-validation"],"status":"current"}],"watch":[]},{"id":"immunotherapy-roadmap","kind":"roadmap","name":"Immunotherapy roadmap: Coley's toxins → checkpoint inhibitors → engineered immunity","aka":[],"tldr":"The immunotherapy roadmap is a 130-year arc from injecting bacteria into tumours to releasing immune brakes, and now to designing the immune response itself with vaccines, engagers, and cells.","summary":"The immunotherapy roadmap covers a 130-year arc that starts with Coley's toxins, BCG for bladder cancer, interferon and IL-2 and sipuleucel-T, an era of sporadic cures and scepticism. The checkpoint revolution followed with ipilimumab, nivolumab, pembrolizumab and atezolizumab and the Nobel Prize to Allison and Honjo, then immunotherapy moved into earlier lines, combinations, T-cell engagers and TIL. The emerging step is engineered immunity: personalised mRNA vaccines, PD-1 and VEGF bispecifics, ADC plus IO, oncolytic viruses, TCR-T and in vivo CAR, with interception vaccines as the speculative end. The route links checkpoint inhibitors, T-cell engagers, CAR-T, TIL and STING agonists, and the cold-tumour and response-prediction bottlenecks.","asOf":"2026-09-04","links":[{"label":"Leach, Krummel and Allison: releasing the CTLA-4 brake makes mice reject tumours (Science 1996)","url":"https://doi.org/10.1126/science.271.5256.1734"},{"label":"Hodi 2010: ipilimumab, the first checkpoint inhibitor, extends survival in metastatic melanoma (New England Journal of Medicine 2010)","url":"https://doi.org/10.1056/NEJMoa1003466"}],"tags":[],"related":["lung-cancer-evidence-roadmap"],"cancers":[],"sections":["immunotherapy"],"technologies":["checkpoint-inhibitor","t-cell-engager","neoantigen-mrna-vaccine","oncolytic-virus","cytokine-therapy","car-t","til-therapy","sting-agonist"],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"steps":[{"era":"1891-2010","title":"Prehistory","description":"The prehistory runs from Coley's toxins (1891) through BCG for bladder cancer (1976) and interferon and IL-2 (1980s-90s) to sipuleucel-T (2010). The era brings sporadic cures, high toxicity and scepticism.","refs":["cytokine-therapy"],"status":"historic"},{"era":"2011-2018","title":"Checkpoint revolution","description":"Ipilimumab (2011), nivolumab and pembrolizumab (2014) and atezolizumab (2016) are approved; the tumour-agnostic MSI-H approval follows (2017) and the Nobel Prize goes to Allison and Honjo (2018). Durable responses follow across >15 tumour types.","refs":["ipilimumab","pembrolizumab","nivolumab","checkmate-067"],"status":"historic"},{"era":"2018-2024","title":"Earlier lines and combinations","description":"Immunotherapy moves earlier and into combinations: neoadjuvant/adjuvant IO in melanoma, NSCLC, TNBC, bladder; IO + chemo, IO + VEGF, IO + IO (LAG-3); T-cell engagers in myeloma and lymphoma; and the first solid-tumour engager (tarlatamab) and TIL (lifileucel).","refs":["keynote-522","relatlimab-nivolumab","tarlatamab","lifileucel"],"status":"current"},{"era":"2024-2027","title":"Engineered immunity arrives","description":"Personalised mRNA vaccines pass phase 3 (intismeran, 2026); PD-1×VEGF bispecifics challenge pembrolizumab; ADC + IO becomes first line; oncolytic virus RP1 approved; TCR-T and solid-tumour CAR-T approvals; in vivo CAR first-in-human.","refs":["interpath-001","ivonescimab","ascent-04","vusolimogene-oderparepvec","in-vivo-car-t"],"status":"emerging"},{"era":"2028+","title":"Speculative","description":"Off-the-shelf shared-neoantigen vaccines for KRAS and TP53; interception vaccines in high-risk carriers; myeloid-reprogramming drugs that make cold tumours hot; immune-PET-guided IO selection; engineered cytokines with tumour-restricted activity.","refs":["shared-antigen-vaccine","immuno-pet","cold-vs-hot"],"status":"speculative"}],"watch":[]},{"id":"kras-roadmap","kind":"roadmap","name":"KRAS roadmap: undruggable → G12C → pan-RAS","aka":[],"tldr":"The most important cancer gene was declared undruggable for 40 years. Then a pocket was found, and now a pan-RAS drug is in phase 3 for pancreatic cancer.","summary":"The KRAS roadmap begins with the gene's discovery as a human oncogene and decades of failure, when farnesyltransferase inhibitors did not work, until the Shokat lab found the switch-II pocket and sotorasib and adagrasib were approved in NSCLC. The current step goes beyond G12C with non-covalent G12D inhibitors and pan-RAS(ON) tri-complex inhibitors such as daraxonrasib in pancreatic cancer, and the emerging step anticipates a first pancreatic approval, combinations, KRAS vaccines, mutant-KRAS TCR-T and RAS degraders. The speculative end is neoadjuvant RAS inhibition and interception in high-risk cyst carriers. KRAS drives the three common cancers with the lowest survival; the route links pancreatic, colorectal and NSCLC, the KRAS target, KRAS and RAS inhibitors and the undruggable-drivers bottleneck.","asOf":"2026-09-04","links":[{"label":"Ostrem and Shokat: the hidden pocket that made KRAS G12C druggable (Nature 2013)","url":"https://doi.org/10.1038/nature12796"},{"label":"CodeBreaK 300: sotorasib plus panitumumab in chemotherapy-refractory KRAS G12C colorectal cancer (New England Journal of Medicine 2023)","url":"https://doi.org/10.1056/NEJMoa2308795"}],"tags":[],"related":["targeted-therapy-roadmap","pancreatic-roadmap","colorectal-roadmap","lung-cancer-evidence-roadmap"],"cancers":["pancreatic","colorectal","nsclc"],"sections":["targeted-therapy"],"technologies":["kras-inhibitors"],"targets":["kras"],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"steps":[{"era":"1982-2012","title":"Discovery and failure","description":"KRAS identified as a human oncogene (1982). Farnesyltransferase inhibitors fail (1990s-2000s); RAS lacks druggable pockets and binds GTP with picomolar affinity. NCI launches the RAS Initiative (2013).","refs":["kras"],"status":"historic"},{"era":"2013-2021","title":"The switch-II pocket","description":"Shokat lab finds a covalent pocket in KRAS G12C (2013). Sotorasib (2021) and adagrasib (2022) approved in NSCLC; colorectal cancer needs EGFR antibody combination.","refs":["sotorasib","adagrasib","kras-plus-egfr-crc"],"status":"historic"},{"era":"2023-2026","title":"Beyond G12C","description":"Non-covalent G12D inhibitors (MRTX1133, zoldonrasib); pan-RAS(ON) tri-complex inhibitors (daraxonrasib) with ~14.5-month OS in second-line pancreatic cancer; phase 3 RASolute 302 enrolled; first-line and adjuvant trials start. Divarasib, olomorasib, and elironrasib improve on first-generation G12C drugs.","refs":["daraxonrasib","revolution-medicines"],"status":"current"},{"era":"2026-2029","title":"Approval and combinations","description":"Expected first pancreatic cancer approval for a RAS inhibitor; combinations with chemotherapy, EGFR/SHP2 inhibitors, and immunotherapy; KRAS vaccines (ELI-002) in adjuvant pancreatic cancer; mutant-KRAS TCR-T; RAS degraders.","refs":["shared-antigen-vaccine","tcr-t"],"status":"emerging"},{"era":"2030+","title":"Speculative","description":"Neoadjuvant RAS inhibition making pancreatic cancer resectable; MCED-detected early pancreatic cancer treated with RAS inhibitor + vaccine; interception in high-risk pancreatic cyst carriers.","refs":["mced","pancreatic"],"status":"speculative"}],"watch":[]},{"id":"lung-cancer-evidence-roadmap","kind":"roadmap","name":"Lung cancer roadmap: from Doll and Hill and the naming of tobacco, through the cytotoxic plateau, computed tomography screening, EGFR and ALK, immunotherapy by PD-L1, the perioperative trials and PACIFIC, to DLL3 in small-cell disease and a 2032 registry watch","aka":["Lung cancer history","Lung cancer evidence roadmap","NSCLC and SCLC roadmap","Thoracic oncology roadmap"],"tldr":"Lung cancer is where modern cancer epidemiology began: two studies in 1950 tied it to cigarettes, and a fifty-year cohort proved it. This roadmap follows the evidence from there through chemotherapy that barely worked, the scans that find the disease early, the drugs for cancers that depend on one broken gene, immunotherapy, and small-cell disease, to 2032.","summary":"Lung cancer kills more people than any other cancer, and it is the cancer whose cause is best understood. Wynder and Graham in the United States and Doll and Hill in Britain published within months of each other in 1950; the British Doctors Study then followed a cohort for fifty years and turned an association into a dose-response relationship with a cessation curve attached. Peto's 2000 analysis gave the number that tobacco control still runs on: stopping before middle age avoids more than 90 percent of the risk.\n\nTreatment took much longer. The 1995 individual-patient meta-analysis of 52 trials showed cisplatin-based chemotherapy helped, by about 5 percent at five years after surgery; E1594 in 2002 showed that no combination of cytotoxic drugs beat any other, with a median survival of 7.9 months. The plateau broke twice. In 2004 Lynch and Paez independently found that the minority who responded dramatically to gefitinib had EGFR mutations, and IPASS in 2009 proved that selecting by that mutation was what made the drug work; in 2007 Soda found the EML4-ALK fusion, and crizotinib was approved four years later. In 2012 Topalian's phase 1 showed durable responses to PD-1 blockade in lung cancer, and by 2018 chemotherapy plus pembrolizumab was standard for most patients without a driver.\n\nEarly detection followed its own track. PLCO showed in 2011 that chest radiography does nothing; NLST that year and NELSON in 2020 showed that low-dose computed tomography cuts lung cancer deaths. Eligibility is the unsolved part: pack-year thresholds exclude high-risk groups systematically, never-smokers are outside the criteria entirely, and uptake among those who qualify remains a fraction of them.\n\nSince 2017 the direction has been earlier and combined. PACIFIC put consolidation durvalumab after chemoradiotherapy in stage III disease and five-year survival reached 42.9 percent; CheckMate 816, KEYNOTE-671, AEGEAN and IMpower010 moved immunotherapy around the operation; ADAURA and ALINA did the same with targeted drugs for EGFR and ALK. Small-cell lung cancer, static since twice-daily radiotherapy in 1999, finally moved: ADRIATIC lifted median survival in limited-stage disease from 33.4 to 55.9 months, and tarlatamab, a DLL3 T-cell engager, became the first drug built for the disease. What has not moved is resistance, which arrives in one to three years for every targeted drug, and the gap between who is eligible for screening and who gets it.\n\nUK and NHS specifics (Targeted Lung Health Check coverage and uptake, NICE positions and Cancer Drugs Fund status, molecular testing turnaround, thoracic surgery and radiotherapy capacity, audit indicators and trial access) are on the UK and NHS page for lung cancer and are not restated here.","status":"active","asOf":"2026-09-25","links":[{"label":"NCI PDQ: lung cancer","url":"https://www.cancer.gov/types/lung"},{"label":"ESMO guidelines: lung and chest tumours","url":"https://www.esmo.org/guidelines/esmo-clinical-practice-guidelines-lung-and-chest-tumours"},{"label":"IASLC: International Association for the Study of Lung Cancer","url":"https://www.iaslc.org/"},{"label":"ClinicalTrials.gov NCT01888601","url":"https://clinicaltrials.gov/study/NCT01888601"}],"tags":[],"related":["prevention-roadmap","early-detection-roadmap","targeted-therapy-roadmap","immunotherapy-roadmap","radiation-roadmap","chemotherapy-roadmap","kras-roadmap","ctdna-tests","diagnostics-roadmap"],"cancers":["lung-cancer","nsclc","sclc"],"sections":["prevention","early-detection","targeted-therapy","immunotherapy","radiation","surgery","diagnostics"],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":["b-early-detection","b-prevention-adoption","b-resistance","b-immunotherapy-response","b-brain-delivery","b-tumor-heterogeneity","b-rare-cancers","b-global-access","b-biomarker-validation"],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"steps":[{"era":"1950 to 1965","title":"The cause is named, and cancer epidemiology is invented to name it","description":"Wynder and Graham's 684 proven cases appeared in JAMA in May 1950 and Doll and Hill's British case-control study in the BMJ in September. Both were attacked as artefacts of how cases were chosen, so Doll and Hill built a prospective cohort of British doctors in 1951 and followed it for fifty years. The method they used, exposure recorded before outcome with a measured dose-response, is the foundation of modern cancer epidemiology; the 1964 United States Surgeon General's report and everything in tobacco control since rests on it.","refs":["paper-wynder-graham-tobacco-bronchiogenic-carcinoma-jama-1950","paper-doll-hill-smoking-lung-cancer-bmj-1950","paper-doll-hill-mortality-of-doctors-smoking-bmj-1954","paper-doll-peto-50-year-doctors-bmj-2004","prevention-roadmap"],"status":"historic"},{"era":"1970 to 2006","title":"Cytotoxic chemotherapy, and the ceiling it hit","description":"Therapeutic nihilism was the default until the Non-small Cell Lung Cancer Collaborative Group pooled individual data on 9,387 patients from 52 trials in 1995 and found a 27 percent reduction in the risk of death when chemotherapy was added to supportive care. E1594 then randomised 1,207 patients between four platinum doublets and found no difference: a 19 percent response rate and a median survival of 7.9 months, whichever drugs were used. LACE later pooled 4,584 resected patients and fixed the adjuvant rule, a 5.4 percent absolute survival gain concentrated in stage II and III disease. The first crack in the ceiling was biological rather than cytotoxic: ECOG 4599 added bevacizumab in 2006 and took median survival past twelve months for the first time, at 12.3 against 10.3 months, in the non-squamous patients without brain metastases who were allowed into the trial.","refs":["paper-nsclc-collaborative-group-chemotherapy-meta-analysis-bmj-1995","paper-schiller-ecog-1594-four-chemotherapy-regimens-nejm-2002","paper-lace-adjuvant-cisplatin-pooled-analysis-jco-2008","paper-sandler-ecog-4599-bevacizumab-nsclc-nejm-2006","chemotherapy-roadmap"],"status":"historic"},{"era":"2004 to 2013","title":"EGFR, ALK, and the invention of precision oncology in solid tumours","description":"Gefitinib worked spectacularly in about one patient in ten and was close to being abandoned. In May 2004 Lynch in the NEJM and Paez in Science independently reported that the responders had activating EGFR mutations; Paez also explained the geography, finding the mutation in 15 of 58 Japanese tumours and 1 of 61 American ones. IPASS in 2009 randomised 1,217 clinically selected patients and showed the benefit lived entirely in the mutation-positive subgroup. In 2007 Soda found the EML4-ALK fusion in 5 of 75 tumours; Kwak screened 1,500 patients to enrol 82 and got a 57 percent response rate with crizotinib, a drug built for a different target. Resistance came with it: Kobayashi's single re-biopsied patient in 2005 carried T790M, and Sequist's 37 patients in 2011 showed resistance could be genetic, histological or even reversible.","refs":["paper-lynch-egfr-activating-mutations-gefitinib-nejm-2004","paper-paez-egfr-mutations-gefitinib-science-2004","paper-mok-ipass-gefitinib-pulmonary-adenocarcinoma-nejm-2009","paper-soda-eml4-alk-fusion-nature-2007","paper-kwak-crizotinib-alk-nsclc-nejm-2010","paper-kobayashi-egfr-t790m-gefitinib-resistance-nejm-2005","paper-sequist-genotypic-histological-evolution-egfr-resistance-sci-transl-med-2011","targeted-therapy-roadmap"],"status":"historic"},{"era":"2011 to 2020","title":"Low-dose computed tomography earns its place, and chest radiography loses its","description":"PLCO randomised 154,901 people to four annual chest radiographs or usual care and after 13 years found 1,213 lung cancer deaths against 1,230: no effect at all. NLST the same year and NELSON in 2020 showed that low-dose computed tomography does reduce lung cancer mortality, and the United States task force widened eligibility in 2021 from age 55 and 30 pack-years to age 50 and 20. Aldrich had already shown what a pack-year threshold does: in a southern United States cohort, 31 percent of white smokers qualified against 17 percent of Black smokers, who develop the disease at lower cumulative exposure.","refs":["paper-plco-chest-radiograph-lung-cancer-mortality-jama-2011","paper-nlst-nejm-2011","paper-nelson-nejm-2020","paper-uspstf-lung-cancer-screening-jama-2021","paper-aldrich-uspstf-screening-african-american-smokers-jama-oncol-2019","early-detection-roadmap"],"status":"historic"},{"era":"2012 to 2019","title":"Immunotherapy, and the trouble with PD-L1 as a gate","description":"Topalian's 2012 phase 1 found durable responses to PD-1 blockade in 18 percent of lung cancer patients and the first hint that PD-L1 expression predicted them. CheckMate 017 and 057 and KEYNOTE-010 established second-line nivolumab and pembrolizumab; KEYNOTE-024 moved pembrolizumab in front of chemotherapy for PD-L1-high tumours; KEYNOTE-189 and KEYNOTE-407 combined it with chemotherapy for everybody else. IMpower110 reproduced the PD-L1-high result with atezolizumab and a different assay, which is where the assay problem became unavoidable: SP142, 22C3 and SP263 do not select the same patients.","refs":["paper-topalian-anti-pd1-nejm-2012","paper-keynote-001-pembrolizumab-nsclc-nejm-2015","paper-checkmate-017-nejm-2015","paper-checkmate-057-nejm-2015","paper-keynote-024-nejm-2016","paper-keynote-189-nejm-2018","paper-keynote-407-n-engl-j-med-2018","paper-herbst-impower110-atezolizumab-pd-l1-nejm-2020","immunotherapy-roadmap"],"status":"historic"},{"era":"2017 to 2024","title":"Stage III, and treatment moving to either side of the operation","description":"PACIFIC put a year of durvalumab after chemoradiotherapy in unresectable stage III disease; the five-year update found 42.9 percent alive against 33.4 percent and a third still free of progression. Resectable disease followed: CheckMate 816 gave nivolumab before surgery, KEYNOTE-671, AEGEAN and CheckMate 77T on both sides, IMpower010 afterwards, and NADIM II showed 93 percent of patients reaching the operating theatre against 69 percent. Targeted drugs made the same move: ADAURA for EGFR, ALINA for ALK, and LAURA for EGFR-mutant stage III disease, where a hazard ratio of 0.16 replaced durvalumab consolidation that had never worked well in that genotype.","refs":["paper-pacific-nejm-2017","paper-spigel-pacific-five-year-survival-jco-2022","paper-checkmate-816-nejm-2022","paper-keynote-671-n-engl-j-med-2023","paper-heymach-aegean-perioperative-durvalumab-nejm-2023","paper-felip-impower010-adjuvant-atezolizumab-lancet-2021","paper-provencio-nadim-ii-perioperative-nivolumab-stage-iii-nejm-2023","paper-adaura-nejm-2020","paper-wu-alina-adjuvant-alectinib-nejm-2024","paper-lu-laura-osimertinib-stage-iii-nejm-2024"],"status":"current"},{"era":"2020 to 2026","title":"The driver list grows, and first-line treatment starts to be intensified","description":"ALK moved from crizotinib to alectinib (ALEX) to lorlatinib (CROWN, 78 percent progression-free at 12 months against 39). MET exon 14 got capmatinib, RET got selpercatinib, ROS1 got crizotinib then entrectinib, BRAF V600E got dabrafenib and trametinib, HER2 got trastuzumab deruxtecan and zongertinib, and KRAS G12C, undruggable for thirty years, got sotorasib and adagrasib, with CodeBreaK 200 showing a 1.1-month gain over docetaxel. In EGFR-mutant disease, FLAURA2 added chemotherapy to osimertinib and MARIPOSA beat it outright with amivantamab and lazertinib, 23.7 months against 16.6, at the cost of ten times the treatment discontinuation.","refs":["paper-peters-alex-alectinib-crizotinib-nejm-2017","paper-shaw-crown-lorlatinib-crizotinib-nejm-2020","paper-wolf-geometry-mono-1-capmatinib-nejm-2020","paper-libretto-001-selpercatinib-nsclc-nejm-2020","paper-codebreak-200-lancet-2023","paper-planchard-flaura2-osimertinib-chemotherapy-nejm-2023","paper-mariposa-nejm-2024","paper-beamion-lung-1-zongertinib-nejm-2025","kras-roadmap"],"status":"current"},{"era":"1999 to 2026","title":"Small-cell lung cancer, static for twenty-five years and then not","description":"Turrisi's twice-daily thoracic radiotherapy in 1999 raised five-year survival from 16 to 26 percent, and the Aupérin overview showed that irradiating a brain with no detectable disease in it extends life. Then nothing, for a quarter of a century. George's 110 genomes explained why: the disease is defined by losing both copies of TP53 and RB1, and a loss cannot be inhibited. Rudin's four transcription-factor subtypes gave the field something to design around, the NOTCH finding pointed at DLL3, and in 2023 tarlatamab produced a 40 percent response rate in twice-treated patients. ADRIATIC then lifted median survival in limited-stage disease from 33.4 to 55.9 months.","refs":["paper-turrisi-twice-daily-thoracic-radiotherapy-limited-sclc-nejm-1999","paper-auperin-prophylactic-cranial-irradiation-sclc-nejm-1999","paper-george-sclc-genomic-profiles-nature-2015","paper-rudin-sclc-molecular-subtypes-nat-rev-cancer-2019","paper-impower133-n-engl-j-med-2018","paper-paz-ares-caspian-durvalumab-es-sclc-lancet-2019","paper-dellphi-301-nejm-2023","paper-adriatic-nejm-2024"],"status":"current"},{"era":"2017 to 2027","title":"Reading the tumour over time: heterogeneity, ctDNA and resistance-directed treatment","description":"TRACERx sequenced 327 regions from 100 resected tumours and found that drivers are almost always clonal while later alterations are heterogeneous in more than three quarters of tumours, with copy-number heterogeneity carrying a hazard ratio of 4.9 for recurrence or death. Abbosh built a per-patient phylogenetic ctDNA assay from the same tumours and identified the patients who would relapse before any scan did. Neither is yet a clinical test in lung cancer: no randomised trial has shown that acting on a positive minimal residual disease result improves survival, which is the gap the ctDNA-guided adjuvant trials are designed to close.","refs":["paper-tracerx-100-nejm-2017","paper-abbosh-phylogenetic-ctdna-lung-cancer-nature-2017","paper-sequist-genotypic-histological-evolution-egfr-resistance-sci-transl-med-2011","ctdna-tests","diagnostics-roadmap"],"status":"emerging"},{"era":"2021 to 2030","title":"Never-smoker disease and the air people breathe","description":"About one lung cancer in five worldwide occurs in someone who never smoked, and the proportion is rising as smoking falls. Sherlock-Lung's 232 whole genomes found three subtypes with no tobacco signature, the dominant one slow-growing with drivers datable to years before diagnosis. Hill and Swanton then proposed a mechanism for at least part of it: fine particulate matter does not create the EGFR mutation, which is already present in 18 percent of histologically normal lungs, but inflames the tissue enough to let it grow. That makes air quality a cancer intervention with a measurable endpoint, and makes the screening eligibility criteria, which exclude never-smokers entirely, the wrong instrument for a growing share of the disease.","refs":["paper-zhang-lung-cancer-never-smokers-nat-genet-2021","paper-hill-lung-adenocarcinoma-air-pollutants-nature-2023","paper-uspstf-lung-cancer-screening-jama-2021","prevention-roadmap","idea-prev-clean-air-never-smoker-endpoints"],"status":"emerging"},{"era":"2026 to 2032","title":"What would have to be true for lung cancer mortality to halve again","description":"Four things, none of them a new drug class. Screening reaching the people at highest risk rather than the people easiest to enrol, which means risk-model eligibility and delivery into deprived areas rather than wider pack-year thresholds. Resistance treated as a diagnosis, with a re-biopsy or a ctDNA profile choosing the next line rather than a default. Brain metastasis prevention measured as a primary endpoint rather than counted as a secondary one. And small-cell lung cancer trialled as the four diseases Rudin's subtypes describe, in a platform with shared controls, rather than as one disease with a 62 percent grade 3 toxicity rate and a two-month gain.","refs":["idea-lung-screening-eligibility-by-risk-not-pack-years","idea-lung-resistance-directed-sequencing-at-every-progression","idea-lung-brain-metastasis-prevention-as-a-primary-endpoint","idea-lung-small-cell-platform-with-shared-controls-and-subtypes","idea-lung-deprivation-gradient-treated-as-a-defect-in-delivery"],"status":"speculative"}],"watch":[{"item":"ADRIATIC: final analysis of durvalumab, and the unblinding of the durvalumab plus tremelimumab arm, in limited-stage small-cell lung cancer","expected":"Study completion 23 October 2026 (estimated, ClinicalTrials.gov NCT03703297)","source":"https://clinicaltrials.gov/study/NCT03703297","refs":["paper-adriatic-nejm-2024","adriatic"]},{"item":"IMpower010: final overall survival for adjuvant atezolizumab after chemotherapy in resected disease","expected":"Study completion 31 August 2027 (estimated, ClinicalTrials.gov NCT02486718)","source":"https://clinicaltrials.gov/study/NCT02486718","refs":["paper-felip-impower010-adjuvant-atezolizumab-lancet-2021"]},{"item":"FLAURA2: overall survival for osimertinib with chemotherapy against osimertinib alone","expected":"Study completion 30 September 2027 (estimated, ClinicalTrials.gov NCT04035486)","source":"https://clinicaltrials.gov/study/NCT04035486","refs":["paper-planchard-flaura2-osimertinib-chemotherapy-nejm-2023","flaura2"]},{"item":"LAURA: overall survival for osimertinib after chemoradiotherapy in stage III EGFR-mutated disease","expected":"Study completion 29 October 2027 (estimated, ClinicalTrials.gov NCT03521154)","source":"https://clinicaltrials.gov/study/NCT03521154","refs":["paper-lu-laura-osimertinib-stage-iii-nejm-2024","laura"]},{"item":"MARIPOSA: final overall survival for amivantamab plus lazertinib against osimertinib in first line","expected":"Study completion 16 February 2028 (estimated, ClinicalTrials.gov NCT04487080)","source":"https://clinicaltrials.gov/study/NCT04487080","refs":["paper-mariposa-nejm-2024","mariposa"]},{"item":"DeLLphi-304: final analysis of tarlatamab against chemotherapy in relapsed small-cell lung cancer","expected":"Study completion 26 March 2028 (estimated, ClinicalTrials.gov NCT05740566)","source":"https://clinicaltrials.gov/study/NCT05740566","refs":["paper-tarlatamab-sclc-n-engl-j-med-2025","paper-dellphi-301-nejm-2023","dellphi-304"]},{"item":"AEGEAN: final overall survival for perioperative durvalumab in resectable disease","expected":"Study completion 11 September 2028 (estimated, ClinicalTrials.gov NCT03800134)","source":"https://clinicaltrials.gov/study/NCT03800134","refs":["paper-heymach-aegean-perioperative-durvalumab-nejm-2023"]},{"item":"CROWN: final analysis of first-line lorlatinib against crizotinib, including long-term intracranial control","expected":"Study completion 31 December 2028 (estimated, ClinicalTrials.gov NCT03052608)","source":"https://clinicaltrials.gov/study/NCT03052608","refs":["paper-shaw-crown-lorlatinib-crizotinib-nejm-2020","crown"]},{"item":"ALINA: overall survival for adjuvant alectinib against chemotherapy in resected ALK-positive disease, the longest-dated of the practice-changing perioperative trials","expected":"Study completion 19 November 2031 (estimated, ClinicalTrials.gov NCT03456076)","source":"https://clinicaltrials.gov/study/NCT03456076","refs":["paper-wu-alina-adjuvant-alectinib-nejm-2024","alina"]},{"item":"TRACERx: the full evolutionary and ctDNA dataset on 814 patients, the deepest longitudinal study of lung cancer evolution","expected":"Study completion November 2035 (estimated, ClinicalTrials.gov NCT01888601)","source":"https://clinicaltrials.gov/study/NCT01888601","refs":["paper-tracerx-100-nejm-2017","paper-abbosh-phylogenetic-ctdna-lung-cancer-nature-2017"]}]},{"id":"lymphoma-roadmap","kind":"roadmap","name":"Lymphoma roadmap: from a jaw tumour in Uganda and the first human cancer virus to gene-expression subtypes, PET-adapted chemotherapy, CAR-T cells, bispecific antibodies and the genetics-directed trials now recruiting","aka":["Lymphoma history","Lymphoma evidence roadmap","Hodgkin and non-Hodgkin lymphoma roadmap","How lymphoma treatment was worked out"],"tldr":"Lymphoma was the first cancer shown to be caused by a virus, the first common cancer sorted into subtypes by reading which genes were switched on, and the first in which a patient's own immune cells were reprogrammed to cure them. This roadmap follows the evidence from 1958 to the trials reading out in 2032.","summary":"Lymphoma has been first at more things than any other cancer, and the reason is that you can get hold of it. A lymph node is easy to biopsy, the cells grow in culture, the disease circulates in blood, and it responds to treatment fast enough that a trial reads out in years rather than decades.\n\nThat is why the first human tumour virus was found in it. Denis Burkitt described a jaw tumour in Ugandan children in 1958 and mapped where it occurred; Epstein, Achong and Barr saw virus particles in cells cultured from one of his biopsies in 1964. Twenty years later the first human retrovirus, now called human T-lymphotropic virus type 1, was isolated from the lymphocytes of a patient with a T-cell lymphoma by Poiesz and Gallo, and tied to adult T-cell leukaemia across a Japanese population by Hinuma.\n\nIt is also why lymphoma was the first common cancer taken apart by gene expression. Alizadeh and Staudt showed in 2000 that diffuse large B-cell lymphoma is at least two diseases; Rosenwald turned that into a survival predictor in 2002; Hans gave pathology laboratories a three-stain version in 2004. The genetic classifications followed in 2018, when Chapuy and Schmitz published five clusters and four subtypes within three weeks of each other, and Wright's LymphGen tool in 2020 made it possible to classify one patient's tumour with a probability attached.\n\nTreatment moved on three tracks. In Hodgkin lymphoma the whole effort since the 1990s has been to take treatment away without losing the cure, because the Dutch cohorts showed that 48.5 per cent of survivors develop a second cancer within 40 years and 50 per cent develop cardiovascular disease. HD10 halved the chemotherapy and cut the radiation dose; HD18 and AHL2011 used the scan after two cycles to shorten or soften the intensive regimen; HD16 and EORTC H10 tried to drop radiotherapy on a clear scan and could not. In aggressive B-cell lymphoma, R-CHOP has survived every challenger except one: obinutuzumab failed in GOYA, dose-adjusted EPOCH-R failed in CALGB 50303, ibrutinib failed overall in PHOENIX, and only polatuzumab vedotin in POLARIX improved on it. In indolent lymphoma the question has been how long to treat rather than how hard, and PRIMA answered it with six extra years before relapse and no change in survival.\n\nThe last decade belongs to the immune treatments. ZUMA-1, JULIET and TRANSCEND NHL 001 made CAR-T a third line in large B-cell lymphoma; ZUMA-7 and TRANSFORM moved it to second line, while BELINDA failed in the same setting with a 52-day manufacturing wait. ELARA and ZUMA-5 brought it to follicular lymphoma. The CD20 bispecific antibodies arrived alongside, off the shelf and without apheresis, and inMIND, ELM-2 and ROSEWOOD show the relapsed indolent setting is now crowded with options.\n\nWhat has not been solved: the genetic subtypes have not yet changed a single first-line treatment, the T-cell lymphomas have almost no randomised evidence at all, no trial has shown that acting on a circulating tumour DNA result improves anything, and the drugs that cure this disease are unavailable to most of the people who get it.","asOf":"2026-10-01","links":[{"label":"NCI PDQ: adult non-Hodgkin lymphoma treatment (health professional)","url":"https://www.cancer.gov/types/lymphoma/hp/adult-nhl-treatment-pdq"},{"label":"NCI PDQ: adult Hodgkin lymphoma treatment (health professional)","url":"https://www.cancer.gov/types/lymphoma/hp/adult-hodgkin-treatment-pdq"},{"label":"ESMO clinical practice guidelines: haematological malignancies","url":"https://www.esmo.org/guidelines/esmo-clinical-practice-guidelines-haematological-malignancies"},{"label":"British Society for Haematology guidelines","url":"https://b-s-h.org.uk/guidelines/"},{"label":"ClinicalTrials.gov NCT04685616","url":"https://clinicaltrials.gov/study/NCT04685616"},{"label":"ClinicalTrials.gov NCT06337318","url":"https://clinicaltrials.gov/study/NCT06337318"}],"tags":[],"related":["immunotherapy-roadmap","chemotherapy-roadmap","radiation-roadmap","idea-chemo-free-hodgkin","idea-cd30-car-t-hodgkin","idea-prev-ebv-vaccine","lymphoma-ev-genetic-subtype-directed-first-line","lymphoma-ev-ctdna-instead-of-the-interim-scan","lymphoma-ev-radiotherapy-free-early-hodgkin","lymphoma-ev-fixed-duration-chemotherapy-free-first-line","lymphoma-ev-randomised-evidence-for-the-t-cell-lymphomas","lymphoma-ev-manufacturing-time-as-a-trial-endpoint","lymphoma-ev-the-drugs-that-cure-and-the-places-without-them","lymphoma-ev-late-effects-of-the-treatments-given-now"],"cancers":["non-hodgkin-lymphoma","dlbcl","follicular-lymphoma","mantle-cell-lymphoma","marginal-zone-lymphoma","malt-lymphoma","primary-cns-lymphoma","primary-mediastinal-b-cell-lymphoma","burkitt-lymphoma","peripheral-t-cell-lymphoma","cutaneous-t-cell-lymphoma","hodgkin-lymphoma","early-stage-classical-hodgkin-lymphoma","advanced-stage-classical-hodgkin-lymphoma","relapsed-refractory-hodgkin-lymphoma","waldenstrom"],"sections":["chemotherapy","immunotherapy","cell-therapy","radiation","targeted-therapy","diagnostics","adcs","prevention"],"technologies":["car-t","bispecific-antibody","t-cell-engager","adc","monoclonal-antibody","checkpoint-inhibitor","pet-ct","radiotherapy","liquid-biopsy","wes-wgs","ngs","cytotoxic-chemotherapy"],"targets":["cd20","cd19","cd30","cd79b","cd3","bcl2","bcl6","myc","myd88","ezh2","btk","notch1","notch2","tp53","ccnd1","pd1"],"drugs":["rituximab","obinutuzumab","polatuzumab-vedotin","brentuximab-vedotin","tafasitamab","lenalidomide","ibrutinib","acalabrutinib","zanubrutinib","bendamustine","axicabtagene-ciloleucel","tisagenlecleucel","lisocabtagene-maraleucel","glofitamab","epcoritamab","mosunetuzumab","odronextamab","nivolumab","pembrolizumab","asparaginase"],"companies":["roche-genentech","novartis","gilead","bms","abbvie","genmab","incyte","regeneron","astrazeneca","pfizer","johnson-johnson"],"institutions":["nci","dana-farber","mskcc","cruk","nice","esmo"],"pathways":["bcr-signalling","jak-stat","apoptosis-bcl2"],"terms":["cell-of-origin","lugano-classification","deauville-score","ipi-score","flipi","ctdna","mrd","crs","icans","r-chop","abvd-beacopp","double-hit-lymphoma","autologous-transplant","maintenance-therapy","lymphoma-tx-pod24","lymphoma-tx-car-t-pathway","lymphoma-tx-regimen-alphabet"],"trials":["polarix","echelon-1","echelon-2","hd21","rathl","zuma-1","zuma-5","zuma-7","transform","belinda","epcore-nhl-1","triangle","gallium","relevance","alcanza","ielsg32","ielsg43","starglo","shine","enrich","lyma","flyer","calgb-50303","goya","remarc","polargo","juliet","transcend-nhl-001","prima-follicular","ielsg-19","trog-99-03","elara","rosewood","hd10","hd16","hd18","ahl2011","eortc-h10","jcog9801","smile-enktl","radar-hodgkin","polar-bear","arched","prima-cns","fortplus","mosun-lbt-fl","mosun-len-mzl"],"people":["louis-staudt","ash-alizadeh","gilles-salles","laurie-sehn","martin-dreyling","michael-wang","peter-borchmann","andreas-engert","catherine-thieblemont","franck-morschhauser","andres-ferreri","caron-jacobson","stephen-schuster","jason-westin","michael-dickinson","john-leonard"],"bottlenecks":["b-tumor-heterogeneity","b-biomarker-validation","b-manufacturing-cell-therapy","b-survivorship","b-toxicity-qol","b-aging-comorbidity","b-rare-cancers","b-global-access","b-trial-design","b-negative-results","b-dormancy-mrd","b-drug-pricing"],"keyPapers":["paper-alizadeh-nature","paper-rosenwald-molecular-profiling-dlbcl-nejm-2002","paper-hans-immunohistochemistry-cell-of-origin-dlbcl-blood-2004","paper-chapuy-molecular-subtypes-dlbcl-nat-med-2018","paper-schmitz-genetics-pathogenesis-dlbcl-nejm-2018","paper-wright-lymphgen-genetic-subtypes-dlbcl-cancer-cell-2020","paper-cheson-j-clin-oncol","paper-casulo-pod24-follicular-lymphoma-jco-2015","paper-scherer-ctdna-lymphoma-subtypes-genome-evolution-sci-transl-med-2016","paper-kurtz-j-clin-oncol","paper-burkitt-sarcoma-involving-jaws-african-children-br-j-surg-1958","paper-epstein-virus-particles-burkitt-lymphoblasts-lancet-1964","paper-poiesz-htlv-retrovirus-cutaneous-t-cell-lymphoma-pnas-1980","paper-hinuma-adult-t-cell-leukaemia-antigen-pnas-1981","paper-schaapveld-second-cancer-risk-40-years-hodgkin-nejm-2015","paper-van-nimwegen-cardiovascular-disease-after-hodgkin-jama-intern-med-2015","paper-polarix-polatuzumab-rchp-nejm-2022","paper-zuma-7-axi-cel-second-line-nejm-2022","paper-belinda-tisagenlecleucel-second-line-nejm-2022","paper-ghsg-hd21-brecadd-vs-ebeacopp-advanced-hodgkin-lancet-2024","paper-prima-final-rituximab-maintenance-follicular-jco-2019","paper-enrich-ibrutinib-rituximab-mantle-cell-lancet-2025","paper-inmind-tafasitamab-lenalidomide-rituximab-follicular-lancet-2026"],"journals":[],"dependsOn":[],"notes":[],"steps":[{"era":"1958-1981","title":"Two viruses, found because lymphoma is the cancer you can get hold of","description":"Denis Burkitt described a tumour involving the jaws in African children in 1958 and mapped where it occurred; the geography pointed at an infectious cause. In 1964 Epstein, Achong and Barr saw virus particles in lymphoblasts cultured from one of his biopsies, the first virus ever found in a human tumour, and the start of the field that now includes human papillomavirus, hepatitis B and C, Helicobacter pylori and human herpesvirus 8. Neither paper has an abstract indexed on Europe PMC, so no figure from them is quoted here.\n\nThe second virus came from the other side of the lymphoid system. Poiesz, Gallo and colleagues isolated type C retrovirus particles from the lymphocytes of a patient with a T-cell lymphoma in 1980, the first human retrovirus, characterising a reverse transcriptase that preferred magnesium to manganese and six particle proteins unlike those of any known primate retrovirus. The year after, Hinuma's group in Japan found antibodies to a related antigen in all 44 patients with adult T-cell leukaemia they tested, in 26 per cent of healthy adults from endemic areas and in almost none from elsewhere. Human T-lymphotropic virus type 1 is now screened for in blood donations.","refs":["paper-burkitt-sarcoma-involving-jaws-african-children-br-j-surg-1958","paper-epstein-virus-particles-burkitt-lymphoblasts-lancet-1964","paper-poiesz-htlv-retrovirus-cutaneous-t-cell-lymphoma-pnas-1980","paper-hinuma-adult-t-cell-leukaemia-antigen-pnas-1981","idea-prev-ebv-vaccine"],"status":"historic"},{"era":"1998-2010","title":"How little is enough: the Hodgkin de-escalation programme begins","description":"Hodgkin lymphoma was curable before anyone knew what it was made of, and by the 1990s the question had become how much treatment could be removed. HD10 answered it for early favourable disease, randomising 1,370 patients in a two by two design and finding no difference between four and two cycles of ABVD (five-year freedom from treatment failure 93.0 against 91.1 per cent, p = 0.39) or between 30 Gy and 20 Gy of involved-field radiotherapy (p = 1.00). Two cycles with 20 Gy became the standard, and the four-cycle, 30 Gy group had the most toxicity.\n\nThe reason the question mattered arrived in full later. The Dutch cohorts measured what cure costs: 48.5 per cent of survivors developed a second cancer within 40 years, with risk still raised at 35 years, and 50 per cent developed cardiovascular disease, with coronary heart disease and heart failure still four to six times the population rate after 35 years. The second-cancer risk did not fall for patients treated between 1989 and 2000 compared with those treated in the 1960s and 1970s, despite the less toxic protocols introduced in between.","refs":["paper-ghsg-hd10-reduced-intensity-early-hodgkin-nejm-2010","paper-schaapveld-second-cancer-risk-40-years-hodgkin-nejm-2015","paper-van-nimwegen-cardiovascular-disease-after-hodgkin-jama-intern-med-2015","paper-travis-breast-cancer-after-hodgkin-radiotherapy-jama-2003","hd10","lymphoma-ev-late-effects-of-the-treatments-given-now"],"status":"historic"},{"era":"2000-2020","title":"Reading the genes, and the twenty years it took to make that useful","description":"Alizadeh and Staudt showed in 2000 that diffuse large B-cell lymphoma contains at least two diseases that look identical under the microscope. Rosenwald profiled 240 biopsies in 2002, found germinal-centre, activated and type 3 subgroups, and built a 17-gene survival predictor independent of the International Prognostic Index; the stromal and immune signatures in that paper anticipated the tumour microenvironment era. Hans put the classification within reach of ordinary pathology in 2004, using CD10, BCL6 and MUM1 to split 152 cases into germinal-centre and non-germinal-centre groups with five-year survival of 76 against 34 per cent.\n\nThen the field stalled. The classification predicted outcome but did not direct treatment, and the trials that selected patients by it, PHOENIX among them, failed. The genetic classifications of 2018 were the answer to why: Chapuy's five clusters from 304 tumours and Schmitz's four subtypes from 574 both cut the disease finer than the stain could, and Schmitz's MCD and BN2 subtypes carried a mechanism, chronic active B-cell receptor signalling, with a drug class already in the clinic. Wright's LymphGen tool in 2020 turned cohort clustering into a probability for one patient's tumour, and extended the classification to seven subtypes that share genetics with indolent and extranodal lymphomas.","refs":["paper-alizadeh-nature","paper-rosenwald-molecular-profiling-dlbcl-nejm-2002","paper-hans-immunohistochemistry-cell-of-origin-dlbcl-blood-2004","paper-chapuy-molecular-subtypes-dlbcl-nat-med-2018","paper-schmitz-genetics-pathogenesis-dlbcl-nejm-2018","paper-wright-lymphgen-genetic-subtypes-dlbcl-cancer-cell-2020","paper-phoenix-ibrutinib-r-chop-non-gcb-dlbcl-jco-2019","cell-of-origin","lymphoma-ev-genetic-subtype-directed-first-line"],"status":"historic"},{"era":"2005-2022","title":"Everything that failed to beat R-CHOP, and the one thing that did","description":"R-CHOP has been the first-line standard for aggressive B-cell lymphoma since rituximab was added to CHOP, and almost nothing has improved on it. CALGB 50303 compared dose-adjusted EPOCH-R, which many centres had adopted on single-arm evidence, and found no difference in progression-free or overall survival with substantially more febrile neutropenia, mucositis and neuropathy. GOYA substituted obinutuzumab in 1,418 patients and got a hazard ratio of 0.92 with more grade 3 to 5 and fatal adverse events, despite the same substitution working in follicular lymphoma and chronic lymphocytic leukaemia. REMARC added two years of lenalidomide maintenance and delayed progression without extending life. PHOENIX added ibrutinib and failed overall, helping patients under 60 and harming those over 60 by stopping them finishing the chemotherapy.\n\nWhat worked was subtraction and substitution rather than addition. FLYER showed that four cycles of R-CHOP with two extra rituximab doses was non-inferior to six in young patients with low-risk limited-stage disease, at three-year progression-free survival of 96 per cent and roughly a quarter fewer adverse events. POLARIX replaced vincristine with polatuzumab vedotin and improved progression-free survival, the only first-line improvement in two decades.","refs":["paper-calgb-50303-da-epoch-r-vs-r-chop-jco-2019","paper-goya-obinutuzumab-vs-rituximab-chop-dlbcl-jco-2017","paper-remarc-lenalidomide-maintenance-dlbcl-jco-2017","paper-phoenix-ibrutinib-r-chop-non-gcb-dlbcl-jco-2019","paper-flyer-four-vs-six-cycles-r-chop-lancet-2019","paper-polarix-polatuzumab-rchp-nejm-2022","flyer","calgb-50303","goya","remarc","polarix"],"status":"current"},{"era":"2006-2019","title":"The scan after two cycles, and what it is good for","description":"Four large trials asked the same question from different directions: can a positron emission tomography scan after two cycles of chemotherapy decide what happens next. The answer turned out to be asymmetric.\n\nIntensifying on a positive scan works. EORTC H10 switched scan-positive early-stage patients from ABVD to escalated BEACOPP with involved-node radiotherapy and raised five-year progression-free survival from 77.4 to 90.6 per cent. De-escalating on a negative scan works for chemotherapy. HD18 shortened escalated BEACOPP from six or eight cycles to four in scan-negative advanced disease with five-year progression-free survival of 92.2 against 90.8 per cent and half the severe infections; AHL2011 switched scan-negative patients to ABVD after two cycles of escalated BEACOPP with five-year progression-free survival of 85.7 against 86.2 per cent and grade 3 to 4 anaemia falling from 69 to 28 per cent. RATHL had already shown that bleomycin could be dropped after a negative scan in advanced disease.\n\nDe-escalating on a negative scan does not work for radiotherapy. HD16 omitted 20 Gy after a negative scan and lost 7.3 percentage points of five-year progression-free survival; H10 could not demonstrate non-inferiority in either risk group, and in the favourable group five-year progression-free survival was 99.0 per cent with radiotherapy against 87.1 per cent without.","refs":["paper-eortc-h10-pet-adapted-early-hodgkin-jco-2017","paper-ghsg-hd18-pet-guided-escalated-beacopp-lancet-2017","paper-ahl2011-pet-adapted-treatment-advanced-hodgkin-lancet-oncol-2019","paper-ghsg-hd16-pet-guided-early-favourable-hodgkin-jco-2019","paper-rathl-interim-pet-adapted-abvd-advanced-hodgkin-nejm-2016","hd16","hd18","ahl2011","eortc-h10","rathl","deauville-score","lymphoma-ev-radiotherapy-free-early-hodgkin"],"status":"current"},{"era":"2011-2026","title":"Indolent lymphoma: how long to treat, and the two-year mark that splits the disease","description":"Follicular lymphoma is treated in episodes across decades, so the questions are about duration and sequence rather than intensity. PRIMA randomised 1,018 responders to two years of rituximab maintenance or observation and reported median progression-free survival of 10.5 against 4.1 years at nine years, with ten-year overall survival of about 80 per cent in both arms: the cleanest demonstration in lymphoma that delaying progression and extending life are different things.\n\nCasulo gave the field the marker that matters. Of 588 patients given first-line R-CHOP, 19 per cent progressed within two years, and their five-year overall survival was 50 per cent against 90 per cent, with an index-adjusted hazard ratio of 6.44. That group now triggers a repeat biopsy, because transformation is the commonest cause, and goes to treatment that does not depend on chemotherapy sensitivity.\n\nFor the rest of the disease the options multiplied. GALLIUM and RELEVANCE changed the first line; ELARA and ZUMA-5 brought CAR-T, with complete responses in 69 and 74 per cent; ELM-2 and the other CD20 bispecific antibodies brought off-the-shelf alternatives, with a 73.4 per cent complete response rate for odronextamab; ROSEWOOD paired a Bruton tyrosine kinase inhibitor with a type II antibody; inMIND added a CD19 antibody to lenalidomide and rituximab for a progression-free survival hazard ratio of 0.43. In marginal zone lymphoma, IELSG-19 remains the only randomised first-line systemic trial.","refs":["paper-prima-final-rituximab-maintenance-follicular-jco-2019","paper-casulo-pod24-follicular-lymphoma-jco-2015","paper-elara-tisagenlecleucel-follicular-nat-med-2022","paper-zuma-5-axi-cel-indolent-lymphoma-lancet-oncol-2022","paper-elm-2-odronextamab-follicular-ann-oncol-2024","paper-inmind-tafasitamab-lenalidomide-rituximab-follicular-lancet-2026","paper-ielsg-19-chlorambucil-rituximab-malt-jco-2017","prima-follicular","elara","zuma-5","rosewood","ielsg-19","lymphoma-tx-pod24"],"status":"current"},{"era":"2015-2026","title":"Cells and engagers: the immune treatments that work when chemotherapy does not","description":"ZUMA-1, JULIET and TRANSCEND NHL 001 established CD19 CAR-T in large B-cell lymphoma after two or more lines between 2017 and 2020, with objective responses in 73 per cent and complete responses in 53 per cent in the largest of them, and grade 3 or worse cytokine release syndrome in 2 per cent for lisocabtagene maraleucel against much higher rates for the other products.\n\nThen the three products split in the second line. ZUMA-7 and TRANSFORM both beat salvage chemotherapy with an autologous transplant. BELINDA, testing tisagenlecleucel in the same setting, did not: median event-free survival was 3.0 months in both arms. The explanation most often offered is the 52-day median interval from leukapheresis to infusion, during which 25.9 per cent of the CAR-T group progressed against 13.8 per cent of the standard-care group, compounded by a baseline imbalance that favoured the comparator. It is a cross-trial inference, and the fact that it is the best available explanation for a 322-patient randomised failure says something about how the field measures what it is doing.\n\nThe CD20 bispecific antibodies arrived alongside and solved the logistics rather than the biology: no apheresis, no manufacturing wait, available the week the decision is made. STARGLO, EPCORE NHL-1, POLARGO and ECHELON-3 between them now give transplant-ineligible relapsed diffuse large B-cell lymphoma four options with randomised or pivotal evidence where a decade ago it had none.","refs":["paper-transcend-nhl-001-liso-cel-lancet-2020","paper-juliet-tisagenlecleucel-dlbcl-nejm-2019","paper-zuma-1-axi-cel-nejm-2017","paper-zuma-7-axi-cel-second-line-nejm-2022","paper-transform-liso-cel-lancet-2022","paper-belinda-tisagenlecleucel-second-line-nejm-2022","paper-polargo-polatuzumab-r-gemox-dlbcl-jco-2026","paper-echelon-3-brentuximab-lenalidomide-rituximab-dlbcl-jco-2025","zuma-7","transform","belinda","transcend-nhl-001","juliet","polargo","lymphoma-ev-manufacturing-time-as-a-trial-endpoint"],"status":"current"},{"era":"2017-2026","title":"Mantle cell lymphoma: three ways to use a Bruton tyrosine kinase inhibitor, and none of them extends life","description":"LyMa established three years of rituximab maintenance after autologous transplantation in patients under 66, with four-year event-free survival of 79 against 61 per cent and an overall survival benefit, which is rare for a maintenance strategy in lymphoma.\n\nFor older patients the question became where to put the Bruton tyrosine kinase inhibitor. SHINE added ibrutinib to bendamustine-rituximab and gained 28 months of progression-free survival (80.6 against 52.9 months, hazard ratio 0.75) with no survival difference. ECHO repeated the design with acalabrutinib and gained 17 months (66.4 against 49.6, hazard ratio 0.73), again with no survival difference and grade 3 or greater adverse events in roughly 89 per cent of both arms. ENRICH took the opposite route and removed the chemotherapy: ibrutinib with rituximab beat immunochemotherapy with an adjusted hazard ratio of 0.69, driven almost entirely by the comparison against R-CHOP (0.37) rather than against bendamustine-rituximab (0.91).\n\nTRIANGLE meanwhile asked whether the autologous transplant is still needed in younger patients when ibrutinib is added to induction and maintenance. Taken together, the four trials mean a person over 60 with mantle cell lymphoma now has a chemotherapy-free first-line option, and that nobody has yet shown any of these strategies makes them live longer.","refs":["paper-lyma-rituximab-maintenance-after-transplant-mantle-cell-nejm-2017","paper-shine-ibrutinib-bendamustine-rituximab-mantle-cell-nejm-2022","paper-echo-acalabrutinib-bendamustine-rituximab-mantle-cell-jco-2025","paper-enrich-ibrutinib-rituximab-mantle-cell-lancet-2025","paper-triangle-ibrutinib-mantle-cell-lymphoma-dreyling-lancet-2024","lyma","shine","enrich","triangle","lymphoma-ev-fixed-duration-chemotherapy-free-first-line"],"status":"current"},{"era":"2007-2026","title":"The T-cell lymphomas, where almost nothing has been randomised","description":"Two trials carry most of the randomised evidence for the T-cell lymphomas, and one of them is not randomised. JCOG9801 is the only controlled trial ever run exclusively in adult T-cell leukaemia/lymphoma: 118 patients, a complete response rate of 40 against 25 per cent for an intensive Japanese regimen over biweekly CHOP, three-year overall survival of 24 against 13 per cent that did not reach significance on two-sided testing, and grade 4 thrombocytopenia in 74 against 17 per cent. SMILE is a 38-patient single-arm phase 2 that made extranodal NK/T-cell lymphoma treatable, with an overall response rate of 79 per cent and one-year overall survival of 55 per cent, by building the regimen on asparaginase rather than on an anthracycline.\n\nECHELON-2 is the exception that shows what is possible: brentuximab vedotin with CHP improved survival in CD30-positive peripheral T-cell lymphoma in a global double-blind randomised trial. ALCANZA did the same for cutaneous T-cell lymphoma.\n\nEverything else, including the choice of first-line regimen in peripheral T-cell lymphoma not otherwise specified, rests on single-arm studies and registry series. Several randomised trials are recruiting at last, in peripheral T-cell lymphoma with the T follicular helper phenotype and in NK/T-cell disease.","refs":["paper-jcog9801-vcap-amp-vecp-adult-t-cell-leukaemia-jco-2007","paper-smile-chemotherapy-nk-t-cell-lymphoma-jco-2011","paper-horwitz-lancet","paper-alcanza-brentuximab-vedotin-lancet-2017","jcog9801","smile-enktl","echelon-2","alcanza","lymphoma-ev-randomised-evidence-for-the-t-cell-lymphomas"],"status":"current"},{"era":"2026-2032","title":"What the registry says is coming","description":"The Hodgkin de-escalation question gets its best-designed attempt yet. RADAR (NCT04685616, 1,042 estimated participants; recruiting) randomises ABVD against A2VD, which replaces the bleomycin with brentuximab vedotin, and omits radiotherapy entirely in anyone with a Deauville score of 1 to 3 after two cycles; primary completion is listed for September 2030.\n\nThe oldest patients with diffuse large B-cell lymphoma finally get their own trials. POLAR BEAR (NCT04332822, 300 estimated participants; recruiting) tests polatuzumab vedotin in place of vincristine in R-miniCHOP in people aged 80 or over, or 75 or over and frail by a geriatric assessment, with a primary completion date of 28 December 2025 that has now passed. ARCHED (NCT05820841, 330 estimated participants; recruiting) adds acalabrutinib to R-miniCHOP, with primary completion listed for February 2029.\n\nThe bispecific antibodies move to the front. A National Cancer Institute trial (NCT06337318, 600 estimated participants; recruiting) compares mosunetuzumab with rituximab as first treatment for low tumour burden follicular lymphoma, with primary completion listed for 31 March 2032, and a European trial (NCT06006117, 260 estimated participants; recruiting) runs mosunetuzumab with lenalidomide against the investigator's choice in relapsed marginal zone lymphoma, primary completion September 2027. In primary central nervous system lymphoma, PRIMA-CNS (NCT06830421, 340 estimated participants; recruiting) compares conventional immunochemotherapy with a short induction and an autologous transplant in elderly patients, primary completion 31 August 2029. FORTplus (NCT05045664, 100 estimated participants; recruiting) tests whether an anti-CD20 antibody makes a 4 Gy radiotherapy dose safe in early follicular lymphoma, primary completion 30 September 2027.","refs":["radar-hodgkin","polar-bear","arched","mosun-lbt-fl","mosun-len-mzl","prima-cns","fortplus","lymphoma-ev-radiotherapy-free-early-hodgkin","lymphoma-ev-fixed-duration-chemotherapy-free-first-line"],"status":"emerging"},{"era":"What sets the pace","title":"Four things no trial on this page has fixed","description":"First, the genetics have not reached the clinic. Three classifications and a probabilistic tool exist, and not one first-line treatment decision anywhere is made by genetic subtype outside a trial. The gap between Schmitz in 2018 and a trial that assigns treatment by LymphGen is the clearest unfinished business in the disease.\n\nSecond, nothing acts on a blood test. Circulating tumour DNA predicts outcome at diagnosis, detects residual disease better than imaging, reads cell of origin from plasma and flags transformation before it declares itself, and no randomised trial has yet shown that changing treatment on the strength of it helps anyone.\n\nThird, the T-cell lymphomas have almost no randomised evidence, and the diseases concentrated in east Asia, the Caribbean, west Africa and Latin America have least of all. Adult T-cell leukaemia/lymphoma has had exactly one controlled trial, in 1998.\n\nFourth, access. Rituximab transformed B-cell lymphoma in 1997 and is still unavailable or unaffordable in much of the world; asparaginase, which makes NK/T-cell lymphoma treatable, is intermittently supplied; CAR-T requires an apheresis service, a cryopreservation chain and a centre able to manage cytokine release syndrome. The treatments on this page cure a higher proportion of people with lymphoma than of any other common cancer, in the places that have them.","refs":["paper-wright-lymphgen-genetic-subtypes-dlbcl-cancer-cell-2020","paper-scherer-ctdna-lymphoma-subtypes-genome-evolution-sci-transl-med-2016","paper-jcog9801-vcap-amp-vecp-adult-t-cell-leukaemia-jco-2007","b-global-access","b-rare-cancers","b-biomarker-validation","lymphoma-ev-genetic-subtype-directed-first-line","lymphoma-ev-ctdna-instead-of-the-interim-scan","lymphoma-ev-randomised-evidence-for-the-t-cell-lymphomas","lymphoma-ev-the-drugs-that-cure-and-the-places-without-them"],"status":"current"}],"watch":[{"item":"POLAR BEAR primary completion: polatuzumab vedotin in place of vincristine in R-miniCHOP for patients aged 80 or over, or 75 or over and frail (300 estimated participants; recruiting). The registry date has passed and no report has appeared","expected":"2025-12-28","source":"https://clinicaltrials.gov/study/NCT04332822","refs":["polar-bear","polatuzumab-vedotin"]},{"item":"Mosunetuzumab with lenalidomide against the investigator's choice in relapsed or refractory marginal zone lymphoma, primary completion (260 estimated participants; recruiting)","expected":"2027-09","source":"https://clinicaltrials.gov/study/NCT06006117","refs":["mosun-len-mzl","mosunetuzumab"]},{"item":"FORTplus primary completion: 4 Gy radiotherapy with an anti-CD20 antibody against standard-dose radiotherapy with rituximab in early-stage follicular lymphoma (100 estimated participants; recruiting)","expected":"2027-09-30","source":"https://clinicaltrials.gov/study/NCT05045664","refs":["fortplus","obinutuzumab"]},{"item":"ARCHED primary completion: acalabrutinib added to R-miniCHOP in older adults with untreated diffuse large B-cell lymphoma (330 estimated participants; recruiting)","expected":"2029-02","source":"https://clinicaltrials.gov/study/NCT05820841","refs":["arched","acalabrutinib"]},{"item":"PRIMA-CNS primary completion: conventional immunochemotherapy against short induction with autologous transplant in elderly primary central nervous system lymphoma (340 estimated participants; recruiting)","expected":"2029-08-31","source":"https://clinicaltrials.gov/study/NCT06830421","refs":["prima-cns"]},{"item":"RADAR primary completion: brentuximab vedotin in place of bleomycin, with radiotherapy omitted entirely after a Deauville score of 1 to 3 in early-stage Hodgkin lymphoma (1,042 estimated participants; recruiting)","expected":"2030-09","source":"https://clinicaltrials.gov/study/NCT04685616","refs":["radar-hodgkin","brentuximab-vedotin"]},{"item":"Mosunetuzumab against rituximab as first treatment for low tumour burden follicular lymphoma, primary completion (600 estimated participants; recruiting)","expected":"2032-03-31","source":"https://clinicaltrials.gov/study/NCT06337318","refs":["mosun-lbt-fl","mosunetuzumab"]}]},{"id":"molecular-imaging-roadmap","kind":"roadmap","name":"Molecular imaging roadmap: FDG → PSMA → FAP → antigen and immune PET","aka":[],"tldr":"From a sugar tracer that lights up most cancers to tracers that show a single protein, a stromal cell type, or the immune cells inside a tumour.","summary":"The molecular imaging roadmap moves from PET scanners and FDG, made routine by PET/CT, to receptor tracers such as 68Ga-DOTATATE and PSMA PET that outperform anatomic imaging and enable theranostics. The current step adds stromal FAPI PET and total-body scanners, and the emerging step brings drug-target and immune PET: TROP2, HER2, B7-H3 and Nectin-4 tracers to select and sequence ADCs, CD8 and granzyme PET to monitor immunotherapy, and PARP PET. The speculative end is multi-tracer same-day imaging, PET-guided adaptive radiotherapy and imaging-derived digital twins. Each new tracer converts a biopsy biomarker into a whole-body map; the route sits in the Imaging section and links PET, PET/CT, FDG PET, PSMA PET, FAPI PET, TROP2 PET, HER2 PET, immuno-PET, PARP PET and PET/MRI.","asOf":"2026-09-04","links":[{"label":"VISION: lutetium-177 PSMA-617 radioligand therapy extends survival in advanced prostate cancer (New England Journal of Medicine 2021)","url":"https://doi.org/10.1056/NEJMoa2107322"},{"label":"DETECT-A: a blood test plus PET-CT found treatable cancers in 10,000 women with no symptoms (Science 2020)","url":"https://doi.org/10.1126/science.abb9601"}],"tags":[],"related":["prostate-roadmap"],"cancers":[],"sections":["imaging"],"technologies":["pet","pet-ct","fdg-pet","psma-pet","fapi-pet","trop2-pet","her2-pet","immuno-pet","parp-pet","pet-mri"],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"steps":[{"era":"1975-2001","title":"PET and FDG","description":"PET scanners (1975) and FDG (1976) developed; FDG PET adopted for lymphoma, lung, melanoma staging in the 1990s; PET/CT (2001) makes it routine.","refs":["fdg-pet","pet-ct"],"status":"historic"},{"era":"2008-2020","title":"Receptor PET: SSTR and PSMA","description":"68Ga-DOTATATE (Netspot 2016) and 68Ga/18F-PSMA (2020-21) show receptor tracers outperform anatomic imaging and enable theranostics.","refs":["psma-pet","sstr2"],"status":"historic"},{"era":"2018-2026","title":"Stromal PET and total-body scanners","description":"FAPI tracers image >90% of epithelial cancers with high contrast; registrational trials underway. Total-body PET (uEXPLORER, Quadra) enables 40x sensitivity, low-dose paediatric and dynamic imaging. 18F-FES (ER) approved 2020; 89Zr-girentuximab (CAIX) filed. Pylarify TruVu approved 2026.","refs":["fapi-pet","pet-ct","united-imaging","pylarify"],"status":"current"},{"era":"2024-2028","title":"Drug-target and immune PET","description":"TROP2, HER2, B7-H3, Nectin-4 antibody and nanobody tracers to select and sequence ADCs; CD8 and granzyme PET to predict and monitor immunotherapy response; PARP PET for PARP-inhibitor selection; AI quantification and radiomics on standard scans.","refs":["trop2-pet","her2-pet","immuno-pet","parp-pet","radiology-ai-screening"],"status":"emerging"},{"era":"2028+","title":"Speculative","description":"Multi-tracer same-day imaging on total-body PET; PET-guided adaptive radiotherapy (biology-guided RT); routine antigen PET before every ADC; imaging-derived digital twins of tumour heterogeneity feeding treatment algorithms.","refs":["reflexion","trop2-pet-to-adc"],"status":"speculative"}],"watch":[]},{"id":"paediatric-oncology-roadmap","kind":"roadmap","name":"Paediatric oncology roadmap: cooperative-group cures → engineered immunity → drugs developed for children first","aka":[],"tldr":"Children's cancers were made curable by decades of cooperative trials that refined chemotherapy dose by dose. The next gains come from immunotherapy and targeted drugs built for children's cancers, from laws that stop companies skipping children, and from protecting the child who is cured from the cost of the cure.","summary":"Childhood leukaemia was fatal in 1948 and is curable today because cooperative groups in North America and Europe ran one randomised trial after another, each refining the previous regimen. The same method made neuroblastoma, Wilms tumour, Ewing sarcoma and medulloblastoma curable in most children, and the Childhood Cancer Survivor Study then documented what those cures cost decades later: heart damage, second cancers, infertility and hearing loss.\n\nThe present era brought engineered immunity to children first. Blinatumomab, the first T-cell engager, and tisagenlecleucel, the first CAR-T ever approved (2017, after ELIANA), both started in childhood leukaemia; anti-GD2 antibodies raised cure rates in high-risk neuroblastoma. Precision medicine followed: Pediatric MATCH screened children nationally for targetable mutations, and paediatric-first drugs arrived for the commonest childhood brain tumour (tovorafenib) and for diffuse midline glioma (dordaviprone). The RACE for Children Act, in force since 2020, requires companies to study new targeted cancer drugs in children whenever the target matters in a childhood cancer, and the ACCELERATE platform brings companies, regulators and parents together to plan those studies.\n\nThe pace is set by the smallness of the market, which no incentive fully corrects; by regulatory divergence between the FDA and EMA; by late effects that are still under-recorded; and by the fact that most children with cancer live in countries where cure rates are a fraction of those in rich ones.","asOf":"2026-09-10","links":[{"label":"ACCELERATE Paediatric Strategy Forums","url":"https://www.accelerate-platform.org/paediatric-strategy-forums/"},{"label":"Childhood Cancer Survivor Study","url":"https://ccss.stjude.org"},{"label":"WHO Global Initiative for Childhood Cancer","url":"https://www.who.int/initiatives/the-global-initiative-for-childhood-cancer"}],"tags":[],"related":["alexs-lemonade-stand","st-baldricks","idea-bio2-paediatric-first-development","idea-tr2-paediatric-combo-prea","idea-reg-single-paediatric-plan","idea-reg-orphan-designation-reciprocity","idea-fund-amc-paediatric-rare","idea-fund-paediatric-deferral-escrow","idea-data-paediatric-rwe-consortium","idea-acc-childhood-medicines-platform-scale","idea-acc-abandonment-stipends","idea-acc-paediatric-palliative-in-every-childhood-unit","idea-gd2-car-t-frontline-consolidation","idea-bio1-fusion-tf-degraders","idea-mfbg-pet-replaces-mibg","idea-moon-hearing-protection-cisplatin","cell-therapy-roadmap","survivorship-roadmap"],"cancers":["neuroblastoma","dipg-dmg","paediatric-low-grade-glioma","all-leukemia"],"sections":[],"technologies":["car-t","tandem-transplant","mibg-theranostics","glioma-car-t","fertility-preservation","survivorship-care-plan","cgp","pdx-models"],"targets":[],"drugs":["methotrexate","vincristine","mercaptopurine","asparaginase","dinutuximab","i131-mibg","blinatumomab","tisagenlecleucel","tovorafenib","dabrafenib-trametinib","selumetinib","larotrectinib","dordaviprone","vorasidenib","sodium-thiosulfate","dexrazoxane","mifamurtide"],"companies":["childrens-oncology-group","itcc","day-one-biopharmaceuticals","y-mabs"],"institutions":["siop-europe","accelerate-platform","st-jude","fda-oce","ema"],"pathways":[],"terms":["race-for-children-act","orphan-drug","accelerated-approval"],"trials":["int-0091","hr-nbl1","anbl0032","anbl0532","anbl1531","aren0533","acns0331","euramos-1","interfant-06","aaml0531","inter-b-nhl-ritux-2010","ccss","tower","eliana","aall1731","gd2-cart01","pediatric-match","firefly-1","tadpole","action-dmg"],"people":[],"bottlenecks":["b-rare-cancers","b-incentive-misalignment","b-regulatory-fragmentation","b-survivorship","b-global-access","b-trial-enrolment"],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"steps":[{"era":"1948-1990s","title":"Cooperative groups make childhood cancer curable","description":"Methotrexate produced the first remissions of childhood leukaemia in 1948; St Jude's Total Therapy and the cooperative groups that became the Children's Oncology Group and SIOP Europe turned remission into cure by combining vincristine, mercaptopurine, asparaginase and methotrexate and testing every change against the last regimen. INT-0091 set the Ewing sarcoma backbone; tandem transplant and busulfan-melphalan (HR-NBL1) defined high-risk neuroblastoma therapy. Almost every child in a rich country was enrolled in a trial, which is why progress was so fast.","refs":["methotrexate","vincristine","mercaptopurine","asparaginase","st-jude","childrens-oncology-group","siop-europe","int-0091","tandem-transplant","anbl0532","hr-nbl1","interfant-06"],"status":"historic"},{"era":"1994-2015","title":"Immunotherapy for neuroblastoma, and counting the cost of cure","description":"The anti-GD2 antibody dinutuximab raised cure rates in high-risk neuroblastoma (ANBL0032) and was approved in 2015; radioactive MIBG treated the tumour from inside. Risk-adapted trials gave less to children who needed less: AREN0533 in Wilms tumour, ACNS0331 in medulloblastoma. The Childhood Cancer Survivor Study, following tens of thousands of survivors from 1994, showed the late effects of anthracyclines, radiation and alkylators and produced the long-term follow-up guidelines every survivor clinic uses.","refs":["dinutuximab","anbl0032","y-mabs","i131-mibg","mibg-theranostics","aren0533","acns0331","euramos-1","mifamurtide","aaml0531","inter-b-nhl-ritux-2010","ccss","survivorship-care-plan"],"status":"historic"},{"era":"2014-2026","title":"Engineered immunity, children first","description":"Blinatumomab, the first T-cell engager (2014), nearly doubled survival in relapsed leukaemia (TOWER) and then, added to standard treatment for average-risk childhood leukaemia (AALL1731), pushed cure rates higher still. Tisagenlecleucel became the first CAR-T ever approved, in 2017, after ELIANA put most children whose leukaemia had returned after every standard treatment into remission. GD2 CAR-T produced durable complete remissions in neuroblastoma (GD2-CART01) and is being taken into the brain for diffuse midline glioma.","refs":["blinatumomab","tower","aall1731","tisagenlecleucel","eliana","car-t","gd2-cart01","idea-gd2-car-t-frontline-consolidation","glioma-car-t","cell-therapy-roadmap"],"status":"current"},{"era":"2017-2026","title":"Precision medicine and the regulatory lever","description":"Pediatric MATCH (from 2017) screened children with relapsed cancer nationally and assigned them to targeted drugs by mutation, with ITCC's ESMART as its European counterpart. The RACE for Children Act, in force for applications from August 2020, ended the exemption that let companies skip children when the drug's target matters in a childhood cancer; the ACCELERATE platform, founded in 2013, convenes companies, the FDA, the EMA and parents to decide which drugs to study and how. Paediatric-first drugs followed: tovorafenib for BRAF-driven low-grade glioma (FIREFLY-1), dabrafenib-trametinib beating chemotherapy in the same disease (TADPOLE), selumetinib for neurofibromatosis, and dordaviprone, the first drug for diffuse midline glioma. ACTION is the first placebo-controlled phase 3 ever run in that disease.","refs":["pediatric-match","itcc","cgp","race-for-children-act","accelerate-platform","fda-oce","ema","tovorafenib","firefly-1","day-one-biopharmaceuticals","tadpole","dabrafenib-trametinib","selumetinib","larotrectinib","dordaviprone","action-dmg","vorasidenib"],"status":"current"},{"era":"2016-2026","title":"Protecting the child who is cured","description":"Sodium thiosulfate, an old antidote, halves permanent hearing loss from cisplatin in two paediatric trials and is now standard; dexrazoxane protects the heart from anthracyclines; fertility preservation is offered before gonadotoxic treatment; risk-based survivorship follow-up is organised from the CCSS evidence. Adults are only now getting the otoprotection children have, a reversal of the usual direction of travel.","refs":["sodium-thiosulfate","idea-moon-hearing-protection-cisplatin","dexrazoxane","fertility-preservation","ccss","survivorship-care-plan","survivorship-roadmap"],"status":"current"},{"era":"2026-2030","title":"Next trials, next targets, one global plan","description":"ANBL1531 adds targeted radiation and immunotherapy into neuroblastoma induction; CAR-T for brain tumours is in early trials; degraders for the fusion transcription factors that drive childhood sarcomas are the first credible attack on those drivers. The regulatory proposals: develop drugs in children first when the target is a children's target, make paediatric combination studies part of every relevant adult approval, one global paediatric development plan instead of separate FDA and EMA plans, and automatic reciprocity of orphan designations. A same-day PET tracer could replace two-day MIBG scans.","refs":["anbl1531","glioma-car-t","idea-bio1-fusion-tf-degraders","idea-bio2-paediatric-first-development","idea-tr2-paediatric-combo-prea","idea-reg-single-paediatric-plan","idea-reg-orphan-designation-reciprocity","idea-mfbg-pet-replaces-mibg","pdx-models"],"status":"emerging"},{"era":"2030+","title":"Every child, everywhere","description":"Most children with cancer live in countries where cure rates are a fraction of those in rich ones, and where families abandon curative treatment because they cannot afford transport and food. Guaranteed-quality childhood cancer medicines free of charge in fifty countries, cash stipends to prevent abandonment, a paediatric palliative team in every childhood unit, and an international consortium pooling the outcome of every treated child are the proposals. Advance market commitments and escrowed adult revenue would pay for the drugs no market will.","refs":["idea-acc-childhood-medicines-platform-scale","idea-acc-abandonment-stipends","idea-acc-paediatric-palliative-in-every-childhood-unit","idea-data-paediatric-rwe-consortium","idea-fund-amc-paediatric-rare","idea-fund-paediatric-deferral-escrow","st-jude","alexs-lemonade-stand","st-baldricks"],"status":"speculative"},{"era":"What sets the pace","title":"Markets, regulators, late effects and geography","description":"Each childhood cancer is too small a market for a company to pursue, and orphan incentives only partly correct that. The FDA and EMA require different paediatric plans, so studies are duplicated or delayed. Late effects are recorded in cohorts, not in routine care. And the children who most need the cures already found live where they are not available. Charities and cooperative groups fill the gap that the market leaves.","refs":["b-rare-cancers","b-incentive-misalignment","b-regulatory-fragmentation","b-survivorship","b-global-access","b-trial-enrolment","orphan-drug","accelerated-approval"],"status":"current"}],"watch":[]},{"id":"pancreatic-roadmap","kind":"roadmap","name":"Pancreatic cancer roadmap: from Whipple's operation to gemcitabine, FOLFIRINOX, adjuvant chemotherapy, PARP inhibition, KRAS inhibition, vaccines and the surveillance question","aka":["PDAC roadmap","Pancreatic ductal adenocarcinoma roadmap","Pancreatic cancer history","Pancreatic cancer evidence roadmap"],"tldr":"Pancreatic cancer has had one operation since 1935 and a handful of chemotherapy drugs since 1997. This roadmap follows the evidence through FOLFIRINOX, chemotherapy before and after surgery, the first inherited-gene drug, the first drugs against the KRAS protein that drives nearly every tumour, personalised vaccines, and the surveillance and blood tests that might catch it earlier, to 2031.","summary":"Pancreatic ductal adenocarcinoma is the cancer where progress has been slowest. Whipple's 1935 operation is still the only cure and about one patient in five presents in time for it; Traverso and Longmire's 1978 modification and the centralisation of surgery into high-volume centres made it safer without changing who can have it. The oncogene was found in 1988, when Almoguera and Perucho showed KRAS codon 12 mutations in 21 of 22 tumours, and the blood marker CA 19-9 was already known to be unreadable in the Lewis-negative tenth of patients (Tempero 1987). Gemcitabine (Burris 1997) then set a standard that lasted 14 years, while the European adjuvant trials (ESPAC-1 2004, CONKO-001 2007, ESPAC-3 2010) established that chemotherapy after surgery helped and chemoradiotherapy did not.\n\nThe second decade of the century brought combination chemotherapy: FOLFIRINOX (Conroy 2011) and gemcitabine with nab-paclitaxel (Von Hoff 2013) for metastatic disease, liposomal irinotecan second line (NAPOLI-1 2016), gemcitabine with capecitabine (ESPAC-4 2017) and then modified FOLFIRINOX (PRODIGE 24 2018, five-year update 2022: median survival 53.5 months) after surgery, and NALIRIFOX first line (NAPOLI 3 2023). The genomes (Waddell 2015, Bailey 2016) and the classical versus basal-like split (Moffitt 2015) gave the disease a molecular vocabulary; Hu 2018 found a germline fault in 5.5 percent of all patients regardless of family history, and POLO (2019) turned the BRCA subset into the first biomarker-directed approval, without a survival gain. Neoadjuvant treatment became standard for borderline resectable disease after PREOPANC (2020, 2022) but PREOPANC-2 (2025) and NORPACT-1 left the resectable question open, and the first attempt at the stroma failed (HALO-301 2020) after mouse work had warned that removing fibroblasts made tumours worse (Özdemir 2014).\n\nThe third decade is the KRAS decade. Ostrem and Shokat's 2013 pocket led to sotorasib in the 1 to 2 percent with G12C (CodeBreaK 100 2023); the RAS(ON) tri-complex chemistry (Holderfield 2024) produced daraxonrasib, which in RASolute 302 (2026) nearly doubled survival in previously treated metastatic disease and became the first RAS inhibitor approved for pancreatic cancer. Personalised mRNA vaccines made T cells that lasted years in responders (Rojas 2023, Sethna 2025), a wearable electric-field device added two months in locally advanced disease (PANOVA-3 2025), and surveillance of germline carriers shifted most detected cancers to stage I (Canto 2018, Dbouk 2022) while the new-onset diabetes score ENDPAC (Sharma 2018) offered a way to enrich the general population for a test. What comes next is on the registry: first-line and adjuvant RAS inhibitor trials, G12D-selective combinations, perioperative chemotherapy trials, the randomised vaccine trial and the 20,000-person PRECEDE surveillance cohort, with dates between 2026 and 2031.","asOf":"2026-09-24","links":[{"label":"NICE NG85: pancreatic cancer in adults, diagnosis and management (published 7 February 2018)","url":"https://www.nice.org.uk/guidance/ng85"},{"label":"National Pancreatic Cancer Audit: State of the Nation Report 2026 (patients diagnosed 2022 to 2023 in England, 2023 to 2024 in Wales)","url":"https://www.natcan.org.uk/reports/npaca-state-of-the-nation-report-2026/"},{"label":"National Pancreatic Cancer Audit: State of the Nation Report 2025","url":"https://www.natcan.org.uk/reports/npaca-state-of-the-nation-report-2025/"},{"label":"National Pancreatic Cancer Audit: State of the Nation Report 2024 (first report)","url":"https://www.natcan.org.uk/reports/npaca-state-of-the-nation-report-2024/"},{"label":"Pancreatic Cancer UK: campaigning for change","url":"https://www.pancreaticcancer.org.uk/about-us/what-we-do/we-campaign-for-change/"},{"label":"ClinicalTrials.gov NCT04927780","url":"https://clinicaltrials.gov/study/NCT04927780"},{"label":"ClinicalTrials.gov NCT04340141","url":"https://clinicaltrials.gov/study/NCT04340141"}],"tags":["pancreatic","gi","roadmap"],"related":["kras-roadmap","early-detection-roadmap","surgery-roadmap","chemotherapy-roadmap","targeted-therapy-roadmap","immunotherapy-roadmap","devices-roadmap","survivorship-roadmap","ctdna-tests","germline-to-parp","g12d-plus-pan-ras","idea-ras-inhibitor-neoadjuvant-pdac","idea-mced-new-onset-diabetes","idea-shared-kras-vaccine-adjuvant","nccn","pancan","idea-pdac-new-onset-diabetes-risk-score-pathway","idea-pdac-surveillance-for-every-germline-carrier","idea-pdac-neoadjuvant-chemotherapy-for-all-resectable-disease","idea-pdac-stromal-reprogramming-not-depletion","idea-pdac-ras-inhibitor-combinations-and-sequencing","idea-pdac-cachexia-trials-embedded-in-chemotherapy-trials","idea-pdac-enzyme-replacement-prescribing-by-default","idea-pdac-uk-active-treatment-rate-audit-and-target","idea-pdac-uk-fast-track-diagnosis-to-treatment-pathway"],"cancers":["pancreatic","resectable-pdac","borderline-resectable-pdac","metastatic-pdac","brca-palb2-pdac"],"sections":["surgery","chemotherapy","targeted-therapy","early-detection","immunotherapy","supportive-care"],"technologies":["kras-inhibitors","parp-inhibitor","cytotoxic-chemotherapy","ttfields","mced","germline-testing","pancreatic-surveillance","neoantigen-mrna-vaccine","wes-wgs"],"targets":["kras","brca","fap"],"drugs":["gemcitabine","folfirinox","gemcitabine-nab-paclitaxel","nalirifox","liposomal-irinotecan","olaparib","daraxonrasib","zoldonrasib","sotorasib","autogene-cevumeran","eli-002-7p","optune","ponsegromab"],"companies":["unicancer","revolution-medicines","ipsen","novocure","biontech","elicio-therapeutics","astrazeneca"],"institutions":["esmo","asco","cruk","mayo-clinic","johns-hopkins","mskcc","erasmus-mc","garvan-institute"],"pathways":["ras-mapk","ddr"],"terms":["whipple","resectability","neoadjuvant-adjuvant","ca19-9","desmoplasia","gbrca-mutation","kras-mutation-subtypes","neoantigen","ppv"],"trials":["prodige-24","espac-4","espac-5","conko-001","lap07","preopanc","napoli-3","polo","panova-3","rasolute-302","amplify-7p","precede","nct05968326","nct07491445","nct07252232","nct07805954","nct07522073","nct07262567"],"people":["thierry-conroy","daniel-von-hoff","eileen-oreilly","talia-golan","zev-wainberg","vinod-balachandran","kevan-shokat","marc-besselink","eric-van-cutsem","anirban-maitra"],"bottlenecks":["b-early-detection","b-hereditary-risk","b-undruggable-targets","b-resistance","b-tme-immunosuppression","b-cachexia-supportive","b-surgery-radiation-innovation","b-aging-comorbidity","b-care-fragmentation","b-negative-results","b-trial-design","b-knowledge-diffusion"],"keyPapers":["paper-whipple-carcinoma-ampulla-of-vater-ann-surg-1935","paper-traverso-longmire-pylorus-preservation-pancreaticoduodenectomy-sgo-1978","paper-tempero-ca19-9-lewis-antigens-cancer-res-1987","paper-almoguera-kras-codon-12-pancreatic-cell-1988","paper-burris-gemcitabine-pancreatic-jco-1997","paper-espac-1-chemoradiotherapy-chemotherapy-resected-pancreatic-nejm-2004","paper-chari-pancreatic-cancer-following-diabetes-gastroenterology-2005","paper-conko-001-adjuvant-gemcitabine-observation-jama-2007","paper-hidalgo-pancreatic-cancer-review-nejm-2010","paper-conroy-folfirinox-pancreatic-nejm-2011","paper-mpact-nab-paclitaxel-gemcitabine-nejm-2013","paper-ostrem-kras-g12c-nature-2013","paper-ozdemir-caf-depletion-accelerates-pancreatic-cancer-cancer-cell-2014","paper-waddell-whole-genomes-pancreatic-nature-2015","paper-moffitt-virtual-microdissection-subtypes-nat-genet-2015","paper-bailey-molecular-subtypes-pancreatic-nature-2016","paper-napoli-1-nanoliposomal-irinotecan-lancet-2016","paper-prodige-24-adjuvant-mfolfirinox-pancreatic-nejm-2018","paper-hu-germline-mutations-pancreatic-cancer-risk-jama-2018","paper-canto-caps-long-term-surveillance-gastroenterology-2018","paper-sharma-endpac-model-new-onset-diabetes-gastroenterology-2018","paper-asco-potentially-curable-pancreatic-guideline-update-jco-2019","paper-polo-olaparib-maintenance-gbrca-pancreatic-nejm-2019","paper-preopanc-preoperative-chemoradiotherapy-jco-2020","paper-halo-301-pegvorhyaluronidase-jco-2020","paper-caps-consortium-surveillance-recommendations-gut-2020","paper-asco-metastatic-pancreatic-cancer-guideline-update-jco-2020","paper-nccn-pancreatic-adenocarcinoma-v2-2021-jnccn-2021","paper-fahrmann-ca19-9-lead-time-gastroenterology-2021","paper-rahib-projection-us-cancer-2040-jama-netw-open-2021","paper-prodige-24-five-year-outcomes-jama-oncol-2022","paper-dbouk-caps5-stage-survival-jco-2022","paper-napoli-3-lancet-2023","paper-rojas-mrna-neoantigen-vaccine-pancreatic-nature-2023","paper-esmo-pancreatic-cancer-guideline-ann-oncol-2023","paper-holderfield-ras-on-multi-selective-inhibitor-nature-2024","paper-groarke-ponsegromab-cancer-cachexia-nejm-2024","paper-sethna-rna-neoantigen-vaccine-long-lived-t-cells-nature-2025","paper-panova-3-ttfields-locally-advanced-pancreatic-jco-2025","paper-preopanc-2-neoadjuvant-folfirinox-vs-chemoradiotherapy-lancet-oncol-2025","paper-daraxonrasib-pancreatic-n-engl-j-med-2026","paper-roberts-pert-survival-pancreatic-cancer-pancreatology-2019"],"journals":[],"dependsOn":[],"notes":["How this stays current: scripts/roadmap-watch.ts (npm run roadmap:watch) checks each trial here against ClinicalTrials.gov and searches Europe PMC for new papers on the acronyms since asOf. Anything it prints that this page does not say is an edit to make; then move asOf forward.","Dates in 'What to watch' are quoted from the registry as read on 2026-09-24 and are not predictions; estimated completion dates move.","The primary papers of Conroy 2011, MPACT, NAPOLI 3, PRODIGE 24 (2018), ESPAC-3, ESPAC-4, ESPAC-5, CONKO-001 (2013), LAP07, NORPACT-1, Alliance A021501, PREOPANC long-term, POLO (2019 and 2022), CodeBreaK 100, KRYSTAL-1, RASolute 302, Rojas 2023, Burris 1997 and Rahib 2014 already existed in the corpus and are linked from the steps; this deep dive adds the guideline, surgical, oncogene, genome, hereditary, surveillance, diabetes, stroma, vaccine follow-up, device and supportive care papers around them.","UK and NHS specifics (referral routes, NICE NG85 positions, Cancer Drugs Fund status, audit indicators, surveillance access, trial access) are held on the UK and NHS page for pancreatic cancer, written by another file of the deep dive, and are not restated here."],"steps":[{"era":"1935-1980","title":"One operation, and still the only cure","description":"Whipple, Parsons and Mullins described removal of the pancreatic head and duodenum for ampullary cancer in 1935; Traverso and Longmire preserved the pylorus in two patients in 1978 and in their 1980 follow-up of 18 found every patient had pancreatic exocrine insufficiency and needed intensive enzyme replacement. Ninety years on, surgery is the only treatment that cures pancreatic cancer, about one patient in five presents with disease that can be removed, and operative mortality fell through centralisation into high-volume centres rather than through any change in what is removed. The enzyme problem Traverso recorded is still under-treated (Roberts 2019).","refs":["paper-whipple-carcinoma-ampulla-of-vater-ann-surg-1935","paper-traverso-longmire-pylorus-preservation-pancreaticoduodenectomy-sgo-1978","whipple","resectability","robotic-surgery","surgery-roadmap","b-surgery-radiation-innovation","pancreatic"],"status":"historic"},{"era":"1979-1988","title":"A blood marker with a blind spot and an oncogene in nearly every tumour","description":"CA 19-9, the serum marker still used to follow the disease, was shown by Tempero and colleagues in 1987 to be unmakeable by patients who lack the Lewis blood group antigens, so a normal value never rules the cancer out; Fahrmann's 2021 pre-diagnostic study later showed it rises about two years before diagnosis and catches half of early cases at 99 percent specificity. In 1988 Almoguera and Perucho found KRAS codon 12 mutations in 21 of 22 exocrine pancreatic carcinomas, present in primary and metastasis alike: the single most uniform driver in any common cancer, and for 33 years an undruggable one.","refs":["paper-tempero-ca19-9-lewis-antigens-cancer-res-1987","paper-fahrmann-ca19-9-lead-time-gastroenterology-2021","paper-almoguera-kras-codon-12-pancreatic-cell-1988","ca19-9","tumour-markers","kras","kras-mutation-subtypes","ras-mapk","b-undruggable-targets","b-biomarker-validation"],"status":"historic"},{"era":"1997-2010","title":"Gemcitabine, and chemotherapy after surgery","description":"Burris (1997) made gemcitabine the standard for advanced disease on a clinical benefit endpoint and a modest survival gain over fluorouracil, a standard that held for 14 years. The European adjuvant trials then settled what to do after surgery: ESPAC-1 (2004, 289 patients) found five-year survival of 21 percent with chemotherapy against 8 percent without and 10 percent with chemoradiotherapy against 20 percent without; CONKO-001 (2007, 368 patients) roughly doubled disease-free survival with six months of gemcitabine (13.4 versus 6.9 months), confirmed for overall survival in 2013; ESPAC-3 (2010, 1,088 patients) showed fluorouracil and gemcitabine equivalent. Hidalgo's 2010 review marks where the field stood before combination chemotherapy.","refs":["paper-burris-gemcitabine-pancreatic-jco-1997","paper-espac-1-chemoradiotherapy-chemotherapy-resected-pancreatic-nejm-2004","paper-conko-001-adjuvant-gemcitabine-observation-jama-2007","paper-conko-001-adjuvant-gemcitabine-long-term-oettle-jama-2013","paper-espac-3-fluorouracil-vs-gemcitabine-adjuvant-neoptolemos-jama-2010","paper-hidalgo-pancreatic-cancer-review-nejm-2010","conko-001","gemcitabine","fluorouracil","cytotoxic-chemotherapy","chemotherapy-roadmap","neoadjuvant-adjuvant"],"status":"historic"},{"era":"2011-2016","title":"Combination chemotherapy for metastatic disease","description":"PRODIGE 4/ACCORD 11 (Conroy 2011, 342 fit patients) gave FOLFIRINOX a median survival of 11.1 months against 6.8 with gemcitabine (hazard ratio 0.57) at the price of neutropenia, diarrhoea and neuropathy; MPACT (Von Hoff 2013, 861 patients) gave gemcitabine with nab-paclitaxel 8.5 against 6.7 months and accepted less fit patients, so fitness rather than stage came to decide the regimen. NAPOLI-1 (2016, 417 patients) added a second line, liposomal irinotecan with fluorouracil, 6.1 against 4.2 months after gemcitabine. Rahib's 2014 projection that pancreatic cancer would become the second cause of cancer death in the United States by 2030 (updated in 2021 to 2040, about 46,000 deaths a year) became the funding argument of the decade.","refs":["paper-conroy-folfirinox-pancreatic-nejm-2011","paper-mpact-nab-paclitaxel-gemcitabine-nejm-2013","paper-napoli-1-nanoliposomal-irinotecan-lancet-2016","paper-rahib-projecting-cancer-deaths-2030-cancerres-2014","paper-rahib-projection-us-cancer-2040-jama-netw-open-2021","folfirinox","gemcitabine-nab-paclitaxel","liposomal-irinotecan","thierry-conroy","daniel-von-hoff","performance-status","b-aging-comorbidity","b-funding-allocation"],"status":"historic"},{"era":"2015-2018","title":"Genomes, subtypes and the inherited five percent","description":"Waddell's 100 whole genomes (2015) sorted tumours by structural variation and noticed that four of five patients with BRCA-type defects responded to platinum; Moffitt (2015) separated tumour from stroma computationally and found the classical and basal-like tumour subtypes and two prognostic stromal subtypes; Bailey (2016) grouped 32 mutated genes in 456 tumours into ten pathways and four expression subtypes, the squamous type with the worst prognosis. Hu's 3,030-patient Mayo series (2018) found a pathogenic variant in one of six genes in 5.5 percent of all patients and 5.2 percent of those without a family history, which moved the guidelines to germline testing for everyone.","refs":["paper-waddell-whole-genomes-pancreatic-nature-2015","paper-moffitt-virtual-microdissection-subtypes-nat-genet-2015","paper-bailey-molecular-subtypes-pancreatic-nature-2016","paper-hu-germline-mutations-pancreatic-cancer-risk-jama-2018","wes-wgs","rna-seq","germline-testing","gbrca-mutation","germline-vs-somatic","desmoplasia","garvan-institute","unc-lineberger","mayo-clinic","b-tumor-heterogeneity","b-hereditary-risk","idea-pdac-surveillance-for-every-germline-carrier"],"status":"historic"},{"era":"2017-2025","title":"Adjuvant modified FOLFIRINOX, and the neoadjuvant question","description":"ESPAC-4 (2017) added capecitabine to adjuvant gemcitabine; PRODIGE 24 (2018) replaced both with modified FOLFIRINOX in fit patients, and its five-year report (2022, 493 patients) gave a median survival of 53.5 against 35.5 months (hazard ratio 0.68) and five-year survival of 43.2 against 31.4 percent, adopted by ASCO in 2019. For treatment before surgery, PREOPANC (2020, 246 patients) missed its primary endpoint (16.0 versus 14.3 months) but raised clear-margin resection from 40 to 71 percent and showed a five-year benefit in 2022; ESPAC-5 and Alliance A021501 supported neoadjuvant treatment for borderline resectable disease; NORPACT-1 (2024) and PREOPANC-2 (2025, 375 patients: 21.9 versus 21.3 months for FOLFIRINOX against gemcitabine chemoradiotherapy) left resectable disease unresolved. LAP07 (2016) had shown chemoradiotherapy added nothing to survival in locally advanced disease.","refs":["espac-4","paper-espac-4-gemcitabine-capecitabine-adjuvant-pancreatic-lancet-2017","prodige-24","paper-prodige-24-adjuvant-mfolfirinox-pancreatic-nejm-2018","paper-prodige-24-five-year-outcomes-jama-oncol-2022","paper-asco-potentially-curable-pancreatic-guideline-update-jco-2019","preopanc","paper-preopanc-preoperative-chemoradiotherapy-jco-2020","paper-preopanc-neoadjuvant-chemoradiotherapy-long-term-jco-2022","espac-5","paper-espac-5-neoadjuvant-borderline-resectable-pancreatic-lancet-gastro-hep-2023","paper-alliance-a021501-mfolfirinox-radiotherapy-borderline-resectable-jama-oncol-2022","paper-norpact-1-neoadjuvant-folfirinox-labori-lancet-gastroenterol-hepatol-2024","paper-preopanc-2-neoadjuvant-folfirinox-vs-chemoradiotherapy-lancet-oncol-2025","lap07","paper-lap07-chemoradiotherapy-locally-advanced-pancreatic-jama-2016","folfirinox","capecitabine","resection-margins","total-neoadjuvant-therapy","unicancer","erasmus-mc","marc-besselink","b-trial-design","idea-pdac-neoadjuvant-chemotherapy-for-all-resectable-disease"],"status":"current"},{"era":"2019-2022","title":"The first biomarker-directed drug, and the first stromal failure","description":"POLO (Golan 2019, 154 patients) gave maintenance olaparib to germline BRCA carriers whose metastatic disease had not progressed on 16 weeks of platinum: progression-free survival hazard ratio 0.53, the first biomarker-directed approval in the disease, and in the 2022 final analysis no overall survival gain (hazard ratio 0.83). ASCO's 2020 update made germline and tumour testing for BRCA, mismatch repair deficiency and TRK fusions routine, each pointing at a drug for a few percent of patients (olaparib, pembrolizumab, larotrectinib, entrectinib), and zenocutuzumab later added NRG1 fusions. The same year HALO-301 (494 patients) showed that dissolving the tumour's hyaluronan raised response rate (47 versus 36 percent) without changing survival (11.2 versus 11.5 months), as Özdemir's 2014 mouse work had warned that removing fibroblasts made tumours worse.","refs":["polo","paper-polo-olaparib-maintenance-gbrca-pancreatic-nejm-2019","paper-polo-overall-survival-olaparib-gbrca-pancreatic-jco-2022","paper-asco-metastatic-pancreatic-cancer-guideline-update-jco-2020","paper-halo-301-pegvorhyaluronidase-jco-2020","paper-ozdemir-caf-depletion-accelerates-pancreatic-cancer-cancer-cell-2014","olaparib","zenocutuzumab","parp-inhibitor","brca","parp","germline-to-parp","platinum-sensitivity","cancer-associated-fibroblasts","talia-golan","hedy-kindler","eric-van-cutsem","astrazeneca","b-negative-results","b-tme-immunosuppression","idea-pdac-stromal-reprogramming-not-depletion"],"status":"current"},{"era":"2005-2022","title":"Surveillance for carriers and the new-onset diabetes signal","description":"Chari's Minnesota cohort (2005) found pancreatic cancer in 0.85 percent of 2,122 people diagnosed with diabetes after 50 within three years, eight times the expected rate; Sharma's ENDPAC score (2018) used weight change, glucose change and age at onset to concentrate that risk into a group with 3.6 percent prevalence, and Fahrmann (2021) showed CA 19-9 rising from two years before diagnosis. For people with inherited risk, the CAPS programme reported in 2018 that 9 of 10 cancers found under surveillance were resectable, published consensus rules in 2020 (start at 50 or 55, endoscopic ultrasound and MRI annually, research settings only) and in 2022 (CAPS5, 1,461 people) found 7 of 9 cancers at stage I, with a median survival of 9.8 years for screen-detected against 1.5 years for cancers found outside surveillance. The 20,000-person PRECEDE cohort is the scale-up.","refs":["paper-chari-pancreatic-cancer-following-diabetes-gastroenterology-2005","paper-sharma-endpac-model-new-onset-diabetes-gastroenterology-2018","paper-fahrmann-ca19-9-lead-time-gastroenterology-2021","paper-canto-caps-long-term-surveillance-gastroenterology-2018","paper-caps-consortium-surveillance-recommendations-gut-2020","paper-dbouk-caps5-stage-survival-jco-2022","precede","pancreatic-surveillance","mced","liquid-biopsy","galleri","ppv","johns-hopkins","diane-simeone","early-detection-roadmap","b-early-detection","b-hereditary-risk","idea-mced-new-onset-diabetes","idea-pdac-new-onset-diabetes-risk-score-pathway","idea-pdac-surveillance-for-every-germline-carrier"],"status":"current"},{"era":"2013-2026","title":"KRAS becomes druggable","description":"Ostrem and Shokat (2013) found the switch-II pocket on KRAS G12C; CodeBreaK 100 (Strickler 2023) gave sotorasib a 21 percent response and 6.9-month survival in the 1 to 2 percent of pancreatic cancers with that mutation, and KRYSTAL-1 did the same for adagrasib. The common alleles needed different chemistry: Holderfield (2024) described the RAS(ON) tri-complex inhibitors that clamp active mutant and wild-type RAS, and daraxonrasib, the clinical compound, nearly doubled survival in RASolute 302 (2026, 500 patients after one line of chemotherapy: 13.2 versus 6.7 months, hazard ratio 0.40), becoming the first RAS inhibitor approved for pancreatic cancer in August 2026. The G12D-selective zoldonrasib and the combination with daraxonrasib (RASolute 309) follow; resistance through secondary RAS mutations and receptor bypass is already described.","refs":["paper-ostrem-kras-g12c-nature-2013","paper-codebreak-100-sotorasib-kras-g12c-pancreatic-nejm-2023","paper-krystal-1-adagrasib-kras-g12c-solid-tumours-jco-2023","paper-holderfield-ras-on-multi-selective-inhibitor-nature-2024","rasolute-302","paper-daraxonrasib-pancreatic-n-engl-j-med-2026","nct07805954","daraxonrasib","zoldonrasib","elironrasib","mrtx1133","sotorasib","adagrasib","kras","kras-inhibitors","kras-roadmap","g12d-plus-pan-ras","kevan-shokat","revolution-medicines","amgen","bms","b-undruggable-targets","b-resistance","idea-pdac-ras-inhibitor-combinations-and-sequencing","idea-ras-inhibitor-neoadjuvant-pdac"],"status":"current"},{"era":"2023-2026","title":"Vaccines that last, a device that adds months, and a first-line chemotherapy answer","description":"Rojas (2023) showed an individualised mRNA neoantigen vaccine, autogene cevumeran, raised T cells in half of 16 resected patients, and Sethna (2025) that at 3.2 years those responders had mostly not relapsed (median recurrence-free survival not reached versus 13.4 months) with vaccine-induced clones estimated to live 7.7 years on average; the randomised IMCODE003 is enrolling 260 patients. The off-the-shelf KRAS vaccine ELI-002 7P missed in AMPLIFY-7P (2026). NAPOLI 3 (2023) made NALIRIFOX a first-line option over gemcitabine with nab-paclitaxel, and PANOVA-3 (2025, 571 patients) gave tumour treating fields with that chemotherapy a survival of 16.2 against 14.2 months in locally advanced disease (hazard ratio 0.82), the basis of the 2026 Optune Pax approval, without improving progression-free survival.","refs":["paper-rojas-mrna-neoantigen-vaccine-pancreatic-nature-2023","paper-sethna-rna-neoantigen-vaccine-long-lived-t-cells-nature-2025","nct05968326","amplify-7p","eli-002-7p","autogene-cevumeran","neoantigen-mrna-vaccine","shared-antigen-vaccine","neoantigen","vinod-balachandran","ugur-sahin","biontech","elicio-therapeutics","idea-shared-kras-vaccine-adjuvant","napoli-3","paper-napoli-3-lancet-2023","nalirifox","panova-3","paper-panova-3-ttfields-locally-advanced-pancreatic-jco-2025","optune","ttfields","novocure","devices-roadmap","immunotherapy-roadmap","b-immunotherapy-response"],"status":"current"},{"era":"2026-2031","title":"What the registry says is coming","description":"The RAS inhibitor moves earlier: RASolute 303 (daraxonrasib alone or with gemcitabine and nab-paclitaxel first line, 900 estimated participants, primary completion June 2028), RASolute 304 (adjuvant daraxonrasib after resection, 500, May 2029) and RASolute 309 (zoldonrasib with daraxonrasib against chemotherapy first line in G12D disease, 400, March 2029), with Incyte's G12D inhibitor in DAWN-303 (588, September 2028). The perioperative question is being answered by PREOPANC-3 (perioperative against adjuvant modified FOLFIRINOX, 378 estimated, January 2027) and Alliance A021806 (358, December 2028). IMCODE003 tests the vaccine (260, January 2031) and PRECEDE follows 20,000 high-risk people to December 2030. RASolute 302 itself lists study completion for December 2027 and AMPLIFY-7P for November 2026.","refs":["nct07491445","nct07252232","nct07805954","nct07522073","nct07262567","rasolute-302","amplify-7p","nct05968326","precede","preopanc","daraxonrasib","zoldonrasib","autogene-cevumeran","kras-inhibitors","pancreatic-surveillance","idea-pdac-ras-inhibitor-combinations-and-sequencing","idea-pdac-neoadjuvant-chemotherapy-for-all-resectable-disease","idea-pdac-surveillance-for-every-germline-carrier"],"status":"emerging"},{"era":"What sets the pace","title":"Late presentation, fitness, wasting and who gets treated at all","description":"Four things no trial on this page has fixed. Four in five patients present with disease that cannot be removed, and neither the new-onset diabetes score nor carrier surveillance has yet been shown in a prospective trial to change that at population scale. Half of patients are not fit for FOLFIRINOX-class chemotherapy, and the pivotal trials enrolled the fit half; whether RAS inhibitors change that is being measured. Cachexia and exocrine insufficiency stop treatment being delivered, enzyme replacement reaches about one patient in five in UK primary care data (Roberts 2019) and cachexia has its first mechanism-based drug (ponsegromab 2024) but no phase 3. And in England and Wales the National Pancreatic Cancer Audit reports each year how many patients receive any active treatment and how quickly, which the UK and NHS page holds; each has an idea on this page.","refs":["paper-roberts-pert-survival-pancreatic-cancer-pancreatology-2019","paper-groarke-ponsegromab-cancer-cachexia-nejm-2024","paper-fearon-lancet-oncol","ponsegromab","performance-status","obstructive-jaundice","biliary-stent","b-early-detection","b-aging-comorbidity","b-cachexia-supportive","b-care-fragmentation","b-knowledge-diffusion","survivorship-roadmap","idea-pdac-new-onset-diabetes-risk-score-pathway","idea-pdac-cachexia-trials-embedded-in-chemotherapy-trials","idea-pdac-enzyme-replacement-prescribing-by-default","idea-pdac-uk-active-treatment-rate-audit-and-target","idea-pdac-uk-fast-track-diagnosis-to-treatment-pathway"],"status":"current"}],"watch":[{"item":"RASolute 302 primary completion on the registry (daraxonrasib versus chemotherapy, previously treated metastatic disease, 500 participants, actual; published and approved 2026)","expected":"2026-06","source":"https://clinicaltrials.gov/study/NCT06625320","refs":["rasolute-302","daraxonrasib","paper-daraxonrasib-pancreatic-n-engl-j-med-2026"]},{"item":"AMPLIFY-7P study completion (ELI-002 7P adjuvant KRAS vaccine, 158 participants; primary completion 20 April 2026, actual)","expected":"2026-11","source":"https://clinicaltrials.gov/study/NCT05726864","refs":["amplify-7p","eli-002-7p","shared-antigen-vaccine"]},{"item":"PREOPANC-3 primary completion: perioperative versus adjuvant modified FOLFIRINOX for resectable pancreatic cancer (378 estimated participants; active, not recruiting)","expected":"2027-01","source":"https://clinicaltrials.gov/study/NCT04927780","refs":["preopanc","folfirinox","neoadjuvant-adjuvant","idea-pdac-neoadjuvant-chemotherapy-for-all-resectable-disease"]},{"item":"RASolute 302 study completion on the registry","expected":"2027-12","source":"https://clinicaltrials.gov/study/NCT06625320","refs":["rasolute-302","daraxonrasib"]},{"item":"RASolute 303 primary completion: daraxonrasib alone or with gemcitabine and nab-paclitaxel versus chemotherapy, first line metastatic (900 estimated participants; recruiting)","expected":"2028-06","source":"https://clinicaltrials.gov/study/NCT07491445","refs":["nct07491445","daraxonrasib","gemcitabine-nab-paclitaxel","idea-pdac-ras-inhibitor-combinations-and-sequencing"]},{"item":"DAWN-303 primary completion: chemotherapy with or without INCB161734 in untreated KRAS G12D metastatic disease (588 estimated participants; recruiting)","expected":"2028-09-15","source":"https://clinicaltrials.gov/study/NCT07522073","refs":["nct07522073","kras-inhibitors","idea-pdac-ras-inhibitor-combinations-and-sequencing"]},{"item":"Alliance A021806 primary completion: perioperative versus adjuvant modified FOLFIRINOX for resectable pancreatic cancer (358 participants, actual; active, not recruiting)","expected":"2028-12-31","source":"https://clinicaltrials.gov/study/NCT04340141","refs":["folfirinox","neoadjuvant-adjuvant","idea-pdac-neoadjuvant-chemotherapy-for-all-resectable-disease"]},{"item":"RASolute 309 primary completion: zoldonrasib plus daraxonrasib versus gemcitabine and nab-paclitaxel, first line KRAS G12D metastatic disease (400 estimated participants; recruiting)","expected":"2029-03","source":"https://clinicaltrials.gov/study/NCT07805954","refs":["nct07805954","zoldonrasib","daraxonrasib","g12d-plus-pan-ras","idea-pdac-ras-inhibitor-combinations-and-sequencing"]},{"item":"RASolute 304 primary completion: adjuvant daraxonrasib in resected pancreatic ductal adenocarcinoma (500 estimated participants; recruiting)","expected":"2029-05-10","source":"https://clinicaltrials.gov/study/NCT07252232","refs":["nct07252232","daraxonrasib","prodige-24"]},{"item":"PRECEDE (Pancreatic Cancer Early Detection Consortium) primary completion: 20,000 estimated high-risk participants under surveillance (recruiting)","expected":"2030-12-31","source":"https://clinicaltrials.gov/study/NCT04970056","refs":["precede","pancreatic-surveillance","idea-pdac-surveillance-for-every-germline-carrier"]},{"item":"IMCODE003 primary completion: adjuvant autogene cevumeran plus atezolizumab and modified FOLFIRINOX versus modified FOLFIRINOX alone after resection (260 estimated participants; phase 2; active, not recruiting)","expected":"2031-01-01","source":"https://clinicaltrials.gov/study/NCT05968326","refs":["nct05968326","autogene-cevumeran","neoantigen-mrna-vaccine","paper-sethna-rna-neoantigen-vaccine-long-lived-t-cells-nature-2025"]}]},{"id":"cure-paths","kind":"roadmap","name":"Paths to cures: interception, eradication, control","aka":[],"tldr":"Three different ways a cancer stops killing someone: stop it before it starts, remove every last cell, or hold it in check for life. Each needs different technology.","summary":"Cure is not one goal. Interception prevents a cancer from forming or removes it while it is still precancerous. Eradication removes every malignant cell, which is what surgery plus adjuvant therapy already achieves in early disease and what cell therapy achieves in some leukaemias. Control converts advanced cancer into a managed chronic condition, which is what endocrine therapy in breast cancer and TKIs in CML already do for many patients.\n\nSeparating them matters because they have different endpoints, different evidence requirements, and different technologies. An interception vaccine needs decades of follow-up in healthy people; an eradication strategy needs a sensitive measure of residual disease; a control strategy needs sequencing, tolerability, and resistance management rather than depth of response.","asOf":"2026-09-08","links":[],"tags":[],"related":[],"cancers":[],"sections":["prevention","early-detection","cell-therapy","targeted-therapy"],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"steps":[{"era":"Interception: established","title":"What already prevents cancer","description":"HPV and hepatitis B vaccination, tobacco control, screening with removal of precancerous lesions, risk-reducing surgery in carriers, and tamoxifen or aspirin chemoprevention are the interventions that have measurably reduced incidence. Almost every future interception technology is competing against, or adding to, this list, and none of it is glamorous.","refs":["hpv-vaccine","chemoprevention","colorectal-screening","germline-testing","risk-reducing-salpingectomy"],"status":"historic"},{"era":"Interception: next","title":"Vaccinating and monitoring people who do not yet have cancer","description":"Shared-neoantigen vaccines in Lynch syndrome and BRCA carriers, multi-cancer blood tests, and breath analysis all aim to act before or at the very beginning of disease. The bar is high: a healthy person accepts risk today for a probabilistic benefit later, so safety must be near-perfect and trials must run for years with surrogate endpoints. A positive interception vaccine trial would be the single largest change on this roadmap.","refs":["interception-vaccination","shared-antigen-vaccine","mced","fragmentomics","breath-vocs","trained-innate-immunity"],"status":"emerging"},{"era":"Eradication: established","title":"Removing every cell, and knowing that you did","description":"Surgery with adjuvant systemic therapy cures a large fraction of early cancers; CAR-T and transplant cure a minority of advanced haematologic malignancies. What has changed is measurement: ctDNA-based residual disease testing turns 'we think it is gone' into a testable claim, and the first ctDNA-guided approval arrived in bladder cancer in 2026.","refs":["mrd-testing","car-t","allogeneic-hsct","robotic-surgery","sbrt"],"status":"current"},{"era":"Eradication: next","title":"Killing the last cell, wherever it is hiding","description":"Micrometastatic disease is where alpha and Auger emitters, in situ vaccination, and logic-gated cell therapy should have their advantage, because each kills single cells rather than bulk. The pairing to watch is a sensitive residual-disease test that says who still has disease, and a single-cell-selective therapy that can clear it, which is the explicit design of several ongoing trials.","refs":["targeted-alpha-therapy","auger-electron-therapy","in-situ-vaccination","logic-gated-therapeutics","continuous-ctdna-monitoring","radionuclide-parp-combination"],"status":"emerging"},{"era":"Control: established","title":"Living with cancer as a chronic disease","description":"Endocrine therapy in hormone-driven breast cancer, androgen-pathway therapy in prostate cancer, BTK and BCL-2 inhibitors in CLL, and TKIs in CML already keep many people alive for years or decades. Control depends less on depth of response than on tolerability, sequencing, and managing resistance, which is why supportive care and cardio-oncology belong in this row.","refs":["endocrine-therapy","androgen-deprivation","kinase-inhibitors","cardio-oncology","exercise-oncology","geriatric-assessment"],"status":"current"},{"era":"Control: next","title":"Steering resistance instead of waiting for it","description":"If a cancer cannot be eradicated, the goal becomes keeping the sensitive clone dominant. Adaptive dosing, timing treatment to the body clock, payload switching guided by resistance biomarkers, and treating the host environment all aim at that. Cachexia therapy belongs here too: patients who keep weight and function tolerate more lines of treatment.","refs":["chronotherapy","cachexia-therapy","cancer-neuroscience","senescence-targeting","spatial-omics-guided-therapy","organoid-guided-therapy-scale","drug-repurposing"],"status":"emerging"},{"era":"The honest caveat","title":"What would have to be true","description":"Every path above assumes measurement improves faster than the cancer adapts: interception needs a test that finds disease while it is still local, eradication needs one that proves nothing is left, control needs one that spots the resistant clone before it takes over. Technology that measures is therefore upstream of technology that treats, which is an unfashionable conclusion but the one the evidence supports.","refs":["mced","mrd-testing","spatial-omics-guided-therapy","continuous-ctdna-monitoring","total-body-pet-screening"],"status":"speculative"}],"watch":[]},{"id":"prostate-roadmap","kind":"roadmap","name":"Prostate cancer roadmap: from Huggins and the discovery that a cancer can depend on a hormone, through the PSA epidemic and what it cost, the androgen receptor drugs, the DNA repair subset and PSMA, to a 2032 registry watch","aka":["Prostate cancer history","Prostate cancer evidence roadmap","History of prostate cancer treatment","Prostate cancer timeline"],"tldr":"Prostate cancer is where hormone therapy for cancer was invented, in 1941, and where a blood test created an epidemic of diagnoses forty-five years later. This roadmap follows the evidence from castration to the modern androgen receptor drugs, through the screening trials and the argument about overdiagnosis they started, to DNA repair, PSMA and the questions still open in 2032.","summary":"In 1941 Charles Huggins and Clarence Hodges castrated men with advanced prostate cancer and watched the disease regress. It was the first demonstration that any human cancer depends on a circulating hormone, and it is still the backbone of treatment: every man who starts androgen deprivation is repeating the experiment. What followed was a long argument about how to do the same thing better, and it turned out that castration resistance is not the cancer ignoring the hormone but adapting to live on less of it. Visakorpi found amplified androgen receptor in a third of recurrent tumours in 1995; Chen showed in 2004 that receptor overexpression alone converts sensitive disease to resistant and turns antagonists into agonists; Attard's 2008 phase 1 of abiraterone proved the point in people, and enzalutamide, built to the specification Chen described, followed.\n\nThe other half of the story is detection. Stamey described prostate-specific antigen as a marker in 1987 and Catalona made it a screening test in 1991, with the 4.0 threshold still on laboratory reports today. Testing spread through primary care before any trial had asked whether it saved lives. When the trials reported in 2009 they disagreed: ERSPC found a 20 percent reduction in prostate cancer mortality at a cost of 1,410 men screened and 48 extra cancers treated per death prevented, and PLCO found nothing, largely because half its control group was being screened anyway. Welch and Albertsen counted what had happened in the meantime: 1.3 million extra American men diagnosed and about a million treated. The United States task force recommended against screening in 2012 and partly reversed itself in 2018.\n\nTreatment moved in the 2000s and then very fast in the 2010s. Docetaxel in 2004 was the first drug to extend survival in castration-resistant disease; cabazitaxel opened the second line in 2010; abiraterone and enzalutamide moved from post-chemotherapy to pre-chemotherapy and then, through CHAARTED, STAMPEDE, LATITUDE, TITAN, ENZAMET, ARASENS and PEACE-1, to the first day of metastatic diagnosis. The genome was mapped in parallel: the TMPRSS2-ERG fusion in 2005, the TCGA taxonomy and the SU2C metastatic cohort in 2015, and the finding that made the biggest practical difference, DNA repair gene alterations in about a fifth of advanced tumours, with 11.8 percent of men carrying an inherited one whatever their family history. PARP inhibitors followed, and PSMA, a protein on the surface of almost every prostate cancer cell, became first an imaging target and then a way of delivering radiation to it.\n\nWhat has not been solved is stated plainly in the open problems on the prostate cancer page. Overdiagnosis is real and unquantified to within a factor of thirty. Nobody knows in what order to give the treatments that now exist. Resistance arrives for all of them, and in a minority the cancer stops being prostate cancer in any recognisable sense and becomes neuroendocrine, for which there is nothing. And a disease that mostly affects older men has its biggest remaining mortality gap in the causes of death that are not cancer.\n\nWhat any of this means for someone treated in Britain, from the screening committee's position and the NICE appraisals to scanner and radiotherapy capacity, waiting times and how to reach a trial, is on the UK and NHS pathway page for prostate cancer.","status":"active","asOf":"2026-09-25","links":[{"label":"NCI PDQ: prostate cancer","url":"https://www.cancer.gov/types/prostate"},{"label":"ESMO clinical practice guidelines: genitourinary cancers (the index the prostate guideline sits under)","url":"https://www.esmo.org/guidelines/esmo-clinical-practice-guidelines-genitourinary-cancers"},{"label":"EAU guidelines: prostate cancer","url":"https://uroweb.org/guidelines/prostate-cancer"},{"label":"ClinicalTrials.gov NCT06320067","url":"https://clinicaltrials.gov/study/NCT06320067"}],"tags":[],"related":["hormonal-therapy-roadmap","early-detection-roadmap","targeted-therapy-roadmap","radiopharma-roadmap","molecular-imaging-roadmap","surgery-roadmap","chemotherapy-roadmap","immunotherapy-roadmap","diagnostics-roadmap"],"cancers":["prostate","prostate-low-risk","prostate-intermediate-risk","prostate-high-risk","prostate-bcr","prostate-mhspc","prostate-nmcrpc","prostate-mcrpc","prostate-nepc"],"sections":["hormonal","early-detection","diagnostics","targeted-therapy","radiopharma","surgery","chemotherapy","imaging"],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":["b-overdiagnosis","b-early-detection","b-resistance","b-biomarker-validation","b-hereditary-risk","b-toxicity-qol","b-immunotherapy-response","b-trial-design","b-global-access","b-survivorship"],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"steps":[{"era":"1941 to 1966","title":"A cancer is shown to depend on a hormone, and systemic cancer therapy begins","description":"Huggins and Hodges measured serum phosphatases in men with metastatic prostate cancer, then castrated them or gave them oestrogen and watched the disease regress; androgen injection sent it the other way. No cancer in any organ had previously been made to shrink by anything other than surgery or radiation. Huggins shared the 1966 Nobel Prize for it. High-dose oestrogen was the first medical castration and was abandoned for cardiovascular harm rather than for lack of effect, which is why luteinising hormone-releasing hormone agonists replaced it and why transdermal oestradiol, which avoids first-pass hepatic effects, is still being tested as an alternative.","refs":["paper-huggins-hodges-castration-serum-phosphatases-prostate-1941","paper-langley-lancet","hormonal-therapy-roadmap"],"status":"historic"},{"era":"1987 to 2005","title":"A blood test arrives, and an epidemic of diagnoses follows it","description":"Stamey described prostate-specific antigen as a marker that tracked tumour volume, fell to nothing after prostatectomy and rose again on recurrence, and stated in the same paper that it is not specific. Catalona turned it into a screening test in 1991 with a threshold of 4.0 micrograms per litre and showed it found cancers a digital rectal examination missed. Testing spread through United States primary care over the following decade without a randomised trial of mortality. By 2005 the consequence was measurable: relative incidence against 1986 was 7.23 in men under 50 and 0.56 in men aged 80 and over, an extra 1,305,600 diagnoses and 1,004,800 definitive treatments.","refs":["paper-stamey-psa-serum-marker-nejm-1987","paper-catalona-psa-screening-test-nejm-1991","paper-welch-albertsen-psa-era-diagnosis-treatment-jnci-2009","paper-damico-risk-groups-jama-1998","early-detection-roadmap"],"status":"historic"},{"era":"1989 to 2023","title":"Does treating localised disease help? Three trials, three answers, one rule","description":"SPCG-4 randomised 695 men with clinically detected cancer from 1989 and found, at 29 years, that surgery cut prostate cancer death by 45 percent and added a mean of 2.9 years of life. PIVOT randomised a largely prostate-specific antigen-detected population from 1994 and found no significant difference at 19.5 years, with more incontinence and sexual dysfunction and less treatment for biochemical progression. ProtecT randomised men found by screening and, at 15 years, found prostate cancer mortality of around 3 percent in all three arms. The rule those three produce is the one that matters at diagnosis: how much radical treatment helps depends on how the cancer was found and how aggressive it is, and a Gleason score above 7 carried ten times the risk of death of a score of 6 or lower in SPCG-4.","refs":["paper-bill-axelson-spcg-4-29-year-nejm-2018","paper-wilt-pivot-prostatectomy-observation-nejm-2017","paper-protect-nejm-2016","paper-protect-15-year-nejm-2023","paper-klotz-active-surveillance-jco-2015","surgery-roadmap"],"status":"historic"},{"era":"2009 to 2018","title":"The screening trials disagree, and the policy swings twice","description":"ERSPC randomised 162,243 men in its core age group and found a rate ratio for prostate cancer death of 0.80, an absolute difference of 0.71 death per 1,000 men, 1,410 to screen and 48 extra cancers to treat for each death prevented, and cumulative incidence of 8.2 percent against 4.8. PLCO, published the same day, found no difference, with control-group screening rising to 52 percent by year six. The United States task force issued a grade D recommendation against screening in 2012 and in 2018 moved men aged 55 to 69 to grade C, shared decision-making, quoting about 1.3 deaths and about 3 metastatic cases prevented per 1,000 men screened against 1 in 5 developing long-term incontinence and 2 in 3 long-term erectile dysfunction after prostatectomy. The modelling work that ran alongside showed why a single overdiagnosis figure is not meaningful: lead time of 5.4 to 6.9 years and overdiagnosis of 23 to 42 percent in the United States calibration, 7.9 years and 66 percent in the Rotterdam one.","refs":["paper-schroder-erspc-screening-mortality-nejm-2009","paper-andriole-plco-prostate-screening-nejm-2009","paper-draisma-lead-time-overdiagnosis-psa-jnci-2009","paper-moyer-uspstf-prostate-screening-ann-intern-med-2012","paper-uspstf-prostate-screening-jama-2018","paper-hugosson-eur-urol","paper-martin-jama"],"status":"historic"},{"era":"2004 to 2014","title":"Chemotherapy works, a little, and then the receptor drugs arrive","description":"TAX 327 and SWOG 9916, published in the same issue in October 2004, both showed docetaxel extends survival in castration-resistant disease, by 2.4 and 1.9 months respectively over mitoxantrone, and TAX 327 also improved pain and quality of life. TROPIC opened the second line in 2010 with cabazitaxel, 15.1 against 12.7 months. Then the hormonal drugs designed on the Visakorpi and Chen biology arrived: abiraterone after chemotherapy in COU-AA-301 and before it in COU-AA-302, enzalutamide after chemotherapy in AFFIRM (18.4 against 13.6 months) and before it in PREVAIL (radiographic progression-free survival 65 percent against 14 percent at 12 months). Within four years castration-resistant prostate cancer went from one treatment to five.","refs":["paper-tannock-tax-327-docetaxel-prednisone-nejm-2004","paper-petrylak-swog-9916-docetaxel-estramustine-nejm-2004","paper-de-bono-tropic-cabazitaxel-lancet-2010","paper-cou-aa-301-abiraterone-de-bono-nejm-2011","paper-abiraterone-acetate-prostate-n-engl-j-med-2013","paper-scher-affirm-enzalutamide-nejm-2012","paper-beer-prevail-enzalutamide-nejm-2014","paper-alsympca-radium-223-nejm-2013","chemotherapy-roadmap"],"status":"historic"},{"era":"2005 to 2016","title":"The genome: a quiet sequence, a rearranged structure, and one actionable fifth","description":"Tomlins found the TMPRSS2-ERG fusion in 2005, the first recurrent rearrangement in a common carcinoma, putting a growth gene under androgen control. Taylor showed copy-number pattern separates risk better than Gleason score. Grasso sequenced 50 lethal cancers at rapid autopsy and found only 2.00 mutations per megabase even after years of treatment, with the recurrent damage in chromatin-modifying genes. Baca named chromoplexy, chains of rearrangement arriving in a burst. In 2015 TCGA classified 333 primary tumours into seven subtypes covering 74 percent of them, and the Stand Up To Cancer cohort sequenced 150 metastatic biopsies prospectively and found DNA repair alterations in 19.3 percent. Gundem reconstructed how the cancer travels and found that metastases seed other metastases, often several clones at a time. Pritchard then showed 11.8 percent of men with metastatic disease carry an inherited DNA repair mutation, with no relation to family history or age.","refs":["paper-tomlins-tmprss2-ets-fusion-science-2005","paper-taylor-integrative-genomic-profiling-cancer-cell-2010","paper-grasso-mutational-landscape-lethal-crpc-nature-2012","paper-baca-punctuated-evolution-chromoplexy-cell-2013","paper-tcga-molecular-taxonomy-primary-prostate-cell-2015","paper-robinson-integrative-clinical-genomics-advanced-prostate-cell-2015","paper-gundem-evolutionary-history-lethal-metastatic-prostate-nature-2015","paper-pritchard-inherited-dna-repair-metastatic-prostate-nejm-2016"],"status":"historic"},{"era":"2013 to 2022","title":"Everything moves to the first day of metastatic diagnosis","description":"GETUG-AFU 15 gave docetaxel with androgen deprivation from the start and found nothing, and told the field not to do it. CHAARTED and STAMPEDE then found the opposite, and the STOpCaP adaptive meta-analysis resolved the three: in metastatic disease, a hazard ratio of 0.77 and an absolute 9 percent gain in four-year survival, with no evidence of benefit from zoledronic acid at all. LATITUDE and STAMPEDE did the same for abiraterone, TITAN for apalutamide, ENZAMET for enzalutamide, and ARASENS and PEACE-1 established the triplet of androgen deprivation, docetaxel and an androgen receptor pathway inhibitor. STAMPEDE also showed that irradiating the prostate itself improves survival in men with a low burden of metastases. In non-metastatic castration-resistant disease, SPARTAN, PROSPER and ARAMIS moved the same class earlier again.","refs":["paper-gravis-getug-afu-15-docetaxel-lancet-oncol-2013","paper-chaarted-nejm-2015","paper-stampede-lancet-2016","paper-vale-stopcap-docetaxel-bisphosphonates-lancet-oncol-2016","paper-latitude-nejm-2017","paper-stampede-abiraterone-nejm-2017","paper-nct02489318-n-engl-j-med-2019","paper-enzamet-n-engl-j-med-2019","paper-arasens-nejm-2022","paper-peace-1-lancet-2022","paper-parker-lancet","paper-spartan-nejm-2018","paper-prosper-nejm-2018","paper-aramis-nejm-2019"],"status":"current"},{"era":"2015 to 2026","title":"DNA repair: the first molecular subset of prostate cancer with a drug of its own","description":"TOPARP-A treated 50 unselected heavily pre-treated men with olaparib and biopsied all of them: 33 percent responded, and 14 of the 16 men with DNA repair defects did, including all 7 with BRCA2 loss, at a biomarker specificity of 94 percent. PROfound made it randomised, TRITON2 got rucaparib approved on response rate and TRITON3 confirmed it, with imaging-based progression-free survival of 11.2 against 6.4 months in the BRCA subgroup and a hazard ratio of 0.95 in the ATM subgroup, which is no effect at all. PROpel, TALAPRO-2 and MAGNITUDE then combined PARP inhibitors with androgen receptor drugs in first-line castration-resistant disease, and TALAPRO-3 and AMPLITUDE have moved the combination into hormone-sensitive disease. The recurring lesson is that homologous recombination repair is not one biomarker: BRCA2 is not ATM and neither is CDK12.","refs":["paper-mateo-toparp-a-olaparib-dna-repair-nejm-2015","paper-profound-nejm-2020","paper-abida-triton2-rucaparib-brca-jco-2020","paper-fizazi-triton3-rucaparib-nejm-2023","paper-propel-lancet-oncol-2023","paper-talapro-2-lancet-2023","paper-magnitude-j-clin-oncol-2023","paper-nct04497844-nat-med-2025","paper-nct04821622-n-engl-j-med-2026","paper-chung-comprehensive-genomic-profiling-prostate-jco-po-2019","targeted-therapy-roadmap"],"status":"current"},{"era":"2017 to 2026","title":"PSMA: the same molecule used to see the cancer and then to irradiate it","description":"Prostate-specific membrane antigen sits on the surface of almost every prostate cancer cell, which makes it both a camera target and a delivery address. proPSMA showed PSMA positron emission tomography beats conventional imaging for staging high-risk disease, changing management in a substantial minority. TheraP compared lutetium-177 PSMA-617 against cabazitaxel and VISION added it to standard care after an androgen receptor drug and a taxane. PSMAfore moved it in front of the taxane and PSMAddition into hormone-sensitive disease. It is the clearest example in any solid tumour of a single molecule carrying both the diagnostic and the therapeutic, and the open question is dosing: the amount of radiation delivered is not currently measured per patient, and the schedule is fixed rather than adapted to response.","refs":["paper-propsma-hofman-lancet-2020","paper-psma-prerp-hope-jama-oncol-2021","paper-therap-lancet-2021","paper-vision-nejm-2021","paper-psmafore-lancet-2024","paper-psmaddition-lancet-2026","radiopharma-roadmap","molecular-imaging-roadmap"],"status":"current"},{"era":"2014 to 2026","title":"What the androgen receptor era created: splice variants, lineage switching and a cold tumour","description":"Antonarakis showed in 2014 that men whose circulating tumour cells carry AR-V7, an androgen receptor missing the part the drugs bind, have a zero percent prostate-specific antigen response rate to enzalutamide and abiraterone. Mu and Ku then showed the more complete escape: losing TP53 and RB1 lets the cell switch on SOX2 and change identity from a luminal cell that needs the androgen receptor to a basal or neuroendocrine cell that does not, and restoring the tumour suppressors reverses it in the laboratory. Aggarwal found treatment-emergent small-cell neuroendocrine carcinoma in 17 percent of metastatic biopsies. Immunotherapy, which might have been the answer, is not: KEYNOTE-199 gave response rates of 5 and 3 percent and PD-L1 expression predicted nothing, which is consistent with a median tumour mutational burden of 2.6 mutations per megabase and mismatch repair deficiency in 4 percent.","refs":["paper-antonarakis-ar-v7-resistance-nejm-2014","paper-mu-sox2-lineage-plasticity-science-2017","paper-ku-rb1-trp53-lineage-plasticity-science-2017","paper-beltran-nepc-divergent-evolution-nat-med-2016","paper-aggarwal-t-sccpc-jco-2018","paper-antonarakis-keynote-199-pembrolizumab-jco-2020","paper-chung-comprehensive-genomic-profiling-prostate-jco-po-2019"],"status":"emerging"},{"era":"2018 to 2030","title":"Reversing the adaptation instead of blocking it, and asking what order to give things in","description":"RESTORE gave supraphysiological testosterone to men who had progressed on enzalutamide: 30 percent responded, and 52 percent of those who then went back on enzalutamide responded to the drug that had failed them. TRANSFORMER randomised the approach and found the primary endpoint flat at 5.7 months in both arms, but progression-free survival through crossover of 28.2 months for testosterone-then-enzalutamide against 19.6 for the reverse, with quality of life favouring testosterone throughout. SWOG 9346 had already shown that taking planned breaks from androgen deprivation is not clearly safe, with a hazard ratio of 1.10 whose confidence interval crossed the non-inferiority boundary. Between them these three trials make the same point from different directions: in a disease with six active treatment classes and no head-to-head sequencing data, the order is itself an untested intervention.","refs":["paper-teply-restore-bipolar-androgen-therapy-lancet-oncol-2018","paper-denmeade-transformer-bipolar-androgen-therapy-jco-2021","paper-hussain-swog-9346-intermittent-androgen-deprivation-nejm-2013","paper-zhang-nat-commun","idea-bio1-alternating-schedules","idea-tr1-adaptive-therapy-randomised-phase-2"],"status":"emerging"},{"era":"2026 to 2032","title":"What would have to be true for prostate cancer mortality to fall substantially again","description":"Five things, only one of which is a new drug. A screening pathway judged on metastatic presentation rather than on incidence, invited by risk rather than by birthday, with magnetic resonance imaging in front of the biopsy so the overdiagnosis half of the trade shrinks. DNA repair testing at the moment of metastatic diagnosis rather than three lines later, because the drugs have already moved there. The order of treatment randomised, in a platform that can compare sequences rather than only drugs. Lineage plasticity watched for in the men whose tumours have lost TP53 and RB1, before the biopsy comes back neuroendocrine. And the mortality gap that survives equal access, which is dying of something other than prostate cancer, measured and treated as an outcome of the cancer service rather than someone else's problem.","refs":["idea-prostate-metastatic-presentation-as-the-screening-endpoint","idea-prostate-hrr-testing-at-metastatic-diagnosis","idea-prostate-randomise-the-sequence-not-only-the-drugs","idea-prostate-plasticity-surveillance-before-it-is-neuroendocrine","idea-prostate-other-cause-mortality-as-a-reported-service-outcome","idea-prostate-per-lesion-mri-audit-before-focal-treatment","idea-prostate-bipolar-androgen-therapy-phase-3-on-pfs2"],"status":"speculative"}],"watch":[{"item":"ProBio: the biomarker-driven outcome-adaptive platform in metastatic prostate cancer, the first trial designed to compare treatment strategies rather than single drugs in this disease","expected":"Primary completion and study completion December 2026 (estimated, ClinicalTrials.gov NCT03903835)","source":"https://clinicaltrials.gov/study/NCT03903835","refs":["idea-prostate-randomise-the-sequence-not-only-the-drugs"]},{"item":"PSMAddition: lutetium-177 PSMA-617 added to standard care in metastatic hormone-sensitive disease, the earliest setting radioligand therapy has been tested in","expected":"Study completion 11 February 2027 (estimated; primary completion 13 January 2025 actual, ClinicalTrials.gov NCT04720157)","source":"https://clinicaltrials.gov/study/NCT04720157","refs":["paper-psmaddition-lancet-2026","psmaddition"]},{"item":"CAPItello-281: capivasertib with abiraterone in PTEN-deficient metastatic hormone-sensitive disease, the first PI3K-pathway result in a biomarker-selected prostate population","expected":"Study completion 31 March 2027 (estimated; primary completion 7 October 2024 actual, ClinicalTrials.gov NCT04493853)","source":"https://clinicaltrials.gov/study/NCT04493853","refs":["paper-capitello-281-ann-oncol-2026","capitello-281","paper-tcga-molecular-taxonomy-primary-prostate-cell-2015"]},{"item":"TALAPRO-3: talazoparib with enzalutamide in DNA damage repair gene-mutated metastatic hormone-sensitive disease, the PARP combination moved to the hormone-sensitive setting","expected":"Study completion 28 August 2027 (estimated; primary completion 18 February 2026 actual, ClinicalTrials.gov NCT04821622)","source":"https://clinicaltrials.gov/study/NCT04821622","refs":["paper-nct04821622-n-engl-j-med-2026","nct04821622","idea-prostate-hrr-testing-at-metastatic-diagnosis"]},{"item":"PROTEUS: perioperative apalutamide with androgen deprivation around radical prostatectomy in high-risk localised disease, the largest test of intensification before the operation","expected":"Primary completion 1 December 2026 and study completion 13 October 2028 (both estimated, ClinicalTrials.gov NCT03767244)","source":"https://clinicaltrials.gov/study/NCT03767244","refs":["paper-nct03767244-n-engl-j-med-2026","nct03767244"]},{"item":"PEACE III: radium-223 with enzalutamide against enzalutamide alone in bone-metastatic castration-resistant disease, and the bone-protecting agent question it raised","expected":"Study completion December 2028 (estimated; primary completion 19 February 2024 actual, ClinicalTrials.gov NCT02194842)","source":"https://clinicaltrials.gov/study/NCT02194842","refs":["paper-alsympca-radium-223-nejm-2013","paper-lutetium-177-vipivotide-tetrax-prostate-oncol-ther-2025"]},{"item":"PSMA-DC: lutetium-177 vipivotide tetraxetan against observation in oligometastatic castration-sensitive disease detected on PSMA imaging, the test of whether a systemic radioligand can replace metastasis-directed treatment","expected":"Primary completion 25 April 2028 and study completion 3 October 2031 (both estimated, ClinicalTrials.gov NCT05939414)","source":"https://clinicaltrials.gov/study/NCT05939414","refs":["nct05939414","paper-phillips-jama-oncol","idea-psma-pet-guided-mdt"]},{"item":"STAMPEDE2: the successor platform, testing stereotactic radiotherapy to metastases, lutetium-177 PSMA-617 and niraparib with abiraterone against contemporary standard care, with 3,360 men planned","expected":"Primary completion April 2031 and study completion March 2032 (both estimated, ClinicalTrials.gov NCT06320067)","source":"https://clinicaltrials.gov/study/NCT06320067","refs":["stampede","paper-stampede-abiraterone-high-risk-attard-lancet-2022","idea-prostate-randomise-the-sequence-not-only-the-drugs"]}]},{"id":"frontier-2035","kind":"roadmap","name":"Radical oncology: what could change the war by 2035","aka":[],"tldr":"Radical oncology is a horizon map of the wilder ideas in cancer, sorted by how close they are to mattering, with the reason each one might never arrive.","summary":"Most of what is celebrated as a breakthrough is an incremental gain on an existing modality. This roadmap collects the ideas that would change the shape of treatment rather than its slope: therapies that read DNA directly, living drugs, radiation delivered in milliseconds, and detection that runs continuously rather than annually.\n\nThe grouping is by horizon, from technologies already producing randomised data to ideas with no human evidence at all. Placement reflects the state of evidence in September 2026, not company timelines. Several steps will not happen: the failure record of hypoxia-activated prodrugs, metabolic therapy, and matrix-softening agents is a reminder that a clean mechanism is not a clinical benefit.","asOf":"2026-09-08","links":[],"tags":[],"related":[],"cancers":[],"sections":["drug-discovery","radiation","cell-therapy","early-detection"],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"steps":[{"era":"Now (randomised data exists)","title":"Ideas already being tested against a control arm","description":"Microbiome modulation, spatially fractionated radiotherapy, sonodynamic therapy in glioblastoma, GDF-15 blockade for cachexia, and repurposed cheap drugs all have randomised or registrational trials running in 2026. These are the frontier ideas closest to a guideline: each has a defined population, a comparator, and a readout inside a few years. Cachexia therapy is the likeliest first approval in a domain with no approved drug at all.","refs":["microbiome-modulation-io","lattice-radiotherapy","sonodynamic-therapy","cachexia-therapy","drug-repurposing","radiodynamic-therapy"],"status":"current"},{"era":"By 2027 (early clinical, readouts imminent)","title":"Living drugs, logic gates, and designed proteins reach decision points","description":"Engineered bacteria, logic-gated cell therapies, molecular glue platforms, and de novo designed binders all have first-in-human programmes running. The question each faces is the same: does the elegant mechanism survive contact with a heterogeneous human tumour? Expect most to disappoint on response rate while establishing safety, which is how bispecific antibodies and ADCs also began.","refs":["engineered-bacteria-therapy","logic-gated-therapeutics","molecular-glue-platforms","de-novo-protein-design","in-situ-vaccination","histotripsy-immune-priming","radionuclide-parp-combination"],"status":"emerging"},{"era":"By 2030 (physics and chemistry maturing)","title":"Radiation and radiopharmaceuticals get a second act","description":"Auger emitters, contained alpha nanogenerators, proton arc delivery, and very-high-energy electrons are all limited today by engineering rather than biology: isotope supply, daughter recoil, gantry speed, and dosimetry at ultra-high dose rate. Those are tractable problems with capital behind them. If FLASH sparing is real in humans, deep FLASH by electron or proton arc would be the largest change to radiotherapy since intensity modulation.","refs":["auger-electron-therapy","alpha-nanogenerators","proton-arc-therapy","vhee-radiotherapy","magnetic-nanoparticle-hyperthermia","photothermal-nanoparticles"],"status":"emerging"},{"era":"By 2030 (detection and decision-making)","title":"Monitoring becomes continuous and selection becomes spatial","description":"Fragmentomics, breath analysis, and near-continuous ctDNA sampling all push detection from an annual event towards a running signal, while spatial omics and organoid testing push treatment choice from genotype towards phenotype and architecture. The gating question for every one of them is not sensitivity but utility: acting earlier has to change outcomes, and no randomised trial has yet shown that for continuous monitoring.","refs":["continuous-ctdna-monitoring","breath-vocs","spatial-omics-guided-therapy","organoid-guided-therapy-scale","digital-twins-trials","n-of-1-platforms","total-body-pet-screening"],"status":"emerging"},{"era":"By 2035 (needs a delivery breakthrough)","title":"Writing to the genome and the epigenome inside a tumour","description":"In vivo base and prime editing, epigenetic silencing, antibody-oligonucleotide conjugates, and programmable DNA-targeting drugs share one blocker: getting a large, charged molecule into most cells of a solid tumour. Liver-directed editing is already in the clinic, so the chemistry works; the tumour delivery problem has resisted thirty years of effort. If it is solved, undruggable drivers such as MYC and TP53 loss become addressable and much of this roadmap is rewritten.","refs":["in-vivo-gene-editing-cancer","epigenetic-editing","antibody-oligonucleotide-conjugates","programmable-dna-targeting-therapeutics","self-amplifying-rna","exosome-therapeutics","dna-origami-nanorobots"],"status":"speculative"},{"era":"By 2035 (attacking the host, not the tumour)","title":"Treating the soil rather than the seed","description":"Stromal CAR-T, nerve blockade, senescence clearance, mechanical decompression, and targeting the tumour's own microbes all treat the environment a cancer needs rather than the cancer itself. The attraction is that the host does not mutate. The risk is visible in the record: PEGPH20 failed, FAP CAR-T caused cachexia in mice, and broad antibiotics blunt immunotherapy. Success here probably requires far better spatial measurement first.","refs":["stroma-directed-car","cancer-neuroscience","senescence-targeting","mechanobiology-therapy","tumour-microbiome-targeting","hypoxia-activated-therapy","trained-innate-immunity"],"status":"speculative"},{"era":"Speculative (no human evidence)","title":"Ideas that are still physics and mouse data","description":"DNA origami nanorobots, phage-based delivery, and quantum-dot imaging agents have striking preclinical demonstrations and no clinical footprint. They belong on the map because the failure modes are known and specific, nuclease degradation, rapid clearance, heavy-metal toxicity, rather than vague. Any of them could move a horizon if a single delivery or materials problem is solved.","refs":["dna-origami-nanorobots","phage-delivery","quantum-dot-imaging","chronotherapy","metabolic-therapy"],"status":"speculative"}],"watch":[]},{"id":"radiopharma-roadmap","kind":"roadmap","name":"Radiopharmaceutical roadmap: iodine → lutetium → actinium","aka":[],"tldr":"The radiopharmaceutical roadmap runs eighty years from radioactive iodine for thyroid cancer to alpha-emitting drugs for prostate and neuroendocrine cancers, with isotope supply as the limiting factor.","summary":"The radiopharmaceutical roadmap runs from radioiodine curing differentiated thyroid cancer, the first theranostic, through radium-223 and Lutathera with its matched 68Ga-DOTATATE PET, to PSMA PET and Pluvicto building the first radioligand franchise. The current steps move Pluvicto and Lutathera into earlier lines amid an M&A wave, while the emerging step brings 225Ac and 212Pb alpha emitters and new targets such as FAP, GRPR, CAIX and B7-H3 into trials, with isotope supply as the limiting factor. The speculative end imagines radioligands as a standard modality with pan-cancer FAP theranostics and personalised dosimetry. The route links radioligand therapy, targeted alpha therapy, PSMA PET and FAPI PET, prostate, thyroid and neuroendocrine cancers, and the manufacturing bottleneck.","asOf":"2026-09-04","links":[{"label":"VISION: lutetium-177 PSMA-617 radioligand therapy extends survival in advanced prostate cancer (New England Journal of Medicine 2021)","url":"https://doi.org/10.1056/NEJMoa2107322"}],"tags":[],"related":["prostate-roadmap"],"cancers":[],"sections":["radiopharma"],"technologies":["radioligand-therapy","targeted-alpha-therapy","psma-pet","fapi-pet","radioimmunotherapy"],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"steps":[{"era":"1946-2000","title":"Radioiodine and early radioimmunotherapy","description":"131I cures differentiated thyroid cancer, the first theranostic. Strontium-89 and samarium-153 palliate bone pain. 90Y-ibritumomab and 131I-tositumomab (2002-03) work in lymphoma but fail commercially.","refs":["thyroid"],"status":"historic"},{"era":"2013-2018","title":"Radium-223 and Lutathera","description":"Radium-223 (ALSYMPCA, 2013) is the first alpha emitter approved, for bone metastases. 177Lu-DOTATATE (NETTER-1, 2018) establishes the modern peptide receptor radionuclide therapy paradigm with a matched 68Ga-DOTATATE PET.","refs":["lutathera","sstr2"],"status":"historic"},{"era":"2020-2022","title":"PSMA theranostics","description":"PSMA PET approved (68Ga-PSMA-11 2020, Pylarify 2021); Pluvicto approved (VISION, 2022). Novartis builds the first radioligand commercial franchise; supply and site-capacity constraints appear.","refs":["psma-pet","pluvicto","vision","pylarify"],"status":"current"},{"era":"2023-2026","title":"Earlier lines, consolidation, and an M&A wave","description":"PSMAfore moves Pluvicto pre-chemotherapy (2025), NETTER-2 moves Lutathera to first line (2024); 2026 label expansions. BMS buys RayzeBio ($4.1B), AstraZeneca buys Fusion ($2.4B), Lilly buys Point; Bayer, Sanofi, Novartis expand. Pylarify TruVu approved March 2026. ITM-11 reads out a positive phase 3.","refs":["psmafore","ryz101","fusion-pharma","rayzebio","itm"],"status":"current"},{"era":"2026-2029","title":"Alpha emitters and new targets","description":"225Ac-PSMA (Novartis, Bayer Trillium, Fusion FPI-2265), 225Ac-DOTATATE (RYZ101) and 212Pb-DOTAMTATE are in phase 3; FAP radioligands (FAP-2286) are in phase 2; GRPR, CAIX, B7-H3, DLL3 radioconjugates are in early trials. TerraPower's Philadelphia Ac-225 plant aims for a 20-fold supply increase. Dosimetry-guided dosing enters trials.","refs":["ac225-psma","ryz101","fap-2286","terrapower-isotopes","orano-med","dosimetry"],"status":"emerging"},{"era":"2029+","title":"Speculative: radioligands as a standard modality","description":"Alpha therapy in hormone-sensitive prostate cancer and after ADC failure; pan-cancer FAP theranostics; radio-ADCs and pretargeting; combination with PARP inhibitors, IO, and ADCs; automated decentralised radiopharmacies; total-body PET for ultra-low-dose dosimetry.","refs":["radioimmunotherapy","beta-then-alpha","pet-ct"],"status":"speculative"}],"watch":[]},{"id":"radiation-roadmap","kind":"roadmap","name":"Radiotherapy roadmap: X-rays → shaped beams → fewer fractions, particles and FLASH","aka":[],"tldr":"Radiotherapy cures more people than any drug and has reinvented itself every decade: from crude X-ray fields to beams shaped by computer, delivered in days instead of weeks, and now in fractions of a second. Its future is precision, fewer visits, and combination with drugs that make radiation work better.","summary":"External beam radiotherapy moved from two-dimensional fields to three-dimensional conformal plans, intensity modulation, daily image guidance and stereotactic delivery that ablates a tumour in one to five sessions. Large randomised trials showed that fewer, larger fractions are as effective and as safe in breast and prostate cancer, cutting a course from weeks to days; protons and carbon ions spare tissue behind the tumour; MR-linacs adapt the plan to the anatomy of the day.\n\nThe present decade is about combination and de-escalation. Immunotherapy after chemoradiation is standard in stage III lung cancer (PACIFIC) and locally advanced cervical cancer (KEYNOTE-A18), and a targeted pill after chemoradiation in EGFR-mutant lung cancer (LAURA); several attempts to add drugs to head and neck chemoradiation failed, and de-escalation for HPV-positive throat cancer fell short. Single-fraction palliative treatment, skipping radioactive iodine in low-risk thyroid cancer and lower doses in children's brain tumours are the de-escalation wins.\n\nAhead are FLASH radiotherapy, which delivers the whole dose in under a second and spares normal tissue in animals, very-high-energy electrons, proton arcs, upright treatment, AI planning and radiation as an immune primer. The pace is set by the underfunding of radiotherapy research relative to drugs, and by the machines, physicists and technicians that most of the world does not have.","asOf":"2026-09-10","links":[{"label":"FAST-Forward: five-fraction breast radiotherapy (Lancet 2020)","url":"https://doi.org/10.1016/S0140-6736(20)30932-6"},{"label":"PACIFIC (NEJM 2017)","url":"https://www.nejm.org/doi/full/10.1056/NEJMoa1709937"},{"label":"Lancet Oncology Commission: expanding global access to radiotherapy (2015)","url":"https://doi.org/10.1016/S1470-2045(15)00222-3"}],"tags":[],"related":["radiopharma-roadmap","idea-acc-single-fraction-palliative-radiotherapy-default","idea-acc-hypofractionation-default-lmic","idea-acc-pooled-procurement-radiotherapy","idea-acc-linac-uptime-contracts","idea-acc-remote-planning-hubs","idea-acc-remote-medical-physics-qa","idea-acc-frugal-hdr-brachytherapy","idea-bio2-radiotherapy-sting-fractionation","idea-cthpv-adapted-deescalation","frontier-2035","devices-roadmap"],"cancers":[],"sections":["radiation"],"technologies":["imrt-igrt","sbrt","brachytherapy","proton-therapy","carbon-ion","mr-linac","flash-rt","vhee-radiotherapy","proton-arc-therapy","lattice-radiotherapy","bnct","hyperthermia","radiodynamic-therapy","radioimmunotherapy","targeted-alpha-therapy","radionuclide-parp-combination","auto-contouring-ai","treatment-planning-systems","palliative-radiotherapy","prophylactic-cranial-irradiation","intraoperative-radiotherapy","hyperbaric-oxygen-radiation-injury","acupuncture-xerostomia"],"targets":[],"drugs":["durvalumab","temozolomide","radioactive-iodine","amifostine"],"companies":["varian","elekta","reflexion","theryq","iba","mevion","raysearch","leo-cancer-care","p-cure","tae-life-sciences","neutron-therapeutics","limbus-ai","therapanacea","nrg-oncology"],"institutions":["the-christie","institut-curie","mayo-clinic-florida","mgh"],"pathways":[],"terms":["hypofractionation"],"trials":["pacific","laura","keynote-a18","cross","interlace","portec-3","convert","javelin-hn-100","trilynx","nrg-hn002-hn005","estimabl2","acns0331","eortc-26981"],"people":[],"bottlenecks":["b-surgery-radiation-innovation","b-global-access","b-workforce","b-trial-design"],"keyPapers":["paper-atun-lancet-oncol","paper-murray-brunt-lancet"],"journals":[],"dependsOn":[],"notes":[],"steps":[{"era":"1895-1990s","title":"From X-rays to conformal beams","description":"Röntgen's X-rays were used against cancer within a year of their discovery, and the Curies' radium became brachytherapy. Cobalt units and then linear accelerators (1950s) delivered higher energies deeper; CT planning in the 1980s let beams be shaped to the tumour in three dimensions. Radioactive iodine for thyroid cancer, from the 1940s, was the first targeted radiotherapy and a preview of the radiopharmaceutical field.","refs":["institut-curie","brachytherapy","radioactive-iodine","imrt-igrt"],"status":"historic"},{"era":"2000s-2020","title":"Modulation, image guidance and fewer fractions","description":"Intensity-modulated and image-guided radiotherapy shaped dose around organs and checked position daily, cutting late toxicity in prostate and head and neck cancer. Stereotactic body radiotherapy ablated early lung cancers and oligometastases in one to five sessions. Large trials proved that fewer, larger fractions match conventional courses: CHHiP in prostate cancer and FAST-Forward (2020), which delivered breast radiotherapy in five sessions over one week. CONVERT settled the small-cell lung schedule debate. Treatment planning software became the real product.","refs":["imrt-igrt","sbrt","hypofractionation","convert","treatment-planning-systems","varian","elekta","raysearch"],"status":"historic"},{"era":"2017-2026","title":"Radiation plus drugs: what worked and what did not","description":"PACIFIC made a year of durvalumab after chemoradiation the standard in stage III lung cancer; KEYNOTE-A18 added pembrolizumab to curative chemoradiation for cervical cancer with a survival gain; LAURA gave osimertinib after chemoradiation in EGFR-mutant lung cancer; INTERLACE showed that six weeks of cheap chemotherapy before cervical chemoradiation cuts deaths. The failures were as instructive: adding a PD-L1 blocker to head and neck chemoradiation did not help (JAVELIN HN 100), a promising radiosensitiser made things worse (TrilynX), and de-escalating radiation for HPV-positive throat cancer fell short (NRG-HN002 and HN005).","refs":["pacific","durvalumab","keynote-a18","laura","interlace","cross","portec-3","javelin-hn-100","trilynx","nrg-hn002-hn005","temozolomide","eortc-26981"],"status":"current"},{"era":"2010s-2026","title":"Particles, magnets and adaptation","description":"Protons stop inside the tumour rather than passing through, which matters most in children and near critical organs; the Christie opened the UK's first NHS proton centre and compact single-room systems are spreading. Carbon ions kill radioresistant tumours and are available at a handful of centres, with North America's first being built at Mayo Clinic Florida. MR-linacs image soft tissue during treatment and adapt the plan daily; PET-guided systems track the tumour by its own emissions. AI auto-contouring now saves hours per plan in hundreds of centres. Clinical proton dose is still reported at RBE 1.1; whether LET-weighted RBE plus tissue alpha/beta can pick the adults who benefit versus IMRT is untested in the randomised trials now running.","refs":["proton-therapy","the-christie","mgh","iba","mevion","carbon-ion","mayo-clinic-florida","mr-linac","elekta","reflexion","auto-contouring-ai","limbus-ai","therapanacea","linear-energy-transfer","relative-biological-effectiveness","idea-bio2-let-rbe-ab-selects-protons"],"status":"current"},{"era":"2016-2026","title":"Doing less: fewer visits and fewer treatments","description":"Single-fraction radiotherapy relieves bone pain as well as ten fractions and is still under-used. ESTIMABL2 showed that most low-risk thyroid cancers can skip radioactive iodine after surgery. ACNS0331 tested lower doses and smaller fields in children with medulloblastoma to reduce cognitive harm. MRI surveillance is replacing prophylactic brain irradiation in small-cell lung cancer. In overloaded systems, one-week hypofractionated courses are the single largest capacity gain available.","refs":["palliative-radiotherapy","idea-acc-single-fraction-palliative-radiotherapy-default","estimabl2","acns0331","prophylactic-cranial-irradiation","idea-acc-hypofractionation-default-lmic","idea-cthpv-adapted-deescalation"],"status":"current"},{"era":"2026-2032","title":"FLASH, arcs, upright and new particles","description":"FLASH radiotherapy delivers a full dose in under a second and, in animals, spares normal tissue while killing tumour; the first human trials of FLASH protons have been run and dedicated electron machines are being built. Very-high-energy electrons and proton arcs are routes to deep FLASH. Upright treatment chairs could cut the cost of particle therapy; boron neutron capture therapy, approved in Japan for head and neck cancer, needs compact neutron sources; lattice radiotherapy deliberately doses a large tumour unevenly. Each is limited by engineering and dosimetry rather than biology.","refs":["flash-rt","theryq","varian","vhee-radiotherapy","proton-arc-therapy","leo-cancer-care","p-cure","bnct","tae-life-sciences","neutron-therapeutics","lattice-radiotherapy","radiodynamic-therapy","hyperthermia"],"status":"emerging"},{"era":"2028+","title":"Radiation as an immune primer, and radiation from inside","description":"Radiation releases tumour antigens and can switch on the innate immune alarm, or switch it off, depending on dose and fractionation; trials are trying to find the schedule that primes rather than suppresses. Systemic radiation is the radiopharmaceutical roadmap: radioligands, radio-antibodies and alpha emitters that deliver dose to every metastasis, increasingly combined with DNA-repair inhibitors. The two fields are converging on the same question: how to kill the last cell wherever it is.","refs":["idea-bio2-radiotherapy-sting-fractionation","radiopharma-roadmap","radioimmunotherapy","targeted-alpha-therapy","radionuclide-parp-combination","frontier-2035"],"status":"speculative"},{"era":"What sets the pace","title":"Machines, physicists and money","description":"Radiotherapy cures a large share of all cured patients and receives a small share of research funding. Most of the world's population lacks access to a working linear accelerator, and where machines exist they are idle for want of physicists and maintenance. Pooled procurement of machines and service, contracts that pay for uptime rather than hardware, remote planning hubs and remote quality assurance, and low-cost brachytherapy for cervical cancer in every regional centre are the proposals that would change that.","refs":["b-surgery-radiation-innovation","b-global-access","b-workforce","b-trial-design","idea-acc-pooled-procurement-radiotherapy","idea-acc-linac-uptime-contracts","idea-acc-remote-planning-hubs","idea-acc-remote-medical-physics-qa","idea-acc-frugal-hdr-brachytherapy"],"status":"current"}],"watch":[]},{"id":"rejuvenation-roadmap","kind":"roadmap","name":"Recovery and rejuvenation roadmap: cure is not enough → survivorship gets a name → the cohorts that measured the cost → exercise proven as treatment → biological ageing measured and sold → repair, if anyone funds it","aka":["Survivorship research roadmap","Recovery roadmap","Rejuvenation roadmap","History of survivorship research"],"tldr":"Recovery became a research subject because children started surviving cancer and someone wrote down what the cure had cost. Sixty years later the damage is well measured, exercise is the only thing proven to change a hard outcome, and the next decade turns on whether anyone funds the trials and the services the evidence already justifies.","summary":"Five things had to happen before this field could exist. Cancer had to become curable, which happened in paediatric oncology first. Someone had to say that cure was not the end of the question, which Giulio D'Angio did in 1975 and Fitzhugh Mullan did for adults in 1985. The people it was happening to had to organise, which they did in Albuquerque in 1986 and which produced the definition of survivor that national institutes now use. The cost had to be measured in cohorts large enough to attribute a late effect to a dose, which the Childhood Cancer Survivor Study and its successors did from 1994. And a report had to define what good survivorship care consists of, which the Institute of Medicine did in 2006.\n\nWhat followed is a more mixed record than that sequence suggests. The instrument the 2006 report invented, the survivorship care plan, was mandated into accreditation standards and then failed its randomised trials; the 2018 systematic review's verdict is that existing research provides little evidence that such plans improve health outcomes and health care delivery. The national programme England ran from 2007 produced a sensible minimum bundle and measured that only a quarter of people were offered the least demanding part of it. Meanwhile de-escalation worked: late mortality after childhood cancer fell because treatment was made gentler on the strength of cohort evidence, which is the field's clearest success and is a success in prevention rather than in repair.\n\nThe decisive result arrived in 2025. The CHALLENGE trial randomised 889 people with resected colon cancer after adjuvant chemotherapy to a three-year coached exercise programme or to health-education materials, and found longer disease-free survival (hazard ratio 0.72) and longer overall survival (hazard ratio for death 0.63), with eight-year overall survival of 90.3 against 83.2 per cent. That is the first randomised proof that something done after treatment changes whether the cancer comes back, and it is the benchmark every rejuvenation claim should now be measured against.\n\nThe frontier runs in the opposite direction. Cancer treatment measurably accelerates epigenetic clocks, senescence markers and physiological frailty; nothing has been shown to reverse any of it; and a retail industry selling stem cell infusions, exosomes, unlicensed peptides, intravenous NAD+ and compounded hormone pellets to people who have just finished treatment has grown up in the gap between the measurement and the evidence. The honest statement of the field's position is that the acceleration is real, nothing sold on the strength of it has been shown to reverse it, and the distance between those two sentences is where the research belongs.\n\nWhat the next decade turns on is unusually clear and unusually unglamorous: endpoints the field has not agreed, registries that do not record late effects, services that are recommended and not commissioned, and follow-up nobody owns. None of it needs a discovery.","asOf":"2026-10-02","links":[{"label":"Mullan, Seasons of survival: reflections of a physician with cancer (New England Journal of Medicine 1985;313:270-273)","url":"https://doi.org/10.1056/NEJM198507253130421"},{"label":"Institute of Medicine and National Research Council, From Cancer Patient to Cancer Survivor: Lost in Transition (National Academies Press 2006)","url":"https://doi.org/10.17226/11468"},{"label":"Courneya et al., Structured exercise after adjuvant chemotherapy for colon cancer, the CHALLENGE trial (NEJM 2025;393:13-25)","url":"https://doi.org/10.1056/NEJMoa2502760"},{"label":"NCI Office of Cancer Survivorship: statistics and graphs","url":"https://cancercontrol.cancer.gov/ocs/statistics"},{"label":"Department of Health, Living With and Beyond Cancer: Taking Action to Improve Outcomes (England, 29 March 2013)","url":"https://www.gov.uk/government/publications/living-with-and-beyond-cancer-taking-action-to-improve-outcomes"}],"tags":[],"related":["survivorship-roadmap","nutrition-lifestyle-roadmap","paediatric-oncology-roadmap","idea-rejuv-registry-randomised-screening-in-survivors","idea-rejuv-biological-age-as-a-randomised-endpoint","idea-rejuv-thymic-regeneration-in-adults","idea-rejuv-core-outcome-set-for-late-effects","idea-rejuv-rehabilitation-prescription-at-discharge","idea-rejuv-second-cancer-latency-cohort-for-new-drugs","idea-rejuv-survivorship-platform-trial","idea-rejuv-exposure-record-a-machine-can-read","sjlife","bccss","pancaresurfup","ighg"],"cancers":[],"sections":["rejuvenation","supportive-care"],"technologies":["exercise-oncology","structured-exercise-survivorship","exercise-prescription-after-cancer","prehabilitation","survivorship-care-plan","cardio-oncology","fertility-preservation","scalp-cooling","cbt-insomnia-cancer","rejuv-frontier-what-works","rejuv-age-epigenetic-clocks","rejuv-paed-late-mortality","rejuv-tx-late-effects-overview","rejuv-mind-fear-of-recurrence","rejuv-life-return-to-work"],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":["rejuv-history-cure-is-not-enough","rejuv-history-seasons-of-survival","rejuv-history-survivorship-movement","rejuv-history-lost-in-transition","rejuv-history-ncsi-england","rejuv-history-counting-survivors","rejuv-second-screening-after-treatment-compared","rejuv-second-cancers-overview"],"trials":["challenge","ccss","rejuv-trial-proffi","rejuv-trial-ex-cipn","rejuv-trial-amico","rejuv-trial-allocare","rejuv-trial-canwork"],"people":["fitzhugh-mullan","ellen-stovall","kerry-courneya"],"bottlenecks":["b-survivorship","rejuv-agenda-screening-without-a-trial","rejuv-agenda-nothing-restores-cognition","rejuv-agenda-thymus-does-not-regrow","rejuv-agenda-biological-age-as-an-untested-target","rejuv-agenda-rehabilitation-not-commissioned","rejuv-agenda-nobody-owns-the-follow-up","rejuv-agenda-late-effects-are-not-counted","rejuv-agenda-no-agreed-outcome-measures","rejuv-agenda-latency-outruns-the-evidence"],"keyPapers":[],"journals":["journal-of-cancer-survivorship"],"dependsOn":[],"notes":[],"steps":[{"era":"1962-1975","title":"Cure arrives, and the bill with it","description":"Combination chemotherapy and radiotherapy made childhood leukaemia and several childhood solid tumours curable within about fifteen years, and the first cured children reached adulthood. Giulio D'Angio's 1975 paper in Cancer, \"Pediatric cancer in perspective: cure is not enough\", named the consequence: a field that measures five-year survival will not see a thirty-year-old with heart failure, a second cancer and no fertility, because none of those is in its denominator. The evidence for the next twenty years was single-hospital case series, enough to raise an alarm and not enough to quantify one.","refs":["rejuv-history-cure-is-not-enough","rejuv-paed-late-mortality","rejuv-paed-second-cancers"],"status":"historic"},{"era":"1985-1996","title":"Survivorship gets a name, a definition and an office","description":"Fitzhugh Mullan's three-page essay in the New England Journal of Medicine divided survival into acute, extended and permanent seasons and asked medicine to map the middle ground. Twenty-three people founded the National Coalition for Cancer Survivorship in Albuquerque in 1986 to replace the words \"cancer victim\" with \"cancer survivor\"; their definition, a survivor from diagnosis for the balance of life, is the National Cancer Institute's definition today. In 1996, after reading the coalition's Imperatives for Quality Cancer Care, the Institute's director established the Office of Cancer Survivorship, which is still the body that counts survivors and funds research into what happens to them.","refs":["rejuv-history-seasons-of-survival","rejuv-history-survivorship-movement","rejuv-mind-the-word-survivor","fitzhugh-mullan","ellen-stovall","rejuv-history-counting-survivors"],"status":"historic"},{"era":"1994-2013","title":"The cohorts that measured the cost","description":"The Childhood Cancer Survivor Study assembled 20,276 eligible five-year survivors from 25 institutions with treatment records abstracted for 98 per cent of participants, which is what lets a late effect be tied to a cumulative dose rather than to a diagnosis. Its 2006 analysis found 62.3 per cent of adult survivors with a chronic health condition and 27.5 per cent with a severe or life-threatening one. The St Jude Lifetime Cohort examined survivors clinically in 2013 and found more than questionnaires had shown. The British and European cohorts and the International Guideline Harmonization Group followed, and risk-based follow-up guidelines were written from the results. Treatment was then de-escalated on the strength of them, and late mortality after childhood cancer fell: the field's clearest success, and a success in prevention rather than repair.","refs":["ccss","sjlife","bccss","pancaresurfup","ighg","rejuv-paed-chronic-disease-burden","rejuv-paed-late-mortality","rejuv-paed-cog-ltfu-guidelines","rejuv-history-cure-is-not-enough"],"status":"historic"},{"era":"2006-2018","title":"The care plan, and the trials that deflated it","description":"The Institute of Medicine's \"Lost in Transition\" defined survivorship care as prevention, surveillance, intervention and coordination, made ten recommendations, and invented the survivorship care plan, which became an accreditation standard. Then it was tested. A randomised trial in breast cancer in 2011 found no difference; a 2018 systematic review of thirteen randomised and eleven non-randomised studies concluded that existing research provides little evidence that such plans improve health outcomes and health care delivery. England's National Cancer Survivorship Initiative ran from 2007, defined a Recovery Package, and measured that 24 per cent of people were offered a written assessment and care plan. The lesson the field took, and is still acting on, is that a document is not a service.","refs":["rejuv-history-lost-in-transition","rejuv-history-ncsi-england","survivorship-care-plan","rejuv-agenda-nobody-owns-the-follow-up","ellen-stovall"],"status":"historic"},{"era":"2017-2026","title":"Exercise becomes a treatment","description":"The American College of Sports Medicine roundtable stated a dose specific enough to prescribe: moderate aerobic exercise at least three times a week for at least thirty minutes over eight to twelve weeks, plus resistance training twice a week. A meta-analysis of 113 studies and 11,525 participants put exercise ahead of psychological therapy and far ahead of drugs for fatigue, with the pharmaceutical effect not reaching significance. Then CHALLENGE randomised 889 people after colon cancer chemotherapy and found longer disease-free and overall survival with a three-year coached programme. For the first time something done after treatment changed whether the cancer came back, and the honest cost was recorded too: more musculoskeletal adverse events in the exercise group.","refs":["challenge","exercise-prescription-after-cancer","exercise-oncology","structured-exercise-survivorship","cancer-related-fatigue-management","rejuv-frontier-what-works","kerry-courneya","rejuv-trial-amico"],"status":"current"},{"era":"2014-2026","title":"Biological ageing becomes measurable, and sellable","description":"Epigenetic clocks, p16INK4a, telomere length and physiological frailty each showed that cancer treatment ages people faster than time does, with the childhood cohorts supplying most of the numbers. None of those measures is a validated clinical test, none is used to make a treatment decision, and no trial has shown that moving one changes anything. In the same decade a market grew in the gap: stem cell infusions, exosomes, unlicensed peptides, intravenous NAD+, ozone and compounded hormone pellets, sold to people who have just finished treatment, several of them the subject of regulatory warnings. This front grades each of them rather than omitting them, because a reader who finds nothing here finds the seller's page instead.","refs":["rejuv-age-epigenetic-clocks","rejuv-age-senescent-cells-after-treatment","rejuv-age-telomere-length","rejuv-age-frailty-and-late-effects","rejuv-frontier-senolytics","rejuv-frontier-stem-cell-tourism","rejuv-frontier-exosome-injections","rejuv-frontier-nad-infusions","rejuv-agenda-biological-age-as-an-untested-target"],"status":"current"},{"era":"2026-2030","title":"Services that exist, and follow-up somebody owns","description":"The nearest available gains need no discovery. A rehabilitation prescription written at the end of treatment and funded like a drug; psychological therapy with a referral route rather than a leaflet; a treatment-exposure record a machine can read, so that a survivor or a general practitioner can be told what surveillance is due this year; accountability for the checks that do not happen. The trials being run now are of exactly these: a stepped-care late-effects service after allogeneic transplant, an occupational-therapy return-to-work programme with a cost-effectiveness analysis attached, a virtual exercise-based rehabilitation programme for persistent chemotherapy nerve damage. The constraint is commissioning rather than evidence.","refs":["rejuv-agenda-rehabilitation-not-commissioned","rejuv-agenda-nobody-owns-the-follow-up","idea-rejuv-rehabilitation-prescription-at-discharge","idea-rejuv-exposure-record-a-machine-can-read","rejuv-trial-allocare","rejuv-trial-canwork","rejuv-trial-ex-cipn","idea-acc-risk-stratified-follow-up","idea-acc-auto-generated-survivorship-plans"],"status":"emerging"},{"era":"2027-2033","title":"Endpoints the field does not yet have","description":"Several of the questions here cannot be answered until the measurements agree. Core outcome sets for the main late effects would let the next systematic review pool rather than narrate, and would end prevalence ranges like the 0 to 84 per cent reported for kidney impairment after childhood cancer. A function endpoint paired with a biological-age secondary would let a trial say whether the clock tracks the thing that matters; PROFFi, testing fisetin with and without exercise against frailty in breast cancer survivors, has that shape. Registry-based randomisation is the only plausible route to asking whether any survivorship screening programme saves lives. And a platform trial would let survivorship interventions share a control arm instead of each raising its own.","refs":["rejuv-agenda-no-agreed-outcome-measures","idea-rejuv-core-outcome-set-for-late-effects","idea-rejuv-biological-age-as-a-randomised-endpoint","idea-rejuv-registry-randomised-screening-in-survivors","idea-rejuv-survivorship-platform-trial","rejuv-trial-proffi","rejuv-agenda-screening-without-a-trial"],"status":"emerging"},{"era":"2033+","title":"Repair rather than surveillance","description":"Almost everything on this front today is prevention, substitution or surveillance. The things that would count as rejuvenation are restoring an immune repertoire rather than revaccinating around a narrowed one, regenerating a thymus in an adult, restoring processing speed rather than teaching strategies to work around its loss, reversing fibrosis that has set in a radiotherapy field, and growing the salivary and dental tissue that head and neck radiotherapy destroys. None has a human trial in cancer survivors. They are listed here as the honest contents of the word rejuvenation, and as the measure of how far the field is from it: everything currently sold under that word has less evidence than a supervised exercise programme.","refs":["rejuv-agenda-thymus-does-not-regrow","rejuv-agenda-nothing-restores-cognition","idea-rejuv-thymic-regeneration-in-adults","rejuv-frontier-mesenchymal-stromal-cells","rejuv-frontier-what-works","dry-mouth-teeth-after-head-neck-radiotherapy","radiation-skin-recovery"],"status":"speculative"},{"era":"What sets the pace","title":"No sponsor, no registry, no owner, no endpoint","description":"Four constraints bind, and none of them is biological. Nothing here is a product, so nothing here has a sponsor to fund its trial or lobby for its payment code. Registries count diagnoses and deaths and not what treatment left behind, so the scale that would justify a budget has never been produced. Follow-up belongs to an oncology service that discharges and a primary care service that was never sent the exposure history, so it belongs to nobody. And the field has not agreed what to measure, so studies cannot be pooled and trials fail for want of an endpoint. Every one of those is fixable with money and agreement rather than with a discovery, which is either the most encouraging or the most frustrating sentence on this roadmap.","refs":["rejuv-agenda-rehabilitation-not-commissioned","rejuv-agenda-late-effects-are-not-counted","rejuv-agenda-nobody-owns-the-follow-up","rejuv-agenda-no-agreed-outcome-measures","rejuv-agenda-latency-outruns-the-evidence","b-survivorship","b-funding-allocation","b-toxicity-qol"],"status":"current"}],"watch":[{"item":"PROFFi: fisetin with and without tailored exercise against frailty in breast cancer survivors, primary endpoint change in six-minute walk distance at day 120","expected":"Primary completion 31 October 2028 (estimated)","source":"https://clinicaltrials.gov/study/NCT06113016","refs":["rejuv-trial-proffi","rejuv-agenda-biological-age-as-an-untested-target"]},{"item":"EX-CIPN: a pragmatic randomised trial of virtual exercise-based rehabilitation for persistent chemotherapy-induced peripheral neuropathy","expected":"Primary completion July 2029 (estimated)","source":"https://clinicaltrials.gov/study/NCT07481149","refs":["rejuv-trial-ex-cipn","cipn-recovery-and-treatment"]},{"item":"AMICO: aerobic and resistance exercise against usual care for chemotherapy dose modification and progression-free survival in metastatic colorectal cancer","expected":"Primary completion March 2026 (estimated)","source":"https://clinicaltrials.gov/study/NCT04754672","refs":["rejuv-trial-amico","exercise-prescription-after-cancer"]},{"item":"AlloCare: a stepped-care late-effects service after allogeneic transplant against usual care, quality of life at twelve months","expected":"Primary completion 1 October 2027 (estimated)","source":"https://clinicaltrials.gov/study/NCT06281496","refs":["rejuv-trial-allocare","rejuv-agenda-nobody-owns-the-follow-up"]},{"item":"CanWork: a cluster-randomised trial of an occupational-therapy return-to-work intervention after breast cancer, with a cost-effectiveness analysis","expected":"Primary completion 30 September 2027 (estimated)","source":"https://clinicaltrials.gov/study/NCT06723899","refs":["rejuv-trial-canwork","rejuv-life-return-to-work"]}]},{"id":"survivorship-roadmap","kind":"roadmap","name":"Supportive care and survivorship roadmap: making treatment bearable → proving it extends life → caring for tens of millions afterwards","aka":[],"tldr":"Supportive care began as the drugs that let people get through chemotherapy. It is now a discipline with randomised proof that exercise, early palliative care and symptom monitoring lengthen life, and its next task is organised lifelong care for the growing population of people living after cancer.","summary":"Modern chemotherapy was made deliverable by supportive care: 5-HT3 antiemetics, growth factors that prevent febrile neutropenia, implanted ports and structured pain management. The second phase recognised what cure costs. The Childhood Cancer Survivor Study, running since 1994, catalogued heart damage, infertility, second cancers and cognitive effects decades after treatment, and cardio-oncology, oncofertility and survivorship care plans grew out of it.\n\nThe third phase, now under way, is evidence that supportive interventions change hard outcomes. Early integrated palliative care, electronic symptom monitoring and geriatric assessment have each improved survival or reduced toxicity in randomised trials, and in 2025 the CHALLENGE trial showed that a coached exercise programme after colon cancer treatment reduces recurrence and death. Cheap fixes with strong evidence (scalp cooling, low-dose olanzapine, sodium thiosulfate for cisplatin hearing loss) are spreading unevenly. Cachexia, which has never had an approved drug in most countries, has its first candidate in GDF-15 blockade.\n\nThe pace is set by funding and organisation rather than science: survivorship research has no industry sponsor, late effects are not systematically recorded, and follow-up is delivered by whoever has capacity rather than by risk.","asOf":"2026-09-10","links":[{"label":"CHALLENGE trial (NEJM 2025)","url":"https://www.nejm.org/doi/full/10.1056/NEJMoa2502760"},{"label":"Childhood Cancer Survivor Study","url":"https://ccss.stjude.org"},{"label":"COG Long-Term Follow-Up Guidelines","url":"http://www.survivorshipguidelines.org"}],"tags":[],"related":["idea-acc-risk-stratified-follow-up","idea-acc-auto-generated-survivorship-plans","idea-acc-national-late-effects-registry","idea-moon-adult-late-effects-registry","idea-acc-tailored-second-cancer-screening","idea-acc-risk-stratified-cardio-oncology-pathway","idea-moon-cardioprotection-by-default","idea-reg-financial-toxicity-vital-sign","idea-acc-return-to-work-rehabilitation","idea-acc-nurse-led-follow-up-clinics","idea-moon-fertility-preservation-default","idea-acc-lymphoedema-prospective-surveillance","idea-bio2-cachexia-function-endpoint","idea-moon-cachexia-as-treatable-disease","idea-acc-survivor-biobank-late-effect-prediction","idea-moon-open-pro-data-commons","idea-nl-exercise-dose-finding","idea-moon-neuropathy-prevention-programme","idea-moon-pro-ctcae-in-every-pivotal-trial","idea-moon-supportive-care-arpa","idea-fund-survivorship-endowment-levy","idea-fund-cachexia-programme","idea-acc-automatic-early-palliative-triggers","idea-acc-geriatric-assessment-by-default","idea-moon-survivor-lifelong-care-model","idea-moon-peer-navigator-workforce","nutrition-lifestyle-roadmap","prostate-roadmap","idea-prostate-other-cause-mortality-as-a-reported-service-outcome"],"cancers":[],"sections":["supportive-care","rejuvenation"],"technologies":["g-csf-growth-factors","infusion-devices-vascular-access","pain-management","hospice-end-of-life","palliative-care","remote-patient-monitoring","geriatric-assessment","cardio-oncology","fertility-preservation","survivorship-care-plan","exercise-oncology","structured-exercise-survivorship","prehabilitation","psycho-oncology","scalp-cooling","integrative-oncology","cbt-insomnia-cancer","lymphoedema-decongestive-therapy","cachexia-therapy","cachexia-appetite-pharmacotherapy","resistance-training-cachexia","oncology-nutrition","cancer-associated-thrombosis","minoxidil-chemotherapy-alopecia"],"targets":[],"drugs":["sodium-thiosulfate","dexrazoxane"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["ccss","challenge","prehab-trial","olanzapine-appetite-tmh","ponsegromab-phase-2","romana-1-2"],"people":[],"bottlenecks":["b-survivorship","b-cachexia-supportive","b-toxicity-qol","b-aging-comorbidity","b-palliative","b-funding-allocation"],"keyPapers":[],"journals":["journal-of-cancer-survivorship"],"dependsOn":[],"notes":[],"steps":[{"era":"1970s-1990s","title":"Making chemotherapy deliverable","description":"Curative regimens depended on drugs and devices that never made a headline: 5-HT3 antiemetics replaced days of vomiting, G-CSF let full doses be given on schedule by preventing febrile neutropenia, implanted ports and ambulatory pumps moved infusions out of hospital, and the WHO analgesic ladder made cancer pain a treatable problem. Hospice and palliative medicine became specialties in the same years.","refs":["g-csf-growth-factors","infusion-devices-vascular-access","pain-management","hospice-end-of-life","cancer-associated-thrombosis"],"status":"historic"},{"era":"1994-2016","title":"Counting the cost of cure","description":"The Childhood Cancer Survivor Study, following tens of thousands of people cured as children, showed that anthracyclines, chest radiation and alkylators leave heart failure, second cancers and infertility decades later, and produced the first risk-based follow-up guidelines. Cardio-oncology, oncofertility and survivorship care plans grew from this evidence; dexrazoxane was shown to protect the heart from anthracyclines.","refs":["ccss","survivorship-care-plan","cardio-oncology","dexrazoxane","fertility-preservation","idea-moon-fertility-preservation-default"],"status":"historic"},{"era":"2010-2026","title":"Supportive care that lengthens life","description":"Randomised trials moved supportive care from kindness to treatment. Early integrated palliative care improved quality of life and, in some trials, survival; weekly electronic symptom reporting with nurse response reduced emergency visits and extended survival; geriatric assessment before chemotherapy cut severe toxicity in older patients. In 2025 CHALLENGE showed that a three-year coached exercise programme after colon cancer treatment reduces recurrence and improves survival, and PREHAB showed that four weeks of training before colorectal surgery cuts complications.","refs":["palliative-care","remote-patient-monitoring","geriatric-assessment","challenge","exercise-oncology","structured-exercise-survivorship","prehabilitation","prehab-trial","psycho-oncology","idea-acc-geriatric-assessment-by-default","idea-acc-automatic-early-palliative-triggers"],"status":"current"},{"era":"2015-2026","title":"Cheap fixes with strong evidence","description":"Scalp cooling preserves hair through chemotherapy, sodium thiosulfate halves permanent hearing loss from cisplatin in children, a 2.5 mg dose of olanzapine restores appetite and weight for pennies (Tata Memorial), acupuncture eases hot flushes and aromatase inhibitor joint pain, cognitive behavioural therapy treats the insomnia that persists for years, and compression and exercise reverse early lymphoedema. Each is proven; none is universally offered.","refs":["scalp-cooling","sodium-thiosulfate","olanzapine-appetite-tmh","integrative-oncology","cbt-insomnia-cancer","lymphoedema-decongestive-therapy","minoxidil-chemotherapy-alopecia","idea-acc-lymphoedema-prospective-surveillance"],"status":"current"},{"era":"2026-2029","title":"Cachexia gets a drug","description":"Wasting kills many patients with advanced cancer and stops many more from tolerating treatment, and no drug has been approved for it in most of the world. Ponsegromab, an antibody that blocks GDF-15, the hormone that drives much of the wasting, improved weight and activity in phase 2; anamorelin is licensed only in Japan; resistance training and protein remain the only widely available intervention. A physical-function endpoint that regulators accept is the gating step for approval.","refs":["cachexia-therapy","ponsegromab-phase-2","cachexia-appetite-pharmacotherapy","romana-1-2","resistance-training-cachexia","oncology-nutrition","idea-bio2-cachexia-function-endpoint","idea-moon-cachexia-as-treatable-disease","idea-fund-cachexia-programme"],"status":"emerging"},{"era":"2026-2030","title":"Survivorship as a system, not a leaflet","description":"Tens of millions of people live after cancer, and follow-up is still organised by habit. The system being built: risk-stratified follow-up with low-risk survivors in primary care and fast re-entry, survivorship plans generated automatically from the treatment record, late-effects registries that link exposures to outcomes decades later, biomarker-guided cardioprotection for everyone on cardiotoxic therapy, screening for financial toxicity as a vital sign, and vocational rehabilitation so people can return to work.","refs":["idea-acc-risk-stratified-follow-up","idea-acc-nurse-led-follow-up-clinics","idea-acc-auto-generated-survivorship-plans","idea-acc-national-late-effects-registry","idea-moon-adult-late-effects-registry","idea-acc-risk-stratified-cardio-oncology-pathway","idea-moon-cardioprotection-by-default","idea-acc-tailored-second-cancer-screening","idea-reg-financial-toxicity-vital-sign","idea-acc-return-to-work-rehabilitation","idea-moon-survivor-lifelong-care-model","idea-moon-peer-navigator-workforce"],"status":"emerging"},{"era":"2030+","title":"Predicting late effects before they happen","description":"A survivor biobank could show who will develop heart failure or a second cancer before they do; an open commons of patient-reported outcome data from trials would let side-effects be compared across drugs the way efficacy is; exercise could be dosed like a drug once dose-finding trials exist; and chemotherapy-induced neuropathy, still without a proven prevention, has candidates in SARM1 inhibitors and limb cooling. An ARPA-style programme for supportive-care drugs that no company will develop is the funding proposal that would make most of this happen.","refs":["idea-acc-survivor-biobank-late-effect-prediction","idea-moon-open-pro-data-commons","idea-nl-exercise-dose-finding","idea-moon-neuropathy-prevention-programme","idea-moon-pro-ctcae-in-every-pivotal-trial","idea-moon-supportive-care-arpa"],"status":"speculative"},{"era":"What sets the pace","title":"No sponsor, no registry, no organiser","description":"Supportive care has no patent to protect, so its trials are publicly funded or not run. Late effects are not systematically recorded, so their scale is estimated rather than known. Toxicity and quality of life are measured less rigorously than survival in registrational trials. And most people who die of cancer worldwide do so without adequate pain relief. A survivorship research endowment funded by a levy on curative therapies is one proposal to fix the first problem.","refs":["b-survivorship","b-cachexia-supportive","b-toxicity-qol","b-aging-comorbidity","b-palliative","b-funding-allocation","idea-fund-survivorship-endowment-levy"],"status":"current"}],"watch":[]},{"id":"surgery-roadmap","kind":"roadmap","name":"Surgery roadmap: radical operations → less surgery → no surgery when a drug has done the work","aka":[],"tldr":"Surgery cures more cancers than any other treatment. Its story for a century has been learning how much can safely be left in, and now whether the operation is needed at all once drugs and radiation have cleared the tumour.","summary":"The radical era removed as much as possible; the trial era showed, one operation at a time, that less was as good: breast conservation instead of mastectomy, sentinel node biopsy instead of clearing every node, and no completion lymphadenectomy after a positive sentinel node (MSLT-II). Minimally invasive and robotic approaches shrank incisions and recovery time, with LACC as the caution that keyhole surgery must be tested rather than assumed.\n\nThe present shift is that systemic therapy now arrives before the surgeon. Immunotherapy or targeted therapy given before the operation improves survival in lung, melanoma, bladder, stomach and triple-negative breast cancer, and in mismatch-repair-deficient bowel cancer it can remove the need for surgery altogether (NICHE-2, AZUR-1). Interventional oncology treats liver, kidney and pancreatic tumours through a needle or a catheter, and margins are becoming visible in the operating theatre through fluorescent dyes and rapid intraoperative sequencing.\n\nWhat decides the pace is not technique but evidence and capacity: surgical trials attract a fraction of drug-trial funding, prehabilitation and geriatric co-management are proven but unevenly delivered, and most of the world lacks safe, timely cancer surgery at all.","asOf":"2026-09-10","links":[{"label":"MSLT-II (NEJM 2017)","url":"https://www.nejm.org/doi/full/10.1056/NEJMoa1613210"},{"label":"NICHE-2 (NEJM 2024)","url":"https://www.nejm.org/doi/full/10.1056/NEJMoa2400634"},{"label":"Lancet Oncology Commission on global cancer surgery","url":"https://www.thelancet.com/commissions/global-cancer-surgery"}],"tags":[],"related":["idea-bio2-prehabilitation-standard","idea-acc-geriatric-co-management-surgery","idea-acc-prehabilitation-older-surgery","idea-tr1-window-of-opportunity-default","idea-tr2-neoadjuvant-combo-platform","idea-prev-opportunistic-salpingectomy-default","idea-prev-small-renal-mass-surveillance","idea-bio2-neoadjuvant-biomarker-engine","oxford-nanopore","histosonics","cure-paths","devices-roadmap","prostate-roadmap"],"cancers":[],"sections":["surgery"],"technologies":["robotic-surgery","sentinel-node","fluorescence-guided-surgery","optical-imaging","thermal-ablation","irreversible-electroporation","hifu-histotripsy","tace","radioembolisation-tare","hipec","endoscopic-resection","tors","robotic-bronchoscopy","liver-transplant-oncology","partial-nephrectomy-active-surveillance","prehabilitation","eras-perioperative-nutrition","mrd-testing","limb-salvage-surgery","intraoperative-radiotherapy"],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["mslt-ii","lacc","fires-sentor","senticol-iii","checkmate-816","keynote-671","nadina","swog-s1801","matterhorn","niagara","keynote-522","destiny-breast11","niche-2","azur-1","sano","mars-2","estimabl2","ovhipec-1","emerald-1","prehab-trial","elective-neck-dissection-tmh","preopanc"],"people":[],"bottlenecks":["b-surgery-radiation-innovation","b-workforce","b-global-access","b-aging-comorbidity"],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"steps":[{"era":"1890s-1990s","title":"From radical to conservative, one trial at a time","description":"Halsted's radical mastectomy set the template that more tissue meant more cure. Randomised trials dismantled it: breast conservation with radiation matched mastectomy, and sentinel lymph node biopsy replaced clearing every node in breast cancer and melanoma. The lesson that survives is that the extent of surgery must be tested, not inferred from anatomy.","refs":["sentinel-node","mslt-ii","fires-sentor","limb-salvage-surgery"],"status":"historic"},{"era":"2000s-2018","title":"Smaller incisions, robots and a warning","description":"Laparoscopic and robotic surgery cut blood loss and recovery time across prostate, kidney, colon and gynaecological cancers, and transoral robotic surgery let throat tumours be removed without splitting the jaw. LACC (2018) showed that keyhole surgery for cervical cancer had more recurrences than open surgery, a reminder that a smaller scar is not automatically the same operation. Endoscopic resection now removes the earliest oesophageal and stomach cancers from the inside.","refs":["robotic-surgery","tors","endoscopic-resection","lacc","robotic-bronchoscopy","elective-neck-dissection-tmh"],"status":"historic"},{"era":"2018-2026","title":"The drug arrives before the surgeon","description":"Giving immunotherapy or targeted therapy before the operation, when the immune system can still see the whole tumour, improved event-free and overall survival in lung cancer (CheckMate 816, KEYNOTE-671), melanoma (SWOG S1801, NADINA), bladder cancer (NIAGARA), stomach cancer (MATTERHORN) and triple-negative breast cancer (KEYNOTE-522). The pathological response at surgery now tells the team how much treatment is needed afterwards, and pre-surgery windows have become the fastest way to test new combinations.","refs":["checkmate-816","keynote-671","swog-s1801","nadina","niagara","matterhorn","keynote-522","destiny-breast11","preopanc","idea-bio2-neoadjuvant-biomarker-engine","idea-tr1-window-of-opportunity-default"],"status":"current"},{"era":"2022-2028","title":"Organ preservation and no surgery at all","description":"In mismatch-repair-deficient bowel cancer, a few weeks of immunotherapy clears most tumours completely (NICHE-2), and AZUR-1 is the registrational test of skipping surgery, radiation and chemotherapy entirely. SANO showed that watching closely after chemoradiation for oesophageal cancer, operating only if the tumour returns, is safe for the third of patients whose tumour has vanished. ESTIMABL2 let most low-risk thyroid cancers skip radioactive iodine; small kidney tumours and papillary microcarcinomas are increasingly watched rather than removed. MARS 2 showed that a major mesothelioma operation did not help, and practice changed.","refs":["niche-2","azur-1","sano","estimabl2","mars-2","partial-nephrectomy-active-surveillance","active-surveillance-thyroid","idea-prev-small-renal-mass-surveillance"],"status":"current"},{"era":"2010s-2026","title":"Treating through a needle or a catheter","description":"Interventional oncology destroys tumours with heat, cold, electric pulses or focused sound, and delivers chemotherapy or radioactive beads through the artery that feeds a liver tumour. EMERALD-1 added immunotherapy to chemoembolisation; OVHIPEC-1 showed that washing the abdomen with heated chemotherapy during ovarian surgery extends survival; liver transplantation cures selected liver cancers and the disease underneath them. Histotripsy, which destroys tissue mechanically with sound, gained approval in the liver and is now being tested as an immune primer.","refs":["thermal-ablation","irreversible-electroporation","hifu-histotripsy","tace","radioembolisation-tare","emerald-1","hipec","ovhipec-1","liver-transplant-oncology","histosonics"],"status":"current"},{"era":"2026-2030","title":"Seeing the margin and preparing the patient","description":"Fluorescent dyes that light up tumour and nerves, and portable sequencers that classify a brain tumour's methylation during the operation, aim to make the margin visible rather than guessed. After surgery, ctDNA testing says whether anything was left. Before it, four weeks of exercise, nutrition and psychological preparation (PREHAB) cut complications, and geriatric co-management does the same for older patients; both are proven and both are rarely funded. Sentinel node mapping is extending to cervical (SENTICOL III) and endometrial cancer to spare women lymphoedema.","refs":["fluorescence-guided-surgery","optical-imaging","oxford-nanopore","mrd-testing","prehabilitation","prehab-trial","eras-perioperative-nutrition","idea-bio2-prehabilitation-standard","idea-acc-geriatric-co-management-surgery","idea-acc-prehabilitation-older-surgery","senticol-iii","intraoperative-radiotherapy"],"status":"emerging"},{"era":"What sets the pace","title":"Funding, workforce and access","description":"Surgery and radiotherapy cure more people than drugs but attract a small share of trial funding, so questions like how much to remove, when to operate and whether to operate at all wait years for an answer. Most of the world lacks timely, safe cancer surgery, and the surgeons and anaesthetists to provide it. Standing pre-surgery platform trials, default prehabilitation, and opportunistic salpingectomy during any pelvic operation are among the answers already on the table.","refs":["b-surgery-radiation-innovation","b-workforce","b-global-access","b-aging-comorbidity","idea-tr2-neoadjuvant-combo-platform","idea-prev-opportunistic-salpingectomy-default"],"status":"current"}],"watch":[]},{"id":"targeted-therapy-roadmap","kind":"roadmap","name":"Targeted therapy roadmap: imatinib → designed for resistance → the undruggable drivers fall","aka":[],"tldr":"Targeted drugs switch off the specific broken protein a cancer depends on. The first ones turned a leukaemia into a chronic condition; the field then learned that resistance is the rule, designed drugs around it, and has now reached the drivers that were called impossible to target.","summary":"Tamoxifen (1977) and trastuzumab (1998) were targeted therapies before the term existed, but imatinib (2001) defined the category: a pill against the one enzyme a cancer cannot live without, matched to the patients whose tumours carry it. EGFR, ALK and BRAF followed within a decade, and with them the lesson that shaped everything since: nearly every targeted drug stops working within months to years, and the mechanism of escape can be read from the tumour and drugged in turn.\n\nThe second generation was designed for resistance and the brain: osimertinib, alectinib and lorlatinib, then their use after surgery (ADAURA, ALINA) and after chemoradiation (LAURA). PARP inhibitors made an inherited DNA-repair defect a treatable target; tissue-agnostic approvals made the mutation, not the organ, the indication. The third generation is reaching targets that were called undruggable: KRAS G12C (sotorasib 2021), then G12D and pan-RAS(ON) inhibitors, HIF-2 in kidney cancer, menin in leukaemia, and protein degraders (vepdegestrant, the first approved PROTAC, 2026) that remove a protein rather than block it.\n\nThe pace is set by resistance biology, by the combinatorial space of pairings that trials cannot search, by prices that compound over years of therapy, and by biomarkers that must be validated before a drug can be matched to a patient.","asOf":"2026-09-10","links":[{"label":"Druker et al., imatinib in CML (NEJM 2001)","url":"https://www.nejm.org/doi/full/10.1056/NEJM200104053441401"}],"tags":[],"related":["kras-roadmap","hormonal-therapy-roadmap","epigenetics-roadmap","idea-bio1-ctdna-adaptive-tki","idea-tr2-resistance-mechanism-baskets","idea-bio1-resistance-platform-trial","idea-bio1-evolution-forecasting","idea-bio1-adaptive-therapy-platform","idea-tr1-adaptive-therapy-randomised-phase-2","idea-bio1-resistance-mutation-vaccine","eprenetapopt","myc","mrtx1133","lung-cancer-evidence-roadmap","prostate-roadmap","idea-prostate-hrr-testing-at-metastatic-diagnosis"],"cancers":[],"sections":["targeted-therapy"],"technologies":["kinase-inhibitors","parp-inhibitor","kras-inhibitors","protac-degrader","molecular-glue-platforms","degrader-antibody-conjugate","synthetic-lethality-approaches","antisense-sirna","de-novo-protein-design","companion-diagnostic","liquid-biopsy","cgp"],"targets":["egfr","alk","kras","her2","braf","ret","ntrk","ros1","prmt5-mtap","btk","flt3","brca"],"drugs":["imatinib","trastuzumab","gefitinib","erlotinib","osimertinib","amivantamab","lazertinib","crizotinib","alectinib","lorlatinib","neladalkib","dabrafenib-trametinib","olaparib","larotrectinib","entrectinib","selpercatinib","sotorasib","adagrasib","divarasib","daraxonrasib","zoldonrasib","elironrasib","olomorasib","vepdegestrant","pirtobrutinib","cabozantinib","pemigatinib","eli-002-7p"],"companies":["nuvalent","frontier-medicines","black-diamond-therapeutics"],"institutions":["ohsu-knight"],"pathways":[],"terms":["tumour-agnostic","resistance"],"trials":["hera-b31-n9831","toga","flaura2","mariposa","adaura","alina","laura","alkove-1","combi-ad","dreamseq","solo-1","olympia","profound","libretto-431","codebreak-200","krystal-12","krascendo-1","codebreak-300","rasolute-302","litespark-005","veritac-2","cadance-304","bruin-cll-321","serena-6","insight-gist","telimet-nsclc-01","gefitinib-chemo-tmh"],"people":[],"bottlenecks":["b-resistance","b-undruggable-targets","b-tumor-heterogeneity","b-combination-space","b-drug-pricing","b-biomarker-validation"],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"steps":[{"era":"1977-2001","title":"The idea of a target","description":"Tamoxifen blocked the oestrogen receptor and trastuzumab (1998) the HER2 protein, each with a test to find the patients whose tumours depended on them. Imatinib (2001) proved the concept in its purest form: a pill against BCR-ABL, the one enzyme chronic myeloid leukaemia cannot live without, that turned a fatal disease into a chronic one and made Brian Druker's Oregon clinic the birthplace of precision oncology.","refs":["tamoxifen","trastuzumab","hera-b31-n9831","toga","imatinib","kinase-inhibitors","ohsu-knight","companion-diagnostic"],"status":"historic"},{"era":"2004-2013","title":"Oncogene addiction, and the resistance lesson","description":"EGFR mutations (2004) explained why gefitinib and erlotinib worked spectacularly in a minority of lung cancers; crizotinib for ALK (2011) and vemurafenib for BRAF (2011) followed within months of the target being found. Then nearly every responder relapsed: T790M in EGFR, gatekeeper mutations in ALK, MAPK reactivation in BRAF. Resistance became the central problem of the field, and reading it from a biopsy became the route to the next drug.","refs":["gefitinib","erlotinib","egfr","crizotinib","alk","braf","dabrafenib-trametinib","resistance","b-resistance","gefitinib-chemo-tmh"],"status":"historic"},{"era":"2014-2020","title":"Designed for resistance, the brain and the adjuvant setting","description":"Osimertinib was built to hit T790M and cross into the brain; alectinib and lorlatinib did the same for ALK. Given after surgery, the pills halved the risk of death in EGFR-mutant lung cancer (ADAURA) and sharply cut recurrence in ALK-positive disease (ALINA); LAURA extended them to after chemoradiation. Olaparib (2014) made an inherited BRCA defect a target in ovarian, breast and prostate cancer (SOLO-1, OlympiA, PROfound). Larotrectinib's approval for any NTRK-fusion tumour (2018) made the mutation, not the organ, the indication; RET (LIBRETTO-431) and ROS1 followed. COMBI-AD proved a year of BRAF-MEK pills after melanoma surgery halves relapse; DREAMseq settled that immunotherapy should come first.","refs":["osimertinib","alectinib","lorlatinib","adaura","alina","laura","parp-inhibitor","olaparib","solo-1","olympia","profound","brca","larotrectinib","entrectinib","selpercatinib","libretto-431","tumour-agnostic","ntrk","ret","ros1","combi-ad","dreamseq"],"status":"current"},{"era":"2021-2026","title":"The undruggable drivers fall","description":"KRAS, mutated in a quarter of cancers and called undruggable for forty years, yielded to sotorasib (2021) and adagrasib, which lock the G12C mutant in its off state; CodeBreaK 200 and KRYSTAL-12 showed they beat chemotherapy, and divarasib beat both head to head (Krascendo 1). The G12D mutation, the commonest in pancreatic cancer, has its first drug in zoldonrasib, and daraxonrasib inhibits every RAS in its active state (RASolute 302). Elsewhere belzutifan drugged HIF-2, menin inhibitors reached leukaemia, and vepdegestrant (2026) became the first approved PROTAC, removing its target rather than blocking it. MARIPOSA and FLAURA2 showed that combinations beat osimertinib alone.","refs":["kras-inhibitors","kras","sotorasib","adagrasib","codebreak-200","krystal-12","divarasib","krascendo-1","codebreak-300","zoldonrasib","mrtx1133","daraxonrasib","rasolute-302","elironrasib","olomorasib","kras-roadmap","litespark-005","protac-degrader","vepdegestrant","veritac-2","mariposa","amivantamab","lazertinib","flaura2"],"status":"current"},{"era":"2026-2030","title":"Fourth generations, degraders and switching on a blood test","description":"Neladalkib is designed to work after lorlatinib (ALKOVE-1); pirtobrutinib works after other BTK inhibitors and a BTK degrader is in phase 3 (CaDAnCe-304); the first MET-directed ADC is in its confirmatory trial. SERENA-6 changed endocrine therapy on a blood test before the scan changed, and INSIGHT is matching GIST drugs to the resistance mutation found in blood. The next trial designs assign treatment by how the tumour escaped rather than where it started.","refs":["neladalkib","alkove-1","nuvalent","pirtobrutinib","bruin-cll-321","cadance-304","btk","telimet-nsclc-01","serena-6","insight-gist","liquid-biopsy","idea-bio1-ctdna-adaptive-tki","idea-tr2-resistance-mechanism-baskets","idea-bio1-resistance-platform-trial"],"status":"emerging"},{"era":"2026-2032","title":"New modalities for the old targets","description":"Molecular glues and degraders reach proteins without a druggable pocket; degrader-antibody conjugates deliver them into the tumour; antisense and siRNA silence the gene rather than the protein; designed proteins grip surfaces no small molecule can. Synthetic lethality finds a second gene a cancer needs only because its first is broken: PRMT5 inhibitors for MTAP-deleted tumours and WRN inhibitors for mismatch-repair-deficient ones are the leading examples. Chemoproteomics is finding covalent handles on KRAS and beyond.","refs":["molecular-glue-platforms","degrader-antibody-conjugate","antisense-sirna","de-novo-protein-design","synthetic-lethality-approaches","prmt5-mtap","frontier-medicines","black-diamond-therapeutics"],"status":"emerging"},{"era":"2030+","title":"Forecasting resistance instead of waiting for it","description":"If the next resistance mutation can be predicted, as flu strains are, it could be blocked or vaccinated against before it takes over; adaptive dosing that keeps the sensitive clone dominant is in randomised phase 2. MYC and mutant p53, the drivers still without a drug, are the open frontier, and eprenetapopt's failure to refold p53 shows how hard it is. A ready-made KRAS vaccine after pancreatic surgery missed its primary goal, but the idea of vaccinating against a driver mutation remains live.","refs":["idea-bio1-evolution-forecasting","idea-bio1-resistance-mutation-vaccine","idea-bio1-adaptive-therapy-platform","idea-tr1-adaptive-therapy-randomised-phase-2","myc","eprenetapopt","b-undruggable-targets","eli-002-7p"],"status":"speculative"},{"era":"What sets the pace","title":"Resistance, combinations, biomarkers and price","description":"Every targeted drug meets resistance; a tumour is many tumours, so the resistant clone is usually already there. There are thousands of possible combinations and sequences and trials can test a few dozen a year. A drug cannot be matched without a validated test, and tests lag drugs. And targeted therapy is priced per month for years, so the cost of a cure-like outcome compounds; the biosimilar and generic wave for the first generation is only now arriving.","refs":["b-resistance","b-tumor-heterogeneity","b-combination-space","b-biomarker-validation","b-drug-pricing","b-undruggable-targets"],"status":"current"}],"watch":[]},{"id":"tnbc-history","kind":"roadmap","name":"TNBC roadmap: from 'nothing to target' to ADC + immunotherapy first line","aka":[],"tldr":"How triple-negative breast cancer went from the subtype with no targeted therapy to one with immunotherapy, PARP inhibitors, three ADCs, and a positive bispecific ADC in six years.","summary":"The TNBC roadmap begins in the chemotherapy-only years, when the basal-like subtype was defined, anthracycline-taxane regimens with carboplatin were all that existed and EGFR, VEGF and PARP inhibitor trials failed. Immunotherapy and PARP inhibitors arrived with IMpassion130, OlympiAD, EMBRACA, KEYNOTE-355 and ASCENT, then KEYNOTE-522 and OlympiA transformed the curative setting and DESTINY-Breast04 opened T-DXd to HER2-low disease. Now ADCs move to first line through ASCENT-03, ASCENT-04 and TROPION-Breast02, with OptimICE-pCR, SCARLET, ctDNA-guided escalation and post-neoadjuvant ADCs as the emerging steps. The turning point was recognising that TNBC could be targeted without an oncogenic driver; the route links the TNBC record and the ADC and immunotherapy sections.","asOf":"2026-09-04","links":[{"label":"KEYNOTE-522: adding pembrolizumab before and after surgery in early triple-negative breast cancer (New England Journal of Medicine 2022)","url":"https://doi.org/10.1056/NEJMoa2112651"},{"label":"ASCENT: sacituzumab govitecan doubles survival in heavily pretreated metastatic triple-negative breast cancer (New England Journal of Medicine 2021)","url":"https://doi.org/10.1056/NEJMoa2028485"}],"tags":[],"related":["tnbc-roadmap"],"cancers":["tnbc"],"sections":["adcs","immunotherapy"],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"steps":[{"era":"2000-2015","title":"Chemotherapy only","description":"Basal-like subtype defined (2000); TNBC named by exclusion (2007). Anthracycline-taxane chemotherapy; carboplatin added (2014). Median metastatic OS was about 13-18 months, and EGFR, VEGF, and PARP inhibitor (iniparib) trials failed repeatedly.","refs":["carboplatin","platinum"],"status":"historic"},{"era":"2018-2020","title":"Immunotherapy and PARP arrive","description":"The pivotal trials are IMpassion130 (atezolizumab, later withdrawn), OlympiAD/EMBRACA (PARP inhibitors in gBRCA), KEYNOTE-355 (pembrolizumab CPS ≥10 first line), ASCENT (sacituzumab govitecan).","refs":["impassion130","olaparib","talazoparib","keynote-355","ascent"],"status":"historic"},{"era":"2021-2022","title":"Curative setting transformed","description":"KEYNOTE-522 makes chemo-immunotherapy the standard for stage II-III; OlympiA adds adjuvant olaparib for gBRCA. DESTINY-Breast04 makes HER2-low TNBC eligible for T-DXd.","refs":["keynote-522","olympia","destiny-breast04"],"status":"historic"},{"era":"2024-2026","title":"ADCs move to first line; bispecific ADC succeeds","description":"KEYNOTE-522 OS benefit confirmed. ASCENT-03/04 and TROPION-Breast02 read out positive, bringing first-line approvals for sacituzumab govitecan and Dato-DXd (2026). Iza-bren posts a positive phase 3 (2026). TIL-based de-escalation in stage I gains evidence.","refs":["ascent-03","ascent-04","tropion-breast02","bl-b01d1-307","tils"],"status":"current"},{"era":"2026-2029","title":"Next: residual disease, de-escalation, selection","description":"OptimICE-pCR (omit adjuvant pembrolizumab after pCR), SCARLET (drop anthracycline), ctDNA-guided escalation for RCB II-III, ADCs in the post-neoadjuvant setting, sac-TMT and TROPION-Breast05 first-line readouts, IZABRIGHT-Breast01, TROP2 PET.","refs":["optimice-pcr","scarlet-s2212","tropion-breast05","izabright-breast01","sacituzumab-tirumotecan","trop2-pet","mrd-testing"],"status":"emerging"},{"era":"2029+","title":"Speculative: cure for most, control for the rest","description":"Neoadjuvant ADC + IO replacing anthracyclines; personalised vaccines in the adjuvant setting for high-risk residual disease; payload-switching ADC algorithms guided by PET and ctDNA; mesenchymal-subtype-specific therapy; brain-penetrant ADCs.","refs":["neoantigen-mrna-vaccine","dual-payload-adc","emt","idea-post-neoadjuvant-adc"],"status":"speculative"}],"watch":[]},{"id":"trial-modernisation-roadmap","kind":"roadmap","name":"Trial modernisation roadmap: the randomised trial → platforms and adaptive designs → decentralised, pragmatic and always-on","aka":[],"tldr":"The randomised trial is how oncology knows what works, and it is slow, expensive and enrols fewer than one in ten patients. The roadmap is the set of designs and tools that keep the rigour while cutting the time, cost and exclusions: platform trials that never close, blood-test endpoints, remote consent, real-world data used honestly, and doses chosen by evidence.","summary":"The randomised controlled trial, introduced to medicine in 1948, and the cooperative groups that ran thousands of them, are why most of what oncology does is evidence-based. But a phase 3 trial takes years and hundreds of millions of dollars, often answers a question the field has moved past, excludes the older and sicker patients who make up most of the disease, and is joined by fewer than one in ten adults with cancer.\n\nThe first generation of fixes changed the design: STAMPEDE, the longest-running platform trial, showed that arms can be added and dropped under one protocol; basket and umbrella trials (Pediatric MATCH) assigned drugs by mutation; tissue-agnostic approvals followed. The second changed operations: remote consent and telehealth visits, electronic symptom monitoring, broadened eligibility, diversity plans, and real-world data with a regulatory framework. The third is changing what trials measure and how doses are chosen: ctDNA residual disease as an endpoint that reads out in months (DYNAMIC, CIRCULATE-Japan, SERENA-6, IMvigor011), pre-surgery windows as the biomarker engine, and the FDA's Project Optimus (final guidance August 2024) requiring randomised dose comparison instead of the maximum tolerated dose.\n\nAhead are AI in trial operations, standing platform infrastructure per cancer, registry-embedded randomisation, and endpoints that weigh how people live alongside how long. The pace is set by enrolment, cost, exclusion, weak real-world data and the incentives that keep failures hidden.","asOf":"2026-09-10","links":[{"label":"FDA final guidance: Optimizing the Dosage of Human Prescription Drugs and Biological Products for the Treatment of Oncologic Diseases (August 2024)","url":"https://www.fda.gov/regulatory-information/search-fda-guidance-documents/optimizing-dosage-human-prescription-drugs-and-biological-products-treatment-oncologic-diseases"},{"label":"STAMPEDE platform trial","url":"https://www.stampedetrial.org/"},{"label":"FDA guidance: decentralized clinical trials (September 2024)","url":"https://www.fda.gov/regulatory-information/search-fda-guidance-documents/conducting-clinical-trials-decentralized-elements"}],"tags":[],"related":["clinicaltrials-gov","flatiron-foundation-cgdb","idea-tr1-standing-platform-per-cancer","idea-tr2-perpetual-platforms","idea-tr2-platform-single-ethics","idea-reg-recovery-style-platform-repurposing","idea-bio2-national-mrd-platform","idea-bio1-resistance-platform-trial","idea-tr2-bandit-allocation","idea-bio2-rare-cancer-umbrella-platform","idea-tr2-neoadjuvant-combo-platform","idea-tr1-justify-every-exclusion","idea-tr1-remote-consent-tele-screening","idea-tr1-ehr-point-of-care-trial-alert","idea-tr1-registry-embedded-randomisation","idea-tr1-external-control-rulebook","idea-tr1-post-approval-pragmatic-trial-in-excluded","idea-tr1-mandatory-older-adult-cohort","idea-tr1-diversity-plans-with-consequences","idea-tr1-eligibility-impact-statement","idea-tr1-ai-central-imaging-reads","idea-tr1-target-trial-emulation-to-prioritise-rcts","idea-tr1-validate-real-world-progression-endpoints","idea-tr2-ctdna-mrd-qualification","idea-bio2-neoadjuvant-biomarker-engine","idea-tr1-window-of-opportunity-default","idea-reg-generic-targeted-therapy-drup","idea-reg-global-dose-optimisation-guideline","idea-tr1-randomised-dose-comparison-before-pivotal","idea-moon-pro-ctcae-in-every-pivotal-trial","idea-tr1-win-ratio-net-benefit-endpoint","idea-tr1-tolerability-estimands","idea-tr1-surrogate-validation-programme","idea-reg-conditional-approval-sunset","idea-reg-confirmatory-trial-escrow","idea-tr1-lmic-sites-in-pivotal-trials","idea-tr1-pay-participants-for-time","idea-tr1-protected-physician-time-for-enrolment","idea-tr2-material-failure-disclosure","idea-tr2-reversal-registry","idea-reg-orbis-work-sharing","global-access-roadmap","diagnostics-roadmap","prostate-roadmap","idea-prostate-randomise-the-sequence-not-only-the-drugs"],"cancers":[],"sections":[],"technologies":["remote-patient-monitoring","telemedicine-teleoncology","ai-trial-matching","digital-twins-trials","mrd-testing","liquid-biopsy","imaging-core-labs","companion-diagnostic","functional-drug-testing"],"targets":[],"drugs":[],"companies":["swog","ecog-acrin","alliance-oncology","nrg-oncology","cctg","childrens-oncology-group","science-37","medidata","trinetx","flatiron-health","tempus","trial-library","massive-bio"],"institutions":["nci","fda-oce","ema","tata-memorial"],"pathways":[],"terms":["real-world-evidence","accelerated-approval","tumour-agnostic","project-orbis","surrogate-endpoint"],"trials":["stampede","pediatric-match","dynamic","circulate-japan","serena-6","imvigor011","niche-2","phergain","keynote-522","add-aspirin","challenge","persephone"],"people":[],"bottlenecks":["b-trial-enrolment","b-trial-design","b-trial-diversity","b-real-world-evidence","b-dose-optimisation","b-negative-results","b-regulatory-fragmentation","b-aging-comorbidity"],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"steps":[{"era":"1948-2000","title":"The randomised trial and the cooperative groups","description":"The first randomised controlled trial in medicine (streptomycin, 1948) gave oncology its method, and the US cooperative groups, the EORTC and later national groups in Canada, the UK and Europe ran the trials that made chemotherapy, adjuvant therapy and combined-modality treatment evidence-based. ClinicalTrials.gov (2000) made registration public. The model worked; it also fixed the template of one question, one comparator, years of follow-up and hundreds of millions of dollars.","refs":["nci","swog","ecog-acrin","alliance-oncology","nrg-oncology","cctg","childrens-oncology-group","clinicaltrials-gov"],"status":"historic"},{"era":"2005-2018","title":"Platforms, baskets and the mutation as the indication","description":"STAMPEDE, opened in 2005, showed that a multi-arm multi-stage platform can add and drop arms under one protocol and answer several questions for the price of one, establishing docetaxel and abiraterone in prostate cancer along the way. Basket and umbrella trials assigned drugs by mutation across cancers; Pediatric MATCH did it nationally for children. Tissue-agnostic approvals (2017, 2018) followed, and accelerated approval on surrogate endpoints became the norm for oncology, with confirmatory trials that were often late or never done.","refs":["stampede","pediatric-match","tumour-agnostic","accelerated-approval","surrogate-endpoint","idea-reg-conditional-approval-sunset","idea-reg-confirmatory-trial-escrow"],"status":"historic"},{"era":"2016-2024","title":"Decentralised, pragmatic and more inclusive","description":"Real-world evidence gained a regulatory framework; the pandemic forced remote consent, telehealth visits and home delivery of study drugs and the FDA wrote them into guidance (2024); weekly electronic symptom reporting became a trial tool as well as a care tool. ASCO and Friends of Cancer Research rewrote eligibility so that brain metastases, prior cancers, controlled HIV and modest organ dysfunction no longer excluded patients by default, and diversity action plans became a filing requirement. Federated real-world networks and curated clinico-genomic databases made external comparison possible, if not yet trusted.","refs":["real-world-evidence","remote-patient-monitoring","telemedicine-teleoncology","science-37","medidata","trinetx","flatiron-health","flatiron-foundation-cgdb","idea-tr1-justify-every-exclusion","idea-tr1-remote-consent-tele-screening","idea-tr1-diversity-plans-with-consequences","idea-tr1-external-control-rulebook"],"status":"current"},{"era":"2022-2026","title":"Better endpoints and evidence-based doses","description":"Molecular residual disease in blood reads out in months rather than years and has now changed treatment in randomised trials: DYNAMIC, CIRCULATE-Japan, SERENA-6 and IMvigor011, the first ctDNA-guided approval. Pre-surgery windows turned pathological response into a fast biomarker engine (NICHE-2, PHERGain, KEYNOTE-522). The FDA's Project Optimus (final guidance August 2024) ended the maximum-tolerated-dose default for new oncology drugs by requiring randomised dose comparison; the harder task of re-optimising approved doses falls to public funders and trials such as PERSEPHONE. Central imaging reads and companion diagnostics are being standardised as trial infrastructure.","refs":["mrd-testing","liquid-biopsy","dynamic","circulate-japan","serena-6","imvigor011","idea-tr2-ctdna-mrd-qualification","niche-2","phergain","keynote-522","idea-bio2-neoadjuvant-biomarker-engine","idea-tr1-window-of-opportunity-default","b-dose-optimisation","idea-reg-global-dose-optimisation-guideline","idea-tr1-randomised-dose-comparison-before-pivotal","persephone","imaging-core-labs","companion-diagnostic"],"status":"current"},{"era":"2025-2029","title":"AI and data in trial operations","description":"Language models that read the record and flag a matching trial at the moment a treatment is chosen, eligibility simulated against real-world data before a protocol is locked, AI-assisted central imaging reads to cut endpoint cost, target-trial emulation in real-world data to decide which randomised trials are worth running, validated real-world progression endpoints so pragmatic trials can use them, and digital twins as virtual controls where randomisation is unethical. Each has a pilot; none has a standard.","refs":["ai-trial-matching","trial-library","massive-bio","tempus","idea-tr1-ehr-point-of-care-trial-alert","idea-tr1-eligibility-impact-statement","idea-tr1-ai-central-imaging-reads","idea-tr1-target-trial-emulation-to-prioritise-rcts","idea-tr1-validate-real-world-progression-endpoints","digital-twins-trials"],"status":"emerging"},{"era":"2026-2032","title":"Standing infrastructure: trials that never close","description":"The proposal that would change the economics most is a perpetual platform trial in every major cancer, funded as infrastructure, with one ethics approval and one consent form across countries, arms added as drugs arrive and dropped as answers come in, and response-adaptive allocation that learns as it goes. Variants: a national platform every ctDNA-positive patient can join, a platform that assigns treatment by resistance mechanism, one umbrella for all rare cancers, a RECOVERY-style platform for cheap repurposed drugs, and a DRUP-style protocol for off-label generics. Registry-embedded randomisation answers everyday questions inside routine care.","refs":["idea-tr1-standing-platform-per-cancer","idea-tr2-perpetual-platforms","idea-tr2-platform-single-ethics","idea-tr2-bandit-allocation","idea-bio2-national-mrd-platform","idea-bio1-resistance-platform-trial","idea-bio2-rare-cancer-umbrella-platform","idea-reg-recovery-style-platform-repurposing","idea-reg-generic-targeted-therapy-drup","idea-tr2-neoadjuvant-combo-platform","idea-tr1-registry-embedded-randomisation","add-aspirin","challenge"],"status":"emerging"},{"era":"2030+","title":"Measuring what matters, including everyone","description":"Trials that report patient-reported side-effects as rigorously as efficacy, win-ratio endpoints that weigh survival, toxicity and quality of life together, tolerability defined as carefully as efficacy, a mandatory over-70s cohort with geriatric assessment in every pivotal trial, a pragmatic trial after approval in the patients the pivotal trial excluded, sponsor-funded sites in Africa, South Asia and Latin America, and participants paid for their time. An independent programme to validate surrogate endpoints setting by setting would tell everyone which shortcuts are safe.","refs":["idea-moon-pro-ctcae-in-every-pivotal-trial","idea-tr1-win-ratio-net-benefit-endpoint","idea-tr1-tolerability-estimands","idea-tr1-mandatory-older-adult-cohort","idea-tr1-post-approval-pragmatic-trial-in-excluded","idea-tr1-lmic-sites-in-pivotal-trials","idea-tr1-pay-participants-for-time","idea-tr1-protected-physician-time-for-enrolment","idea-tr1-surrogate-validation-programme","global-access-roadmap"],"status":"speculative"},{"era":"What sets the pace","title":"Enrolment, cost, exclusion and hidden failures","description":"Fewer than one in ten adults with cancer joins a trial, and trials close for lack of patients rather than lack of questions. A phase 3 costs hundreds of millions and takes years. Older, poorer, rural and minority patients are under-represented, so results do not transfer. Real-world data are too weak to fill the gap. Negative results and abandoned programmes are rarely published, so mistakes repeat; a reversal registry and mandatory disclosure of top-line data are the proposed fixes. Regulators still review the same dossier separately in each region.","refs":["b-trial-enrolment","b-trial-design","b-trial-diversity","b-real-world-evidence","b-aging-comorbidity","b-negative-results","idea-tr2-material-failure-disclosure","idea-tr2-reversal-registry","b-regulatory-fragmentation","project-orbis","idea-reg-orbis-work-sharing"],"status":"current"}],"watch":[]},{"id":"tnbc-roadmap","kind":"roadmap","name":"Triple-negative breast cancer roadmap: from a remainder defined by three negative tests to immunotherapy, antibody-drug conjugates and the residual disease problem","aka":["TNBC evidence roadmap","Basal-like breast cancer roadmap","Triple-negative breast cancer history"],"tldr":"Triple-negative breast cancer was named for what it lacks, the three receptors other breast cancers are treated through. This roadmap follows it from the receptor discoveries and the basal-like signature of 2000, through chemotherapy, platinum, PARP inhibitors, immunotherapy and antibody-drug conjugates, to the trials asking who can have less and who needs more, with registry dates to 2030.","summary":"For most of its history triple-negative breast cancer was a remainder. Oestrogen receptor testing, then HER2 (Slamon 1987), sorted breast cancers into those with a target; the tumours negative for all three were left with chemotherapy alone. Gene expression profiling gave the remainder a biology (Perou 2000; Sørlie 2001, 2003), linked it to germline BRCA1 (Sørlie 2003; Foulkes 2003; Atchley 2008) and to the founder mutations that concentrate hereditary disease in particular populations (Struewing 1997; Górski 2000), and registry studies of 2006 to 2007 gave it a name, a natural history (relapse peaking at three years, then subsiding) and a demography: younger women, Black and Hispanic women, poorer women, worse survival at every stage. In the United Kingdom the POSH cohort found the same excess in young Black women within a health service with equal access.\n\nChemotherapy was the whole of treatment until 2017, and it worked: anthracycline and taxane regimens cut breast cancer deaths by a third (EBCTCG 2012), tumours disappeared before surgery twice as often as in other subtypes (Liedtke 2008), and those that disappeared were largely cured (Cortazar 2014). Residual disease was the problem, graded from 2007 by the residual cancer burden score. Platinum raised the response rate (GeparSixto and CALGB 40603, 2014 to 2015) and later relapse-free survival (BrighTNess, GeparSixto follow-up), and capecitabine after residual disease became the first post-neoadjuvant treatment (CREATE-X 2017). Molecular subtyping (Lehmann 2011, 2016; Burstein 2015) showed the disease was several diseases, but pathway-targeted small molecules failed, most recently the AKT inhibitor capivasertib (CAPItello-290, 2026).\n\nThree classes then arrived in six years. PARP inhibitors for germline BRCA carriers (OlympiAD, EMBRACA 2017 to 2018; OlympiA 2021, with a survival benefit sustained at six years). Immunotherapy: atezolizumab first (IMpassion130, 2018, later withdrawn after IMpassion131 and an assay dispute), then pembrolizumab first line for PD-L1 combined positive score of 10 or more (KEYNOTE-355) and before and after surgery for stage II to III disease (KEYNOTE-522, with a 4.9-point overall survival gain at five years, 86.6 against 81.7 percent, reported in 2024). Antibody-drug conjugates: sacituzumab govitecan after two lines (ASCENT 2021), trastuzumab deruxtecan for the third of triple-negative tumours that are HER2-low (DESTINY-Breast04, 2022), then first line for all comers (ASCENT-03, ASCENT-04, TROPION-Breast02, 2025 to 2026), with median survival approaching two years against 13 months in 2008.\n\nThe open questions are now about selection and quantity. Who can have less: pembrolizumab omission after pathological complete response (OptimICE-pCR), anthracycline omission (SCARLET), chemotherapy omission in lymphocyte-rich stage I tumours. Who needs more: residual disease trials with antibody-drug conjugates (ASCENT-05, TROPION-Breast03) and the ctDNA-guided designs that c-TRAK TN showed must test earlier and more sensitively. And what the trials have not settled: PD-L1 assay concordance, the order of two topoisomerase-payload antibody-drug conjugates, brain metastases in half of metastatic patients, HER2-low scoring reproducibility, and a disparity in incidence and outcome that trial enrolment has not reflected. UK and NHS specifics are on the UK and NHS page for triple-negative breast cancer.","asOf":"2026-09-24","links":[{"label":"Slamon et al.: HER-2/neu amplification and survival in breast cancer (Science 1987)","url":"https://europepmc.org/article/MED/3798106"},{"label":"Perou et al.: molecular portraits of human breast tumours (Nature 2000)","url":"https://europepmc.org/article/MED/10963602"},{"label":"Sorlie et al.: repeated observation of breast tumour subtypes; BRCA1 predisposes to the basal subtype (PNAS 2003)","url":"https://europepmc.org/article/MED/12829800"},{"label":"Struewing et al.: cancer risk of BRCA1 and BRCA2 founder mutations among Ashkenazi Jews (NEJM 1997)","url":"https://europepmc.org/article/MED/9145676"},{"label":"Dent et al.: triple-negative breast cancer, clinical features and patterns of recurrence (Clin Cancer Res 2007)","url":"https://europepmc.org/article/MED/17671126"},{"label":"Carey et al.: race, breast cancer subtypes and survival in the Carolina Breast Cancer Study (JAMA 2006)","url":"https://europepmc.org/article/MED/16757721"},{"label":"Copson et al.: ethnicity and outcome of young breast cancer patients in the UK, the POSH study (Br J Cancer 2014)","url":"https://europepmc.org/article/MED/24149174"},{"label":"Lehmann et al.: identification of human triple-negative breast cancer subtypes (J Clin Invest 2011)","url":"https://europepmc.org/article/MED/21633166"},{"label":"EBCTCG: polychemotherapy regimens for early breast cancer, 100,000 women in 123 trials (Lancet 2012)","url":"https://europepmc.org/article/MED/22152853"},{"label":"Cortazar et al.: pathological complete response and long-term benefit, CTNeoBC pooled analysis (Lancet 2014)","url":"https://europepmc.org/article/MED/24529560"},{"label":"CREATE-X: adjuvant capecitabine after preoperative chemotherapy (NEJM 2017)","url":"https://europepmc.org/article/MED/28564564"},{"label":"OlympiA six-year update: sustained benefit of adjuvant olaparib (Ann Oncol 2026)","url":"https://europepmc.org/article/MED/42636977"},{"label":"Rugo et al.: PD-L1 assay comparison in IMpassion130 (J Natl Cancer Inst 2021)","url":"https://europepmc.org/article/MED/34097070"},{"label":"Leon-Ferre et al.: tumour-infiltrating lymphocytes in triple-negative breast cancer treated without chemotherapy (JAMA 2024)","url":"https://europepmc.org/article/MED/38563834"},{"label":"c-TRAK TN: ctDNA surveillance and pembrolizumab in early triple-negative breast cancer (Ann Oncol 2023)","url":"https://europepmc.org/article/MED/36423745"},{"label":"TROPION-Breast02: datopotamab deruxtecan first line (Ann Oncol 2026)","url":"https://europepmc.org/article/MED/41937088"},{"label":"CAPItello-290: capivasertib plus paclitaxel first line (Ann Oncol 2026)","url":"https://europepmc.org/article/MED/41422862"},{"label":"ESMO Clinical Practice Guideline: early breast cancer (Ann Oncol 2024)","url":"https://europepmc.org/article/MED/38101773"},{"label":"St Gallen 2025 consensus on early breast cancer (Ann Oncol 2025)","url":"https://europepmc.org/article/MED/41072918"},{"label":"ClinicalTrials.gov NCT03036488","url":"https://clinicaltrials.gov/study/NCT03036488"},{"label":"ClinicalTrials.gov NCT02032823","url":"https://clinicaltrials.gov/study/NCT02032823"},{"label":"ClinicalTrials.gov NCT05374512","url":"https://clinicaltrials.gov/study/NCT05374512"},{"label":"ClinicalTrials.gov NCT03997123","url":"https://clinicaltrials.gov/study/NCT03997123"},{"label":"ClinicalTrials.gov NCT05812807","url":"https://clinicaltrials.gov/study/NCT05812807"},{"label":"ClinicalTrials.gov NCT05929768","url":"https://clinicaltrials.gov/study/NCT05929768"},{"label":"ClinicalTrials.gov NCT05633654","url":"https://clinicaltrials.gov/study/NCT05633654"},{"label":"ClinicalTrials.gov NCT05629585","url":"https://clinicaltrials.gov/study/NCT05629585"},{"label":"ClinicalTrials.gov NCT06103864","url":"https://clinicaltrials.gov/study/NCT06103864"},{"label":"ClinicalTrials.gov NCT06926868","url":"https://clinicaltrials.gov/study/NCT06926868"},{"label":"ClinicalTrials.gov NCT06382142","url":"https://clinicaltrials.gov/study/NCT06382142"},{"label":"ClinicalTrials.gov NCT06419621","url":"https://clinicaltrials.gov/study/NCT06419621"}],"tags":["tnbc","breast","roadmap"],"related":["tnbc-history","trop2-adc-roadmap","adc-generations","immunotherapy-roadmap","chemotherapy-roadmap","targeted-therapy-roadmap","ctdna-tests","platinum-plus-hrd","germline-to-parp","idea-tnbc-de-escalation-for-exceptional-responders","idea-tnbc-ctdna-guided-adjuvant-decisions","idea-tnbc-disparities-in-access-and-outcomes","idea-tnbc-pd-l1-assay-harmonisation","idea-tnbc-adc-sequencing-trial","idea-tnbc-brain-metastasis-trials","idea-tnbc-her2-ultralow-testing-uptake","idea-tnbc-uk-trial-access-and-germline-testing-audit","idea-tnbc-uk-ethnicity-stratified-outcome-reporting"],"cancers":["tnbc","breast-hr-positive","breast-her2-positive","her2-low-metastatic-breast-cancer"],"sections":["adcs","immunotherapy","chemotherapy","targeted-therapy"],"technologies":["adc","bispecific-adc","checkpoint-inhibitor","parp-inhibitor","platinum","liquid-biopsy","mrd-testing","germline-testing","digital-pathology-ai","rna-seq","trop2-pet"],"targets":["trop2","pdl1","her2","brca","androgen-receptor","akt"],"drugs":["pembrolizumab","atezolizumab","sacituzumab-govitecan","datopotamab-deruxtecan","trastuzumab-deruxtecan","izalontamab-brengitecan","olaparib","talazoparib","capecitabine","carboplatin","paclitaxel","nab-paclitaxel","doxorubicin","cyclophosphamide","capivasertib","ventana-pd-l1-sp142","signatera"],"companies":["gbg","merck","gilead","astrazeneca","daiichi-sankyo","roche-genentech","pfizer","bms","systimmune"],"institutions":["unc-lineberger","md-anderson","dana-farber","royal-marsden","mayo-clinic","nci","cruk","esmo","asco"],"pathways":["ddr","emt","pi3k-akt-mtor","pd1-checkpoint"],"terms":["pcr","rcb","tils","cps","hrd","her2-low","her2-ultralow","ctdna","mrd","de-escalation","neoadjuvant-adjuvant","germline-testing","brain-metastases","adc-sequencing","adc-after-adc-caution","pam50","anthracycline","taxane","efs","os","pfs"],"trials":["keynote-522","keynote-355","impassion130","impassion131","impassion031","ascent","ascent-03","ascent-04","ascent-05","olympia","olympiad","embraca","brightness","geparsixto","tropion-breast01","tropion-breast02","tropion-breast03","tropion-breast05","destiny-breast04","optimice-pcr","scarlet-s2212","izabright-breast01","bl-b01d1-307","nct03997123","nct06419621"],"people":["peter-schmid","javier-cortes","rebecca-dent","hope-rugo","sibylle-loibl","charles-perou","judy-garber","andrew-tutt","nicholas-turner","sara-tolaney","aditya-bardia","jennifer-litton","mark-robson","lajos-pusztai","nancy-lin","giuseppe-curigliano","charles-geyer","gunter-von-minckwitz","mary-claire-king","richard-peto"],"bottlenecks":["b-dormancy-mrd","b-biomarker-validation","b-trial-diversity","b-resistance","b-brain-delivery","b-toxicity-qol","b-hereditary-risk","b-tumor-heterogeneity","b-immunotherapy-response","b-negative-results"],"keyPapers":["paper-slamon-her2-amplification-science-1987","paper-perou-molecular-portraits-breast-tumours-nature-2000","paper-sorlie-repeated-observation-subtypes-brca1-basal-pnas-2003","paper-struewing-brca-founder-mutations-ashkenazi-nejm-1997","paper-dent-tnbc-clinical-features-recurrence-ccr-2007","paper-carey-race-breast-cancer-subtypes-cbcs-jama-2006","paper-copson-posh-ethnicity-young-breast-cancer-uk-bjc-2014","paper-lehmann-tnbc-subtypes-jci-2011","paper-liedtke-neoadjuvant-response-survival-tnbc-jco-2008","paper-cortazar-ctneobc-pcr-pooled-analysis-lancet-2014","paper-symmans-j-clin-oncol","paper-yau-rcb-pooled-analysis-5161-lancet-oncol-2022","paper-geparsixto-lancet-oncol-2014","paper-create-x-adjuvant-capecitabine-nejm-2017","paper-olympiad-nejm-2017","paper-embraca-n-engl-j-med-2018","paper-olympia-nejm-2021","paper-olympia-6-year-update-ann-oncol-2026","paper-impassion130-n-engl-j-med-2018","paper-impassion131-ann-oncol-2021","paper-rugo-pd-l1-assay-comparison-impassion130-jnci-2021","paper-keynote-355-nejm-2022","paper-keynote-522-n-engl-j-med-2020","paper-keynote-522-n-engl-j-med-2024-update","paper-ascent-nejm-2021","paper-destiny-breast04-nejm-2022","paper-tropion-breast02-ann-oncol-2026","paper-capitello-290-capivasertib-paclitaxel-ann-oncol-2026","paper-leon-ferre-tils-tnbc-no-chemotherapy-jama-2024","paper-turner-c-trak-tn-ctdna-pembrolizumab-ann-oncol-2023","paper-esmo-early-breast-cancer-guideline-ann-oncol-2024","paper-nccn-breast-cancer-v4-2026-jnccn-2026","paper-st-gallen-2025-consensus-ann-oncol-2025"],"journals":[],"dependsOn":[],"notes":["How this stays current: scripts/roadmap-watch.ts (npm run roadmap:watch) checks each trial here against ClinicalTrials.gov and searches Europe PMC for new papers on the acronyms since asOf. Anything it prints that this page does not say is an edit to make; then move asOf forward.","Dates in 'What to watch' are quoted from the registry as read on 2026-09-24 and are not predictions; estimated completion dates move.","The primary papers of the pivotal trials (KEYNOTE-522, KEYNOTE-355, IMpassion130 and 131, ASCENT, DESTINY-Breast04, OlympiA, OlympiAD, EMBRACA, BrighTNess, GeparSixto) are linked from the steps to their existing records; this deep dive adds the guideline, discovery, disparity, residual disease and 2026 trial papers around them.","UK and NHS specifics (referral routes, NICE positions, Cancer Drugs Fund status, germline testing criteria, trial access) are held on the UK and NHS page for triple-negative breast cancer and are not restated here."],"steps":[{"era":"1987-2010","title":"Defined by three negative tests","description":"Oestrogen receptor assays sorted breast cancers into those that would respond to endocrine therapy and those that would not; in 1987 Slamon and colleagues found HER-2/neu amplified in 30 percent of 189 tumours and predictive of early relapse, adding a third test. The tumours negative for all three were a remainder with chemotherapy as their only treatment. The thresholds that define the remainder are conventions: the 2010 ASCO and CAP guideline fixed oestrogen and progesterone receptor positivity at 1 percent of nuclei after finding up to 20 percent of tests worldwide might be wrong, and the 1 to 10 percent low-positive band it created still behaves like triple-negative disease in many series.","refs":["paper-slamon-her2-amplification-science-1987","paper-asco-cap-er-pr-testing-guideline-jco-2010","her2","ihc","tnbc"],"status":"historic"},{"era":"2000-2003","title":"The basal-like subtype and its link to BRCA1","description":"Perou and colleagues read 8,102 genes in 65 tumours in 2000 and found breast cancer fell into groups, one of them basal epithelial-like; Sørlie showed in 2001 that the basal-like group had the worst outcome and in 2003 that the subtypes reproduced in other laboratories' data and that tumours from BRCA1 carriers fell into the basal group. Foulkes confirmed the BRCA1 link the same year with a cytokeratin 5/6 stain (odds ratio 9.0). The remainder now had a biology and a hereditary cause; basal-like and triple-negative overlap but are not the same set.","refs":["paper-perou-molecular-portraits-breast-tumours-nature-2000","paper-sorlie-breast-carcinoma-subclasses-pnas-2001","paper-sorlie-repeated-observation-subtypes-brca1-basal-pnas-2003","paper-foulkes-brca1-basal-phenotype-jnci-2003","charles-perou","pam50","rna-seq","brca"],"status":"historic"},{"era":"1997-2008","title":"Founder mutations: hereditary disease has a geography","description":"Struewing's 1997 study of 5,318 Ashkenazi Jewish volunteers put the breast cancer risk of the three founder mutations carried by over 2 percent of that population at 56 percent by age 70; Górski found in 2000 that three BRCA1 changes accounted for 82 percent of the mutations in 66 Polish families, one of them (5382insC) shared with the Ashkenazi set. Atchley's 2008 MD Anderson series showed 57 percent of BRCA1 carriers' tumours were triple-negative against 14 percent in non-carriers, which made a triple-negative diagnosis itself a reason to test. Founder panels make population testing cheap where they exist; where they do not, full sequencing is needed and uptake lags.","refs":["paper-struewing-brca-founder-mutations-ashkenazi-nejm-1997","paper-gorski-brca1-founder-mutations-poland-ajhg-2000","paper-atchley-brca-status-triple-negative-jco-2008","paper-asco-hereditary-breast-cancer-guideline-jco-2020","germline-testing","brca","mary-claire-king","b-hereditary-risk","idea-tnbc-uk-trial-access-and-germline-testing-audit"],"status":"historic"},{"era":"2006-2008","title":"A name, a natural history and a disparity","description":"Dent's Toronto cohort (2007) found triple-negative disease in 11.2 percent of 1,601 patients with a distant relapse hazard ratio of 2.6 that peaked at three years and faded after five; Bauer's California registry study (2007) of 6,370 cases fixed its demography as younger, Black, Hispanic and poorer women with worse survival at every stage. Carey's Carolina Breast Cancer Study (2006) had found the basal-like subtype in 39 percent of premenopausal African American women against 16 percent of others, and Lin (2008) showed 46 percent of metastatic patients developed brain metastases with a median survival of 13.3 months. National counts followed: 12.2 percent of US cases in 2010 (Howlader 2014), odds ratio 2.27 for Black women in 1.15 million cases (Scott 2019). In the UK the POSH cohort of women under 41 found 26.1 percent triple-negative disease in Black women against 18.6 percent in White women and five-year survival of 71.1 versus 82.4 percent despite equal chemotherapy use.","refs":["paper-dent-tnbc-clinical-features-recurrence-ccr-2007","paper-bauer-triple-negative-california-registry-cancer-2007","paper-carey-race-breast-cancer-subtypes-cbcs-jama-2006","paper-lin-tnbc-cns-metastases-dfci-cancer-2008","paper-howlader-us-incidence-breast-subtypes-jnci-2014","paper-scott-tnbc-disparities-uscs-cancer-2019","paper-copson-posh-ethnicity-young-breast-cancer-uk-bjc-2014","rebecca-dent","nancy-lin","brain-metastases","b-trial-diversity","idea-tnbc-disparities-in-access-and-outcomes","idea-tnbc-brain-metastasis-trials"],"status":"historic"},{"era":"1990s-2014","title":"Anthracycline and taxane chemotherapy, and the residual disease paradox","description":"The Oxford overview of 123 trials (EBCTCG 2012) showed taxane-plus-anthracycline regimens cut breast cancer deaths by about a third regardless of receptor status, so chemotherapy's absolute benefit was largest in the high-risk remainder. Liedtke's MD Anderson series (2008) found triple-negative tumours disappeared completely before surgery twice as often as others (22 versus 11 percent) yet survival was worse, because women with residual disease relapsed early. Symmans graded residual disease with the residual cancer burden score in 2007; the CTNeoBC pooled analysis (2014) found pathological complete response predicted survival most strongly in triple-negative disease (event-free survival hazard ratio 0.24) but could not validate it as a trial-level surrogate. The US regulator nonetheless built an accelerated approval pathway on it.","refs":["paper-ebctcg-polychemotherapy-regimens-meta-analysis-lancet-2012","paper-liedtke-neoadjuvant-response-survival-tnbc-jco-2008","paper-symmans-j-clin-oncol","paper-symmans-rcb-long-term-prognosis-subtype-jco-2017","paper-yau-rcb-pooled-analysis-5161-lancet-oncol-2022","paper-cortazar-ctneobc-pcr-pooled-analysis-lancet-2014","paper-asco-neoadjuvant-therapy-breast-guideline-jco-2021","anthracycline","taxane","pcr","rcb","neoadjuvant-adjuvant","chemotherapy"],"status":"historic"},{"era":"2011-2016","title":"Several diseases: molecular subtypes","description":"Lehmann's 2011 analysis of 587 tumours defined six subtypes (basal-like 1 and 2, immunomodulatory, mesenchymal, mesenchymal stem-like, luminal androgen receptor), each with candidate drugs from cell line work; the 2016 refinement showed two came from immune and stromal cells, cut the scheme to four, and found pathological complete response ranged from 41 percent in basal-like 1 to 18 percent in basal-like 2. Burstein's Baylor study (2015) reached a similar four-way split and showed immune activation within basal-like tumours separated longer from shorter survival. The subtypes shaped trial design (androgen receptor antagonists for the luminal androgen receptor group, platinum for basal-like 1) but no subtype-directed small molecule has succeeded in phase 3.","refs":["paper-lehmann-tnbc-subtypes-jci-2011","paper-lehmann-tnbctype-4-refinement-plos-one-2016","paper-burstein-tnbc-genomic-subtypes-ccr-2015","androgen-receptor","emt","ddr","b-tumor-heterogeneity"],"status":"historic"},{"era":"2014-2022","title":"Platinum","description":"GeparSixto (2014) and CALGB 40603 (2015) showed carboplatin raised pathological complete response, in CALGB 40603 from 41 to 54 percent in breast and axilla. Survival followed: GeparSixto's final analysis (2018) gave a disease-free survival hazard ratio of 0.56 in triple-negative disease and found 70 percent of tumours homologous recombination deficient whether or not BRCA was mutated, with the deficiency predicting response but not carboplatin benefit; BrighTNess at 4.5 years (2022) gave an event-free survival hazard ratio of 0.57 for carboplatin over paclitaxel alone and nothing for added veliparib. The TNT trial showed carboplatin's advantage in metastatic disease was confined to germline BRCA carriers. St Gallen 2025 made platinum a consensus recommendation for early triple-negative disease.","refs":["geparsixto","paper-geparsixto-lancet-oncol-2014","paper-loibl-geparsixto-survival-hrd-ann-oncol-2018","paper-sikov-calgb-40603-carboplatin-bevacizumab-jco-2015","brightness","paper-brightness-lancet-oncol-2018","paper-geyer-brightness-4-year-follow-up-ann-oncol-2022","paper-tutt-nat-med","paper-st-gallen-2025-consensus-ann-oncol-2025","carboplatin","platinum","hrd","platinum-plus-hrd","sibylle-loibl","gbg"],"status":"current"},{"era":"2017","title":"Residual disease becomes treatable: capecitabine after neoadjuvant chemotherapy","description":"CREATE-X randomised 910 Japanese and Korean women with HER2-negative residual disease after neoadjuvant chemotherapy to six months of capecitabine or nothing: five-year overall survival 89.2 versus 83.6 percent (hazard ratio 0.59), and in the triple-negative group 78.8 versus 70.3 percent (0.52), with hand-foot syndrome in 73 percent. It was the first proof that the post-neoadjuvant window could be used, the design OlympiA, ASCENT-05 and TROPION-Breast03 inherited, and capecitabine remains the option for residual disease without a BRCA variant in ESMO, NCCN and UK practice. Whether it adds to adjuvant pembrolizumab has never been tested.","refs":["paper-create-x-adjuvant-capecitabine-nejm-2017","capecitabine","rcb","neoadjuvant-adjuvant","paper-esmo-early-breast-cancer-guideline-ann-oncol-2024","idea-tnbc-ctdna-guided-adjuvant-decisions"],"status":"current"},{"era":"2017-2026","title":"PARP inhibition for germline BRCA carriers","description":"OlympiAD (2017) and EMBRACA (2018) showed olaparib and talazoparib beat chemotherapy for progression-free survival in metastatic germline BRCA-mutated breast cancer, without a clear survival gain. OlympiA (2021) gave a year of adjuvant olaparib to 1,836 high-risk carriers, 82 percent with triple-negative disease, and improved invasive disease-free survival; the 2022 analysis showed an overall survival hazard ratio of 0.68 and the 2026 six-year update 0.72 (six-year survival 87.5 versus 83.2 percent) with no excess of leukaemia and fewer new BRCA-related cancers. Neoadjuvant PARP inhibition in unselected disease failed (BrighTNess veliparib arm). The 2020 ASCO, ASTRO and SSO hereditary guideline sets the surgical and systemic rules for carriers; whether olaparib adds to pembrolizumab or capecitabine in the same patient is untested.","refs":["olympiad","paper-olympiad-nejm-2017","embraca","paper-embraca-n-engl-j-med-2018","olympia","paper-olympia-nejm-2021","paper-olympia-overall-survival-ann-oncol-2022","paper-olympia-6-year-update-ann-oncol-2026","paper-asco-hereditary-breast-cancer-guideline-jco-2020","olaparib","talazoparib","parp-inhibitor","brca","germline-testing","germline-to-parp","judy-garber","andrew-tutt","mark-robson","jennifer-litton","astrazeneca","pfizer"],"status":"current"},{"era":"2018-2024","title":"Immunotherapy: an assay dispute, then a new standard for early disease","description":"IMpassion130 (2018) showed atezolizumab with nab-paclitaxel lengthened progression-free survival in PD-L1-positive metastatic disease by the SP142 assay; IMpassion131 with paclitaxel was negative, the US indication was withdrawn in 2021, and Rugo's assay comparison showed SP142, SP263 and 22C3 called 46, 75 and 73 percent of the same tumours positive with 69 percent concordance. KEYNOTE-355 (2020, survival 2022) established pembrolizumab with chemotherapy for 22C3 combined positive score of 10 or more. KEYNOTE-522 (2020) added pembrolizumab before and after surgery for stage II to III disease: pathological complete response 64.8 versus 51.2 percent, event-free survival gain in 2022, and in 2024 a 4.9-point five-year overall survival gain (86.6 against 81.7 percent), the first survival benefit of immunotherapy in early breast cancer. ASCO reversed its 2021 guideline within 15 months; ESMO, NCCN and St Gallen followed. Leon-Ferre (2024) showed lymphocyte-rich stage I tumours do well without any chemotherapy, and OptimICE-pCR now asks whether adjuvant pembrolizumab can be dropped after complete response.","refs":["impassion130","paper-impassion130-n-engl-j-med-2018","impassion131","paper-impassion131-ann-oncol-2021","paper-rugo-pd-l1-assay-comparison-impassion130-jnci-2021","keynote-355","paper-keynote-355-nejm-2022","keynote-522","paper-keynote-522-n-engl-j-med-2020","paper-keynote-522-nejm-2022","paper-keynote-522-n-engl-j-med-2024-update","paper-asco-pembrolizumab-early-tnbc-rapid-update-jco-2022","paper-leon-ferre-tils-tnbc-no-chemotherapy-jama-2024","optimice-pcr","pembrolizumab","atezolizumab","checkpoint-inhibitor","cps","tils","pdl1","peter-schmid","javier-cortes","hope-rugo","merck","roche-genentech","immunotherapy","idea-tnbc-pd-l1-assay-harmonisation","idea-tnbc-de-escalation-for-exceptional-responders"],"status":"current"},{"era":"2020-2026","title":"Antibody-drug conjugates move from third line to first","description":"ASCENT (2021) doubled survival with sacituzumab govitecan after two or more lines (12.1 versus 6.7 months); DESTINY-Breast04 (2022) showed trastuzumab deruxtecan worked in HER2-low tumours, which are 36.6 percent of triple-negative disease though biologically indistinguishable from HER2-zero (Schettini 2021). ASCENT-03 and ASCENT-04 (2025 to 2026) and TROPION-Breast02 (2026: progression-free survival 10.8 versus 5.6 months, overall survival 23.7 versus 18.7) moved TROP2 antibody-drug conjugates to first line, alone or with pembrolizumab, and the bispecific EGFR and HER3 conjugate izalontamab brengitecan posted a positive phase 3 in pretreated disease. The same year the AKT inhibitor capivasertib failed to improve survival first line (CAPItello-290), the latest pathway-targeted small molecule to do so. Median survival in first-line trials now approaches two years against 13.3 months in the 2008 Dana-Farber series.","refs":["ascent","paper-ascent-nejm-2021","destiny-breast04","paper-destiny-breast04-nejm-2022","paper-schettini-her2-low-features-npj-breast-cancer-2021","ascent-03","paper-ascent-03-n-engl-j-med-2025","ascent-04","paper-ascent-04-n-engl-j-med-2026","tropion-breast02","paper-tropion-breast02-ann-oncol-2026","bl-b01d1-307","nct03997123","paper-capitello-290-capivasertib-paclitaxel-ann-oncol-2026","sacituzumab-govitecan","datopotamab-deruxtecan","trastuzumab-deruxtecan","izalontamab-brengitecan","capivasertib","trop2","her2-low","adc","bispecific-adc","trop2-adc-roadmap","adc-generations","rebecca-dent","aditya-bardia","sara-tolaney","gilead","astrazeneca","daiichi-sankyo","adcs","idea-tnbc-adc-sequencing-trial","idea-tnbc-her2-ultralow-testing-uptake"],"status":"current"},{"era":"2020-2026","title":"Residual disease and the blood test that might guide it","description":"Radovich (2020) showed ctDNA after neoadjuvant chemotherapy in 142 residual-disease patients carried a distant relapse hazard ratio of 2.99 and a death hazard ratio of 4.16. The UK c-TRAK TN trial (2023) then tested acting on it: 27 percent of 161 women turned ctDNA-positive within a year, but 72 percent of those already had metastases on staging and none of five given pembrolizumab cleared their DNA, so later designs test earlier, with tumour-informed assays, and use drugs with more single-agent activity. Meanwhile the residual cancer burden score, validated across 5,161 patients (Yau 2022), became the entry criterion for antibody-drug conjugate trials after neoadjuvant therapy: ASCENT-05 (sacituzumab govitecan with pembrolizumab, 1,514 patients) and TROPION-Breast03 (datopotamab deruxtecan with or without durvalumab, 1,174 patients).","refs":["paper-radovich-ctdna-ctc-bre12-158-jama-oncol-2020","paper-turner-c-trak-tn-ctdna-pembrolizumab-ann-oncol-2023","paper-yau-rcb-pooled-analysis-5161-lancet-oncol-2022","ascent-05","tropion-breast03","ctdna","mrd","rcb","liquid-biopsy","mrd-testing","signatera","ctdna-tests","nicholas-turner","royal-marsden","b-dormancy-mrd","idea-tnbc-ctdna-guided-adjuvant-decisions"],"status":"emerging"},{"era":"2026-2030","title":"What the registry says is coming","description":"The de-escalation trials are large and slow: OptimICE-pCR (pembrolizumab versus observation after pathological complete response, 1,295 estimated, primary completion May 2033) and SCARLET (anthracycline-free chemo-immunotherapy, 2,400 estimated, March 2033). The escalation trials report sooner: ASCENT-05 (June 2027) and TROPION-Breast03 (September 2027) for residual disease. First-line combinations follow: TROPION-Breast05 (datopotamab deruxtecan with durvalumab against chemotherapy with pembrolizumab in PD-L1-positive disease, 625 estimated, July 2027), IZABRIGHT-Breast01 (izalontamab brengitecan first line in immunotherapy-ineligible disease, 600, March 2028) and the PD-L1 and VEGF bispecific PM8002 with nab-paclitaxel (392, July 2027). KEYNOTE-522 completed on the registry in October 2025; OlympiA's study completion is listed for May 2029.","refs":["optimice-pcr","scarlet-s2212","ascent-05","tropion-breast03","tropion-breast05","izabright-breast01","nct06419621","keynote-522","olympia","de-escalation","idea-tnbc-de-escalation-for-exceptional-responders","idea-tnbc-ctdna-guided-adjuvant-decisions"],"status":"emerging"},{"era":"What sets the pace","title":"Selection, sequence, sanctuary and who gets enrolled","description":"Four things the trials have not settled. PD-L1 assays disagree on a quarter of patients and only one, 22C3 combined positive score of 10, has an approved drug attached. Two TROP2 antibody-drug conjugates and trastuzumab deruxtecan share a topoisomerase I payload and no randomised trial has asked which to give first or whether the second works after the first. Brain metastases occur in about half of metastatic patients (Lin 2008) and most trials exclude active brain disease. And the disease is twice as common in Black women in the United States, with worse survival in the UK POSH cohort despite equal access, yet trial enrolment does not reflect it. Each has an idea on this page; the UK-specific gaps are set out on the UK and NHS page for triple-negative breast cancer.","refs":["paper-rugo-pd-l1-assay-comparison-impassion130-jnci-2021","paper-lin-tnbc-cns-metastases-dfci-cancer-2008","paper-scott-tnbc-disparities-uscs-cancer-2019","paper-copson-posh-ethnicity-young-breast-cancer-uk-bjc-2014","adc-sequencing","adc-after-adc-caution","brain-metastases","b-biomarker-validation","b-resistance","b-brain-delivery","b-trial-diversity","idea-tnbc-pd-l1-assay-harmonisation","idea-tnbc-adc-sequencing-trial","idea-tnbc-brain-metastasis-trials","idea-tnbc-disparities-in-access-and-outcomes","idea-tnbc-uk-ethnicity-stratified-outcome-reporting"],"status":"current"}],"watch":[{"item":"TROPION-Breast02 study completion on the registry (datopotamab deruxtecan first line, immunotherapy-ineligible; primary completion 25 August 2025, actual)","expected":"2026-12-31","source":"https://clinicaltrials.gov/study/NCT05374512","refs":["tropion-breast02","datopotamab-deruxtecan"]},{"item":"CAPItello-290 study completion on the registry (capivasertib plus paclitaxel first line; published negative for overall survival in 2026)","expected":"2026-03-16","source":"https://clinicaltrials.gov/study/NCT03997123","refs":["nct03997123","capivasertib","paper-capitello-290-capivasertib-paclitaxel-ann-oncol-2026"]},{"item":"ASCENT-05 / OptimICE-RD primary completion: sacituzumab govitecan with pembrolizumab vs physician's choice for residual invasive disease after neoadjuvant therapy (1,514 estimated participants)","expected":"2027-06","source":"https://clinicaltrials.gov/study/NCT05633654","refs":["ascent-05","sacituzumab-govitecan","pembrolizumab","rcb"]},{"item":"TROPION-Breast05 primary completion: datopotamab deruxtecan with or without durvalumab vs chemotherapy with pembrolizumab, first line, PD-L1-positive (625 estimated participants)","expected":"2027-07-28","source":"https://clinicaltrials.gov/study/NCT06103864","refs":["tropion-breast05","datopotamab-deruxtecan","cps"]},{"item":"PM8002 (PD-L1 and VEGF bispecific) plus nab-paclitaxel vs placebo plus nab-paclitaxel, first line: primary completion (392 estimated participants)","expected":"2027-07","source":"https://clinicaltrials.gov/study/NCT06419621","refs":["nct06419621","nab-paclitaxel"]},{"item":"TROPION-Breast03 primary completion: datopotamab deruxtecan with or without durvalumab vs investigator's choice for stage I to III disease without pathological complete response (1,174 participants; active, not recruiting)","expected":"2027-09-20","source":"https://clinicaltrials.gov/study/NCT05629585","refs":["tropion-breast03","datopotamab-deruxtecan","rcb"]},{"item":"BL-B01D1-307 / PANKU-Breast02 study completion (izalontamab brengitecan vs chemotherapy in pretreated disease; primary completion 13 January 2026, actual)","expected":"2027-12","source":"https://clinicaltrials.gov/study/NCT06382142","refs":["bl-b01d1-307","izalontamab-brengitecan"]},{"item":"IZABRIGHT-Breast01 primary completion: izalontamab brengitecan vs chemotherapy, first line, anti-PD-(L)1-ineligible (600 estimated participants)","expected":"2028-03-13","source":"https://clinicaltrials.gov/study/NCT06926868","refs":["izabright-breast01","izalontamab-brengitecan","bispecific-adc"]},{"item":"OlympiA study completion on the registry (adjuvant olaparib; primary completion 27 March 2020, actual; six-year update published 2026)","expected":"2029-05-28","source":"https://clinicaltrials.gov/study/NCT02032823","refs":["olympia","olaparib","paper-olympia-6-year-update-ann-oncol-2026"]},{"item":"SCARLET (S2212) primary completion: shorter anthracycline-free chemo-immunotherapy vs the KEYNOTE-522 regimen (2,400 estimated participants)","expected":"2033-03-31","source":"https://clinicaltrials.gov/study/NCT05929768","refs":["scarlet-s2212","keynote-522","anthracycline","de-escalation"]},{"item":"OptimICE-pCR primary completion: adjuvant pembrolizumab vs observation after pathological complete response to chemotherapy plus pembrolizumab (1,295 estimated participants)","expected":"2033-05-31","source":"https://clinicaltrials.gov/study/NCT05812807","refs":["optimice-pcr","pembrolizumab","pcr","de-escalation"]},{"item":"A randomised trial of antibody-drug conjugate sequence (TROP2 conjugate then trastuzumab deruxtecan or the reverse, with or without chemotherapy between); none found on ClinicalTrials.gov on 24 September 2026","source":"https://europepmc.org/article/MED/41937088","refs":["adc-sequencing","idea-tnbc-adc-sequencing-trial"]},{"item":"A ctDNA-guided adjuvant trial in triple-negative breast cancer with early, tumour-informed sampling that reports after c-TRAK TN; the design lesson is recorded in the 2023 paper","source":"https://europepmc.org/article/MED/36423745","refs":["ctdna","mrd-testing","idea-tnbc-ctdna-guided-adjuvant-decisions"]}]},{"id":"trop2-adc-roadmap","kind":"roadmap","name":"TROP2 ADC roadmap: sacituzumab govitecan → Dato-DXd → sac-TMT → bispecifics and PET","aka":[],"tldr":"One target, three approved-or-nearly-approved drugs, and a fourth wave. How TROP2 went from an obscure trophoblast antigen to the centre of breast and lung cancer treatment.","summary":"TROP2 is not a driver but an address, so this roadmap follows what is delivered to it. It starts with target discovery on trophoblasts and Immunomedics humanising the RS7 antibody, moves to sacituzumab govitecan proving the target in ASCENT, then to datopotamab deruxtecan and the first-line phase 3 trials ASCENT-03, ASCENT-04 and TROPION-Breast02. Sacituzumab tirumotecan and the Merck TroFuse programme form a third wave, while selection, sequencing and cross-resistance among TOP1 payloads remain unsolved, with TROP2 PET and ctDNA biomarkers entering trials. The speculative end is bispecific and next-payload TROP2 ADCs in early-stage disease. The route links TNBC, HR-positive breast cancer, NSCLC and urothelial cancer, the TROP2 target and the incentive-misalignment bottleneck.","asOf":"2026-09-04","links":[{"label":"ASCENT: sacituzumab govitecan doubles survival in heavily pretreated metastatic triple-negative breast cancer (New England Journal of Medicine 2021)","url":"https://doi.org/10.1056/NEJMoa2028485"}],"tags":[],"related":[],"cancers":["tnbc","breast-hr-positive","nsclc","urothelial"],"sections":["adcs"],"technologies":[],"targets":["trop2"],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"steps":[{"era":"1981-2015","title":"Target discovery and antibody development","description":"TROP2 identified on trophoblasts (1981); overexpression across epithelial cancers established in the 2000s. Immunomedics humanises the RS7 antibody and conjugates SN-38 (IMMU-132) with a moderately stable, hydrolysable linker designed to release payload in the tumour microenvironment.","refs":["trop2"],"status":"historic"},{"era":"2020-2021","title":"Sacituzumab govitecan proves the target","description":"ASCENT: OS 12.1 vs 6.7 months in pretreated metastatic TNBC; accelerated then full approval. Gilead acquires Immunomedics for $21B. Benefit irrespective of TROP2 IHC, so no companion diagnostic is required.","refs":["ascent","sacituzumab-govitecan","gilead"],"status":"historic"},{"era":"2023-2025","title":"Second entrant: datopotamab deruxtecan","description":"Datopotamab deruxtecan carries the DXd payload at DAR 4 on a different anti-TROP2 antibody. TROPION-Breast01 (HR+, PFS only) and TROPION-Lung01 (mixed) produce narrow approvals (HR+ breast 2025; EGFR-mutant NSCLC 2025). Stomatitis and ocular toxicity define its profile versus sacituzumab's neutropenia and diarrhoea. Sacituzumab expands to HR+ (TROPiCS-02) but loses its urothelial indication.","refs":["datopotamab-deruxtecan","tropion-breast01","tropion-lung01"],"status":"current"},{"era":"2025-2026","title":"First line: three positive phase 3 trials","description":"ASCENT-03 (sacituzumab, PD-1-ineligible), ASCENT-04 (sacituzumab + pembrolizumab, PD-L1+), and TROPION-Breast02 (Dato-DXd, PD-1-ineligible, first OS benefit) all read out positive, with FDA approvals in Q2 2026. TROP2 ADCs displace chemotherapy in first-line metastatic TNBC. TROPION-Breast05 (Dato-DXd + durvalumab) is pending.","refs":["ascent-03","ascent-04","tropion-breast02","tropion-breast05"],"status":"current"},{"era":"2024-2027","title":"Third entrant: sacituzumab tirumotecan and the Merck programme","description":"Kelun's sac-TMT, with a belotecan-derived payload and a more stable linker, is approved in China (2024) and licensed to Merck, which is running >10 phase 3 TroFuse trials across TNBC, HR+ breast, NSCLC, endometrial, and cervical cancer, often with pembrolizumab. FDA priority voucher July 2026; US approval expected to follow positive first-line TNBC data.","refs":["sacituzumab-tirumotecan","kelun-biotech","merck"],"status":"emerging"},{"era":"2026-2029","title":"Unsolved: selection, sequencing, resistance","description":"IHC does not predict benefit. Cross-resistance among TOP1 payloads limits sequencing (T-DXd → sacituzumab or vice versa). TROP2 PET tracers (89Zr-antibody, 68Ga/18F-nanobody) enter phase 1 to map antigen, guide choice, and monitor loss. ctDNA and SLFN11/TOP1 biomarkers for payload resistance are under study.","refs":["trop2-pet","adc-sequencing","adc-after-adc-caution","trop2-pet-to-adc"],"status":"emerging"},{"era":"2027+","title":"Next generation: bispecific and next-payload TROP2 ADCs","description":"Nectin-4×TROP2 bispecific ADCs (AK146D1, AVZO-103), TROP2 ADCs with non-TOP1 or dual payloads, TROP2-directed radioconjugates, and TROP2 CAR-T. The class moves into early-stage disease (neoadjuvant/post-neoadjuvant TNBC) and into lung, gastric, and endometrial cancer. A TROP2 PET-guided, payload-switching treatment algorithm is the field's implicit goal.","refs":["ak146d1","bispecific-adc","dual-payload-adc","radioimmunotherapy","idea-trop2-pet-selection"],"status":"speculative"}],"watch":[]},{"id":"virtual-cell","kind":"roadmap","name":"Virtual cell roadmap: from bulk omics to a predictive model of a cancer cell","aka":[],"tldr":"The attempt to build a computer model of a cell good enough to predict what a drug or mutation will do before anyone runs the experiment.","summary":"A virtual cell would let researchers test thousands of drug ideas in silico and personalise treatment from a patient's own tumour profile. The field moved from static atlases to perturbation-trained models in five years; the honest status is that current models generalise poorly to unseen contexts and barely beat simple baselines on rigorous benchmarks, while data generation has begun to scale to the size the problem needs.","asOf":"2026-09-08","links":[{"label":"Defining a Cancer Dependency Map: which genes each cancer cell line cannot live without (Cell 2017)","url":"https://doi.org/10.1016/j.cell.2017.06.010"}],"tags":[],"related":[],"cancers":[],"sections":["ai-computation","drug-discovery"],"technologies":["geneformer","scgpt","state-arc","c2s-scale","universal-cell-embedding","gears","transcriptformer","single-cell-spatial","crispr-screens"],"targets":[],"drugs":[],"companies":["vevo-therapeutics","chan-zuckerberg-initiative","google-deepmind"],"institutions":["arc-institute","stanford","yale-school-of-medicine"],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"steps":[{"era":"2008-2018","title":"Atlases and bulk omics","description":"TCGA catalogues the genomes of 11,000 tumours; single-cell RNA-seq matures; the Human Cell Atlas begins. Models are statistical, per-dataset, and descriptive.","refs":["tcga-gdc","cellxgene-hca","single-cell-spatial"],"status":"historic"},{"era":"2019-2022","title":"Pooled perturbation screens meet single cells","description":"Perturb-seq and genome-wide CRISPR screens (DepMap) give causal training data; GEARS shows graph models can predict some unseen knockouts.","refs":["crispr-screens","depmap","gears"],"status":"historic"},{"era":"2023-2024","title":"First single-cell foundation models","description":"Geneformer, scGPT, UCE, scFoundation and others pretrain on tens of millions of cells. Benchmarks reveal that perturbation prediction often does not beat linear or mean baselines, forcing better evaluation.","refs":["geneformer","scgpt","universal-cell-embedding","scfoundation","gears"],"status":"current"},{"era":"2025-2026","title":"Data at scale and context-aware models","description":"Tahoe-100M (100M cells, 1,100 drugs, 50 cancer lines), Arc's Virtual Cell Atlas and Challenge, State trained on 100M+ perturbed cells, C2S-Scale's lab-validated hypothesis, CZI's cross-species models. The problem becomes one of held-out generalisation across cell contexts.","refs":["tahoe-100m","arc-virtual-cell-atlas","state-arc","c2s-scale","transcriptformer","nicheformer"],"status":"current"},{"era":"2027-2029","title":"Patient-derived contexts and spatial niches","description":"Models trained on perturbations in patient-derived organoids and spatial data (tumour niches, immune contexts) rather than cell lines alone; coupling with structure models for mechanism; prospective use to rank drug combinations for organoid confirmation.","refs":["organoids","functional-drug-testing","nicheformer","boltz"],"status":"emerging"},{"era":"2030+","title":"Speculative: in silico trials and digital twins","description":"A tumour's multi-omic profile seeds a patient-specific virtual cell population; treatment sequences are simulated before the first cycle; models are updated from ctDNA and imaging during care. Requires validation standards that do not yet exist.","refs":["idea-multimodal-foundation-model","mrd-testing"],"status":"speculative"}],"watch":[]}]