{"id":"tnbc-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","route":"/roadmaps/tnbc-roadmap/","eras":[{"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.","status":"historic","refs":[{"id":"paper-slamon-her2-amplification-science-1987","kind":"paper","name":"Slamon 1987: HER2 gene amplification marks an aggressive form of breast cancer","route":"/key-papers/paper-slamon-her2-amplification-science-1987/","tldr":"Extra copies of the HER2 gene were found in about a quarter to a third of breast cancers and picked out the patients most likely to relapse, the discovery that made HER2 a drug target and a test."},{"id":"paper-asco-cap-er-pr-testing-guideline-jco-2010","kind":"paper","name":"American Society of Clinical Oncology/College Of American Pathologists guideline recommendations for immunohistochemical testing of estrogen and progesterone receptors in breast cancer","route":"/key-papers/paper-asco-cap-er-pr-testing-guideline-jco-2010/","tldr":"The 2010 rule that fixed the line between hormone receptor-positive and negative breast cancer at 1 percent of stained tumour nuclei, after finding that up to a fifth of receptor tests worldwide might be wrong; it is the threshold that defines triple-negative disease."},{"id":"her2","kind":"target","name":"HER2","route":"/targets/her2/","tldr":"A growth-signal receptor. Some cancers make far too much of it, and drugs that block it or use it as a docking site have transformed those cancers."},{"id":"ihc","kind":"term","name":"Immunohistochemistry (IHC)","route":"/terms/ihc/","tldr":"Staining a tissue slice with antibodies so a protein shows up in colour under the microscope."},{"id":"tnbc","kind":"cancer","name":"Triple-negative breast cancer (TNBC)","route":"/cancers/tnbc/","tldr":"A breast cancer that lacks the three receptors (oestrogen, progesterone, HER2) that other breast cancers can be treated through. It was the hardest subtype for decades; since 2020 immunotherapy and ADCs have changed that."}],"trials":[],"papers":[{"id":"paper-slamon-her2-amplification-science-1987","name":"Slamon 1987: HER2 gene amplification marks an aggressive form of breast cancer","route":"/key-papers/paper-slamon-her2-amplification-science-1987/","journal":"Science","year":1987,"whatItMeans":"Every HER2 test, every trastuzumab prescription and the whole HER2-positive breast cancer category trace back to this observation. It is the model for how a genomic marker of bad prognosis became a drug target and then the basis for one of the largest survival gains in solid tumour oncology."},{"id":"paper-asco-cap-er-pr-testing-guideline-jco-2010","name":"American Society of Clinical Oncology/College Of American Pathologists guideline recommendations for immunohistochemical testing of estrogen and progesterone receptors in breast cancer","route":"/key-papers/paper-asco-cap-er-pr-testing-guideline-jco-2010/","journal":"Journal of Clinical Oncology","year":2010,"whatItMeans":"Triple-negative is a laboratory definition; this guideline wrote the oestrogen and progesterone half of it, and the 1 to 10 percent low-positive band it created is still argued over."}]},{"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.","status":"historic","refs":[{"id":"paper-perou-molecular-portraits-breast-tumours-nature-2000","kind":"paper","name":"Molecular portraits of human breast tumours","route":"/key-papers/paper-perou-molecular-portraits-breast-tumours-nature-2000/","tldr":"The 2000 study that read the activity of 8,102 genes in 65 breast tumours and found the tumours fell into distinct groups, one of them the basal-like group that most triple-negative cancers belong to."},{"id":"paper-sorlie-breast-carcinoma-subclasses-pnas-2001","kind":"paper","name":"Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications","route":"/key-papers/paper-sorlie-breast-carcinoma-subclasses-pnas-2001/","tldr":"The 2001 follow-up showing that the gene-expression groups of breast cancer predict how patients fare, with the basal-like group doing worst; it made the subtypes clinical rather than descriptive."},{"id":"paper-sorlie-repeated-observation-subtypes-brca1-basal-pnas-2003","kind":"paper","name":"Repeated observation of breast tumor subtypes in independent gene expression data sets","route":"/key-papers/paper-sorlie-repeated-observation-subtypes-brca1-basal-pnas-2003/","tldr":"The 2003 paper that found the same breast cancer subtypes in other laboratories' data and showed that tumours from women with an inherited BRCA1 fault fall into the basal-like group, linking hereditary and triple-negative disease."},{"id":"paper-foulkes-brca1-basal-phenotype-jnci-2003","kind":"paper","name":"Germline BRCA1 mutations and a basal epithelial phenotype in breast cancer","route":"/key-papers/paper-foulkes-brca1-basal-phenotype-jnci-2003/","tldr":"A 2003 study using an ordinary pathology stain, cytokeratin 5/6, to show that breast cancers in women with an inherited BRCA1 fault are nine times more likely to have the basal pattern; it brought the basal-like idea from the microarray to the pathology bench."},{"id":"charles-perou","kind":"person","name":"Charles M. Perou","route":"/people/charles-perou/","tldr":"Defined the molecular subtypes of breast cancer (luminal, HER2-enriched, basal-like) that clinicians now use every day."},{"id":"pam50","kind":"term","name":"PAM50 / intrinsic subtypes","route":"/terms/pam50/","tldr":"A 50-gene test that sorts breast cancers into luminal A, luminal B, HER2-enriched, and basal-like."},{"id":"rna-seq","kind":"technology","name":"RNA sequencing & expression profiling","route":"/technologies/rna-seq/","status":"established","tldr":"Measuring which genes a tumour is actively using, which reveals its subtype and finds gene fusions."},{"id":"brca","kind":"target","name":"BRCA1 / BRCA2 (HRD)","route":"/targets/brca/","tldr":"DNA repair genes. Inheriting a broken copy raises breast and ovarian cancer risk, but tumours that lose them become uniquely vulnerable to PARP inhibitors and platinum."}],"trials":[],"papers":[{"id":"paper-perou-molecular-portraits-breast-tumours-nature-2000","name":"Molecular portraits of human breast tumours","route":"/key-papers/paper-perou-molecular-portraits-breast-tumours-nature-2000/","journal":"Nature","year":2000,"whatItMeans":"The origin of the intrinsic subtypes and of the word basal-like; triple-negative breast cancer is the clinical shadow of this molecular group, though the two overlap imperfectly."},{"id":"paper-sorlie-breast-carcinoma-subclasses-pnas-2001","name":"Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications","route":"/key-papers/paper-sorlie-breast-carcinoma-subclasses-pnas-2001/","journal":"Proceedings of the National Academy of Sciences","year":2001,"whatItMeans":"The first evidence that the basal-like group is not just biologically distinct but clinically dangerous, the observation that triple-negative outcome studies of 2007 confirmed in the clinic."},{"id":"paper-sorlie-repeated-observation-subtypes-brca1-basal-pnas-2003","name":"Repeated observation of breast tumor subtypes in independent gene expression data sets","route":"/key-papers/paper-sorlie-repeated-observation-subtypes-brca1-basal-pnas-2003/","journal":"Proceedings of the National Academy of Sciences","year":2003,"whatItMeans":"The molecular bridge between germline BRCA1 and triple-negative breast cancer; it is why every triple-negative patient under 60 is now offered germline testing and why PARP inhibitors were tried in this disease first."},{"id":"paper-foulkes-brca1-basal-phenotype-jnci-2003","name":"Germline BRCA1 mutations and a basal epithelial phenotype in breast cancer","route":"/key-papers/paper-foulkes-brca1-basal-phenotype-jnci-2003/","journal":"Journal of the National Cancer Institute","year":2003,"whatItMeans":"Confirmed the BRCA1 to basal link with a stain any laboratory could run, which is how the basal-like concept reached clinical pathology and how the Carolina Breast Cancer Study defined its subtypes three years later."}]},{"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.","status":"historic","refs":[{"id":"paper-struewing-brca-founder-mutations-ashkenazi-nejm-1997","kind":"paper","name":"The risk of cancer associated with specific mutations of BRCA1 and BRCA2 among Ashkenazi Jews","route":"/key-papers/paper-struewing-brca-founder-mutations-ashkenazi-nejm-1997/","tldr":"The 1997 study of 5,318 Ashkenazi Jewish volunteers that measured the real-world breast cancer risk of the three founder mutations carried by more than 2 percent of that population: 56 percent by age 70, lower than the 85 percent estimated from high-risk families."},{"id":"paper-gorski-brca1-founder-mutations-poland-ajhg-2000","kind":"paper","name":"Founder mutations in the BRCA1 gene in Polish families with breast-ovarian cancer","route":"/key-papers/paper-gorski-brca1-founder-mutations-poland-ajhg-2000/","tldr":"A 2000 study of 66 Polish families with breast and ovarian cancer in which three BRCA1 mutations accounted for more than four in five of the faults found, showing that a short national test panel could replace full gene sequencing in Poland."},{"id":"paper-atchley-brca-status-triple-negative-jco-2008","kind":"paper","name":"Clinical and pathologic characteristics of patients with BRCA-positive and BRCA-negative breast cancer","route":"/key-papers/paper-atchley-brca-status-triple-negative-jco-2008/","tldr":"A 2008 MD Anderson series showing that 57 percent of breast cancers in BRCA1 carriers were triple-negative against 14 percent in women without a BRCA fault, the clinical number behind the rule that triple-negative diagnosis should prompt a genetic test."},{"id":"paper-asco-hereditary-breast-cancer-guideline-jco-2020","kind":"paper","name":"Management of Hereditary Breast Cancer: American Society of Clinical Oncology, American Society for Radiation Oncology, and Society of Surgical Oncology Guideline","route":"/key-papers/paper-asco-hereditary-breast-cancer-guideline-jco-2020/","tldr":"The 2020 joint US guideline for breast cancer in people who carry an inherited fault in BRCA1, BRCA2 or another risk gene: breast-conserving surgery is allowed, bilateral mastectomy should be discussed, platinum beats taxanes in advanced disease and PARP inhibitors beat single-agent chemotherapy."},{"id":"germline-testing","kind":"technology","name":"Germline (hereditary) testing","route":"/technologies/germline-testing/","status":"standard-of-care","tldr":"A test of the DNA you were born with, to find inherited risk genes such as BRCA or Lynch syndrome."},{"id":"brca","kind":"target","name":"BRCA1 / BRCA2 (HRD)","route":"/targets/brca/","tldr":"DNA repair genes. Inheriting a broken copy raises breast and ovarian cancer risk, but tumours that lose them become uniquely vulnerable to PARP inhibitors and platinum."},{"id":"mary-claire-king","kind":"person","name":"Mary-Claire King","route":"/people/mary-claire-king/","tldr":"In 1990 she showed that a single gene on chromosome 17, BRCA1, causes inherited breast and ovarian cancer, when most of the field doubted such a gene existed. Genetic testing and risk-reducing care followed."},{"id":"b-hereditary-risk","kind":"bottleneck","name":"Inherited risk is mostly unidentified","route":"/bottlenecks/b-hereditary-risk/","tldr":"Most people who carry a high-risk cancer gene do not know it until they or a relative gets cancer."},{"id":"idea-tnbc-uk-trial-access-and-germline-testing-audit","kind":"idea","name":"A UK audit of trial access and germline testing uptake in triple-negative breast cancer","route":"/ideas/idea-tnbc-uk-trial-access-and-germline-testing-audit/","tldr":"Every triple-negative patient under 60 in the UK should be offered a BRCA test at diagnosis because the result now changes treatment, and many should be offered a trial, but no one publishes how many are. A national audit through existing cancer registration and genomic laboratory data would show the gap by region before anyone tries to close it."}],"trials":[],"papers":[{"id":"paper-struewing-brca-founder-mutations-ashkenazi-nejm-1997","name":"The risk of cancer associated with specific mutations of BRCA1 and BRCA2 among Ashkenazi Jews","route":"/key-papers/paper-struewing-brca-founder-mutations-ashkenazi-nejm-1997/","journal":"New England Journal of Medicine","year":1997,"whatItMeans":"Founder mutations make population-level testing feasible because a three-variant panel finds most carriers; the BRCA1 founder variants in particular predispose to basal-like, triple-negative tumours, so ancestry shapes who gets this disease and who is eligible for PARP inhibitors."},{"id":"paper-gorski-brca1-founder-mutations-poland-ajhg-2000","name":"Founder mutations in the BRCA1 gene in Polish families with breast-ovarian cancer","route":"/key-papers/paper-gorski-brca1-founder-mutations-poland-ajhg-2000/","journal":"American Journal of Human Genetics","year":2000,"whatItMeans":"The basis of Poland's founder-mutation testing programme, and an example of how the geography of BRCA1 variants shapes the geography of hereditary triple-negative breast cancer; 5382insC is shared with the Ashkenazi founder set."},{"id":"paper-atchley-brca-status-triple-negative-jco-2008","name":"Clinical and pathologic characteristics of patients with BRCA-positive and BRCA-negative breast cancer","route":"/key-papers/paper-atchley-brca-status-triple-negative-jco-2008/","journal":"Journal of Clinical Oncology","year":2008,"whatItMeans":"Turned the laboratory link between BRCA1 and basal-like biology into a clinical rule: a triple-negative diagnosis is itself a reason to offer germline testing, now embedded in NICE, NCCN and ESMO criteria."},{"id":"paper-asco-hereditary-breast-cancer-guideline-jco-2020","name":"Management of Hereditary Breast Cancer: American Society of Clinical Oncology, American Society for Radiation Oncology, and Society of Surgical Oncology Guideline","route":"/key-papers/paper-asco-hereditary-breast-cancer-guideline-jco-2020/","journal":"Journal of Clinical Oncology","year":2020,"whatItMeans":"Sets the surgical and systemic rules for the one in nine to one in six triple-negative patients who carry a germline BRCA variant (11 to 17 percent by cohort); the adjuvant gap it named was filled by OlympiA the following year."}]},{"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.","status":"historic","refs":[{"id":"paper-dent-tnbc-clinical-features-recurrence-ccr-2007","kind":"paper","name":"Triple-negative breast cancer: clinical features and patterns of recurrence","route":"/key-papers/paper-dent-tnbc-clinical-features-recurrence-ccr-2007/","tldr":"The 2007 Toronto study that gave triple-negative breast cancer its clinical portrait: 11 percent of cases, a risk of distant relapse 2.6 times higher than other breast cancers, a peak at three years and then a fall, so that women who reach five years without relapse are largely safe."},{"id":"paper-bauer-triple-negative-california-registry-cancer-2007","kind":"paper","name":"Descriptive analysis of estrogen receptor (ER)-negative, progesterone receptor (PR)-negative, and HER2-negative invasive breast cancer, the so-called triple-negative phenotype: a population-based study from the California cancer Registry","route":"/key-papers/paper-bauer-triple-negative-california-registry-cancer-2007/","tldr":"The 2007 population study of 6,370 Californian women that fixed the demographics of triple-negative breast cancer: younger, more often Black or Hispanic, poorer, diagnosed later and with worse survival at every stage; Black women with late-stage disease had 14 percent five-year survival."},{"id":"paper-carey-race-breast-cancer-subtypes-cbcs-jama-2006","kind":"paper","name":"Race, breast cancer subtypes, and survival in the Carolina Breast Cancer Study","route":"/key-papers/paper-carey-race-breast-cancer-subtypes-cbcs-jama-2006/","tldr":"The 2006 North Carolina study that found the basal-like subtype in 39 percent of breast cancers in premenopausal African American women against 16 percent in other women, offering a biological reason for the worse survival of young Black women with breast cancer."},{"id":"paper-lin-tnbc-cns-metastases-dfci-cancer-2008","kind":"paper","name":"Sites of distant recurrence and clinical outcomes in patients with metastatic triple-negative breast cancer: high incidence of central nervous system metastases","route":"/key-papers/paper-lin-tnbc-cns-metastases-dfci-cancer-2008/","tldr":"A 2008 Dana-Farber series of 116 women with metastatic triple-negative breast cancer in which 46 percent developed brain metastases before death, median survival after spread was 13.3 months and after a brain diagnosis 4.9 months."},{"id":"paper-howlader-us-incidence-breast-subtypes-jnci-2014","kind":"paper","name":"US incidence of breast cancer subtypes defined by joint hormone receptor and HER2 status","route":"/key-papers/paper-howlader-us-incidence-breast-subtypes-jnci-2014/","tldr":"The first US national count of breast cancer by receptor subtype, from 2010 when cancer registries began recording HER2: 12.2 percent of cases were triple-negative, and Black women had the highest rate of that subtype."},{"id":"paper-scott-tnbc-disparities-uscs-cancer-2019","kind":"paper","name":"Update on triple-negative breast cancer disparities for the United States: A population-based study from the United States Cancer Statistics database, 2010 through 2014","route":"/key-papers/paper-scott-tnbc-disparities-uscs-cancer-2019/","tldr":"A count of 1.15 million US breast cancers from 2010 to 2014 in which Black women had 2.27 times the odds of a triple-negative diagnosis and women under 40 nearly twice the odds, confirming the disparity at national scale."},{"id":"paper-copson-posh-ethnicity-young-breast-cancer-uk-bjc-2014","kind":"paper","name":"Ethnicity and outcome of young breast cancer patients in the United Kingdom: the POSH study","route":"/key-papers/paper-copson-posh-ethnicity-young-breast-cancer-uk-bjc-2014/","tldr":"The UK cohort of 2,915 women diagnosed with breast cancer at 40 or younger in which Black women had more triple-negative tumours (26 versus 19 percent) and worse survival despite the same access to care and the same use of chemotherapy."},{"id":"rebecca-dent","kind":"person","name":"Rebecca Dent","route":"/people/rebecca-dent/","tldr":"Breast medical oncologist and Deputy CEO for clinical operations at the National Cancer Centre Singapore, an international leader in triple-negative breast cancer trials."},{"id":"nancy-lin","kind":"person","name":"Nancy U. Lin","route":"/people/nancy-lin/","tldr":"Nancy Lin is the leading authority on brain metastases from breast cancer, including the HER2CLIMB tucatinib data in patients with active brain disease."},{"id":"brain-metastases","kind":"term","name":"Brain metastases (intracranial disease)","route":"/terms/brain-metastases/","tldr":"Tumour deposits that have travelled to the brain from a cancer elsewhere, ten times more common than cancers that start in the brain, mostly from lung, breast, melanoma and kidney cancer. Because the blood-brain barrier excludes most drugs, whether a medicine reaches and shrinks them now decides which drug is chosen, and trials report intracranial progression separately."},{"id":"b-trial-diversity","kind":"bottleneck","name":"Trials do not represent the people who get cancer","route":"/bottlenecks/b-trial-diversity/","tldr":"Older, Black, Hispanic, Asian, rural, poor and multimorbid patients are under-represented, so results may not apply to them."},{"id":"idea-tnbc-disparities-in-access-and-outcomes","kind":"idea","name":"Close the gap between who gets triple-negative breast cancer and who is in its trials","route":"/ideas/idea-tnbc-disparities-in-access-and-outcomes/","tldr":"Black women in the United States have about twice the odds of a triple-negative diagnosis and, in the UK POSH cohort, worse survival than White women despite equal chemotherapy use. The pivotal trials enrolled few of them. Enrolment targets tied to incidence, reported by ethnicity in every primary paper, would make the evidence match the disease."},{"id":"idea-tnbc-brain-metastasis-trials","kind":"idea","name":"Trials that include, and report, brain metastases in triple-negative breast cancer","route":"/ideas/idea-tnbc-brain-metastasis-trials/","tldr":"Nearly half of women with metastatic triple-negative breast cancer develop brain metastases and survive under five months after the diagnosis, yet the trials that set the standard mostly exclude active brain disease. Requiring a brain metastasis cohort in every phase 3, with intracranial response as an endpoint, would answer whether the new drugs reach the brain."}],"trials":[],"papers":[{"id":"paper-dent-tnbc-clinical-features-recurrence-ccr-2007","name":"Triple-negative breast cancer: clinical features and patterns of recurrence","route":"/key-papers/paper-dent-tnbc-clinical-features-recurrence-ccr-2007/","journal":"Clinical Cancer Research","year":2007,"whatItMeans":"Explains why triple-negative trials can use three-year event-free survival, why follow-up is front-loaded, and why survivors past five years are told their risk has largely passed."},{"id":"paper-bauer-triple-negative-california-registry-cancer-2007","name":"Descriptive analysis of estrogen receptor (ER)-negative, progesterone receptor (PR)-negative, and HER2-negative invasive breast cancer, the so-called triple-negative phenotype: a population-based study from the California cancer Registry","route":"/key-papers/paper-bauer-triple-negative-california-registry-cancer-2007/","journal":"Cancer","year":2007,"whatItMeans":"The first registry-scale description of the disparity that every later triple-negative disparity paper confirms; the phrase so-called triple-negative phenotype in the title marks the moment the term entered population science."},{"id":"paper-carey-race-breast-cancer-subtypes-cbcs-jama-2006","name":"Race, breast cancer subtypes, and survival in the Carolina Breast Cancer Study","route":"/key-papers/paper-carey-race-breast-cancer-subtypes-cbcs-jama-2006/","journal":"JAMA","year":2006,"whatItMeans":"The paper that made race a biological as well as a social variable in triple-negative breast cancer, and the reason the US disparity is described as roughly twice the incidence in Black women; the UK POSH study later found a smaller but real excess."},{"id":"paper-lin-tnbc-cns-metastases-dfci-cancer-2008","name":"Sites of distant recurrence and clinical outcomes in patients with metastatic triple-negative breast cancer: high incidence of central nervous system metastases","route":"/key-papers/paper-lin-tnbc-cns-metastases-dfci-cancer-2008/","journal":"Cancer","year":2008,"whatItMeans":"The 13.3-month median is the pre-immunotherapy, pre-antibody-drug conjugate benchmark against which first-line trials now reporting medians near two years are measured; the brain metastasis rate is why trials that exclude active brain disease leave the question unanswered."},{"id":"paper-howlader-us-incidence-breast-subtypes-jnci-2014","name":"US incidence of breast cancer subtypes defined by joint hormone receptor and HER2 status","route":"/key-papers/paper-howlader-us-incidence-breast-subtypes-jnci-2014/","journal":"Journal of the National Cancer Institute","year":2014,"whatItMeans":"The denominator for US triple-negative disparity statistics and the origin of the 10 to 15 percent figure quoted for the subtype's share of breast cancer."},{"id":"paper-scott-tnbc-disparities-uscs-cancer-2019","name":"Update on triple-negative breast cancer disparities for the United States: A population-based study from the United States Cancer Statistics database, 2010 through 2014","route":"/key-papers/paper-scott-tnbc-disparities-uscs-cancer-2019/","journal":"Cancer","year":2019,"whatItMeans":"The most recent national figure behind the statement that Black women in the United States have about twice the incidence of triple-negative breast cancer; trial enrolment has not matched it."},{"id":"paper-copson-posh-ethnicity-young-breast-cancer-uk-bjc-2014","name":"Ethnicity and outcome of young breast cancer patients in the United Kingdom: the POSH study","route":"/key-papers/paper-copson-posh-ethnicity-young-breast-cancer-uk-bjc-2014/","journal":"British Journal of Cancer","year":2014,"whatItMeans":"The UK's own evidence that the disparity is not only American and not only about access: within the NHS, with equal chemotherapy use, young Black women had more triple-negative disease and worse survival. It anchors the disparities idea on the triple-negative page and the UK and NHS page."}]},{"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.","status":"historic","refs":[{"id":"paper-ebctcg-polychemotherapy-regimens-meta-analysis-lancet-2012","kind":"paper","name":"Comparisons between different polychemotherapy regimens for early breast cancer: meta-analyses of long-term outcome among 100,000 women in 123 randomised trials","route":"/key-papers/paper-ebctcg-polychemotherapy-regimens-meta-analysis-lancet-2012/","tldr":"The Oxford overview of 123 trials and 100,000 women showing that anthracycline and taxane chemotherapy cuts breast cancer deaths by about a third, largely regardless of age, nodes, size, grade or hormone receptor status; it is the foundation triple-negative chemotherapy rests on."},{"id":"paper-liedtke-neoadjuvant-response-survival-tnbc-jco-2008","kind":"paper","name":"Response to neoadjuvant therapy and long-term survival in patients with triple-negative breast cancer","route":"/key-papers/paper-liedtke-neoadjuvant-response-survival-tnbc-jco-2008/","tldr":"The 2008 MD Anderson series of 1,118 women that defined the triple-negative paradox: these tumours disappear completely with pre-surgery chemotherapy twice as often as other breast cancers, yet survival is worse, because the women left with residual disease relapse early and often."},{"id":"paper-symmans-j-clin-oncol","kind":"paper","name":"Measurement of residual breast cancer burden to predict survival after neoadjuvant chemotherapy","route":"/key-papers/paper-symmans-j-clin-oncol/","tldr":"Paper cited by one term page, indexed on Europe PMC as PubMed record 17785706 and published in Journal of Clinical Oncology; the citing page links this DOI, which is how the record was matched."},{"id":"paper-symmans-rcb-long-term-prognosis-subtype-jco-2017","kind":"paper","name":"Long-Term Prognostic Risk After Neoadjuvant Chemotherapy Associated With Residual Cancer Burden and Breast Cancer Subtype","route":"/key-papers/paper-symmans-rcb-long-term-prognosis-subtype-jco-2017/","tldr":"The 2017 validation of the residual cancer burden score, which graded how much triple-negative tumour is left after pre-surgery chemotherapy and found ten-year relapse-free survival of 86 percent with no residual tumour, 81 percent with minimal, 55 percent with moderate and 23 percent with extensive residual disease."},{"id":"paper-yau-rcb-pooled-analysis-5161-lancet-oncol-2022","kind":"paper","name":"Residual cancer burden after neoadjuvant chemotherapy and long-term survival outcomes in breast cancer: a multicentre pooled analysis of 5161 patients","route":"/key-papers/paper-yau-rcb-pooled-analysis-5161-lancet-oncol-2022/","tldr":"A pooled analysis of 5,161 patients from 12 European and US institutions and trials confirming that the residual cancer burden score predicts relapse in every breast cancer subtype, and proposing it become part of standard pathology reporting after pre-surgery chemotherapy."},{"id":"paper-cortazar-ctneobc-pcr-pooled-analysis-lancet-2014","kind":"paper","name":"Pathological complete response and long-term clinical benefit in breast cancer: the CTNeoBC pooled analysis","route":"/key-papers/paper-cortazar-ctneobc-pcr-pooled-analysis-lancet-2014/","tldr":"The US regulator's pooled analysis of 11,955 patients in 12 trials that found complete disappearance of the tumour before surgery predicts survival most strongly in triple-negative disease, but that a trial raising the complete response rate does not reliably improve survival."},{"id":"paper-asco-neoadjuvant-therapy-breast-guideline-jco-2021","kind":"paper","name":"Neoadjuvant Chemotherapy, Endocrine Therapy, and Targeted Therapy for Breast Cancer: ASCO Guideline","route":"/key-papers/paper-asco-neoadjuvant-therapy-breast-guideline-jco-2021/","tldr":"The US oncology society's 2021 rules for treatment before surgery: triple-negative tumours of 1 cm or more, or with involved nodes, should get anthracycline and taxane chemotherapy, carboplatin may be added, and at that date the evidence for adding immunotherapy was judged insufficient."},{"id":"anthracycline","kind":"term","name":"Anthracyclines (doxorubicin, epirubicin)","route":"/terms/anthracycline/","tldr":"A family of red chemotherapy drugs derived from a soil bacterium that damage cancer DNA. Cornerstones of breast cancer, lymphoma, leukaemia and sarcoma treatment, but they weaken the heart in a dose-dependent way, so there is a lifetime limit."},{"id":"taxane","kind":"term","name":"Taxanes (paclitaxel, docetaxel, nab-paclitaxel)","route":"/terms/taxane/","tldr":"Chemotherapy drugs originally from the yew tree that freeze the cell's internal scaffolding (microtubules) so it cannot divide. Used in breast, lung, ovarian, prostate, gastric and head and neck cancers; their main lasting side effect is nerve damage in the hands and feet."},{"id":"pcr","kind":"term","name":"Pathologic complete response (pCR)","route":"/terms/pcr/","tldr":"No invasive cancer left in the breast and lymph nodes when the surgeon removes the tissue after pre-surgery treatment."},{"id":"rcb","kind":"term","name":"Residual cancer burden (RCB)","route":"/terms/rcb/","tldr":"A pathology score for how much cancer remains in the breast and lymph nodes after pre-surgery treatment, from 0 (none) to III (a large amount), combining tumour bed size, cellularity and nodal involvement. RCB-II or III after neoadjuvant therapy predicts a high risk of relapse and defines who enters escalation trials."},{"id":"neoadjuvant-adjuvant","kind":"term","name":"Neoadjuvant / adjuvant / perioperative","route":"/terms/neoadjuvant-adjuvant/","tldr":"Neoadjuvant therapy is treatment given before surgery, adjuvant therapy is treatment given after it, and perioperative therapy is both. Neoadjuvant treatment shrinks tumours and shows whether the drug works in the living patient; adjuvant treatment aims to kill microscopic disease left behind."},{"id":"chemotherapy","kind":"section","name":"Chemotherapy","route":"/fronts/chemotherapy/","tldr":"Drugs that kill fast-dividing cells. Still the backbone of many cures, and now the warhead inside smarter drugs."}],"trials":[],"papers":[{"id":"paper-ebctcg-polychemotherapy-regimens-meta-analysis-lancet-2012","name":"Comparisons between different polychemotherapy regimens for early breast cancer: meta-analyses of long-term outcome among 100,000 women in 123 randomised trials","route":"/key-papers/paper-ebctcg-polychemotherapy-regimens-meta-analysis-lancet-2012/","journal":"The Lancet","year":2012,"whatItMeans":"Chemotherapy works in receptor-negative disease at least as well as in receptor-positive disease in proportional terms, and because triple-negative absolute risk is high the absolute gain is large; this is why anthracycline and taxane backbone survived into KEYNOTE-522 and why SCARLET now asks whether the anthracycline can go."},{"id":"paper-liedtke-neoadjuvant-response-survival-tnbc-jco-2008","name":"Response to neoadjuvant therapy and long-term survival in patients with triple-negative breast cancer","route":"/key-papers/paper-liedtke-neoadjuvant-response-survival-tnbc-jco-2008/","journal":"Journal of Clinical Oncology","year":2008,"whatItMeans":"Made pathological complete response the organising endpoint of triple-negative drug development and residual disease its central unsolved problem; every post-neoadjuvant trial from CREATE-X to ASCENT-05 follows from this observation."},{"id":"paper-symmans-j-clin-oncol","name":"Measurement of residual breast cancer burden to predict survival after neoadjuvant chemotherapy","route":"/key-papers/paper-symmans-j-clin-oncol/","journal":"Journal of Clinical Oncology","year":2007,"whatItMeans":"One term page on OnCo cites this paper by its DOI; this record gives the citation a page of its own so a reader can follow it without leaving OnCo. Read the abstract above alongside the citing page listed under Related; the record was created automatically from the Europe PMC entry and its figures have not been checked by hand."},{"id":"paper-symmans-rcb-long-term-prognosis-subtype-jco-2017","name":"Long-Term Prognostic Risk After Neoadjuvant Chemotherapy Associated With Residual Cancer Burden and Breast Cancer Subtype","route":"/key-papers/paper-symmans-rcb-long-term-prognosis-subtype-jco-2017/","journal":"Journal of Clinical Oncology","year":2017,"whatItMeans":"Turned residual disease from yes or no into a graded score; RCB II and III are now the entry criteria for post-neoadjuvant trials (ASCENT-05, TROPION-Breast03) and the population the ctDNA-guided idea targets."},{"id":"paper-yau-rcb-pooled-analysis-5161-lancet-oncol-2022","name":"Residual cancer burden after neoadjuvant chemotherapy and long-term survival outcomes in breast cancer: a multicentre pooled analysis of 5161 patients","route":"/key-papers/paper-yau-rcb-pooled-analysis-5161-lancet-oncol-2022/","journal":"The Lancet Oncology","year":2022,"whatItMeans":"The external validation the 2017 paper asked for; it is why residual cancer burden is reported in UK and European pathology and used as a trial entry criterion rather than an MD Anderson curiosity."},{"id":"paper-cortazar-ctneobc-pcr-pooled-analysis-lancet-2014","name":"Pathological complete response and long-term clinical benefit in breast cancer: the CTNeoBC pooled analysis","route":"/key-papers/paper-cortazar-ctneobc-pcr-pooled-analysis-lancet-2014/","journal":"The Lancet","year":2014,"whatItMeans":"The basis of the US accelerated approval pathway on pathological complete response that KEYNOTE-522 and neoadjuvant trials since have used, together with the warning that a higher response rate in a trial is a promise, not a proof, of longer life."},{"id":"paper-asco-neoadjuvant-therapy-breast-guideline-jco-2021","name":"Neoadjuvant Chemotherapy, Endocrine Therapy, and Targeted Therapy for Breast Cancer: ASCO Guideline","route":"/key-papers/paper-asco-neoadjuvant-therapy-breast-guideline-jco-2021/","journal":"Journal of Clinical Oncology","year":2021,"whatItMeans":"The last major guideline written before KEYNOTE-522 changed the standard; the 2022 rapid update reversed the immunotherapy line within a year."}]},{"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.","status":"historic","refs":[{"id":"paper-lehmann-tnbc-subtypes-jci-2011","kind":"paper","name":"Identification of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapies","route":"/key-papers/paper-lehmann-tnbc-subtypes-jci-2011/","tldr":"The 2011 Vanderbilt analysis of 587 triple-negative tumours that split the disease into six molecular groups, two basal-like, an immune group, two mesenchymal groups and a luminal androgen receptor group, and matched each to cell lines and candidate drugs."},{"id":"paper-lehmann-tnbctype-4-refinement-plos-one-2016","kind":"paper","name":"Refinement of Triple-Negative Breast Cancer Molecular Subtypes: Implications for Neoadjuvant Chemotherapy Selection","route":"/key-papers/paper-lehmann-tnbctype-4-refinement-plos-one-2016/","tldr":"The 2016 revision that cut the six triple-negative subtypes to four after showing the immune and stem-like signals came from surrounding cells, and found that response to standard chemotherapy before surgery ranged from 41 percent in basal-like 1 to 18 percent in basal-like 2."},{"id":"paper-burstein-tnbc-genomic-subtypes-ccr-2015","kind":"paper","name":"Comprehensive genomic analysis identifies novel subtypes and targets of triple-negative breast cancer","route":"/key-papers/paper-burstein-tnbc-genomic-subtypes-ccr-2015/","tldr":"A 2015 Baylor study of 198 triple-negative tumours that found four stable subtypes, luminal androgen receptor, mesenchymal, basal-like immune-suppressed and basal-like immune-activated, with the immune-activated group faring best and the immune-suppressed worst."},{"id":"androgen-receptor","kind":"target","name":"Androgen receptor","route":"/targets/androgen-receptor/","tldr":"The hormone switch that drives prostate cancer, attacked by castration and by pills that block the receptor."},{"id":"emt","kind":"pathway","name":"Epithelial-mesenchymal transition & drug efflux","route":"/pathways/emt/","tldr":"How a cancer cell changes shape to migrate and to shrug off drugs. Transcription factors like ZEB1 and SNAIL loosen the cell, switch on pumps that eject chemotherapy, and hide it from the immune system."},{"id":"ddr","kind":"pathway","name":"DNA damage response & homologous recombination","route":"/pathways/ddr/","tldr":"The DNA damage response is the cell's set of repair crews. Single-strand breaks are patched by PARP; double-strand breaks by BRCA-dependent homologous recombination. Lose one crew and the cell survives; lose both and it dies. That is how PARP inhibitors work."},{"id":"b-tumor-heterogeneity","kind":"bottleneck","name":"Tumour heterogeneity and clonal evolution","route":"/bottlenecks/b-tumor-heterogeneity/","tldr":"Every tumour is a population of genetically distinct clones: in multi-region sequencing of kidney tumours, roughly two thirds of mutations were missing from at least one region. Treatment kills the dominant clones and leaves resistant minor clones to grow back, yet a single diagnostic biopsy is still treated as the whole disease."}],"trials":[],"papers":[{"id":"paper-lehmann-tnbc-subtypes-jci-2011","name":"Identification of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapies","route":"/key-papers/paper-lehmann-tnbc-subtypes-jci-2011/","journal":"Journal of Clinical Investigation","year":2011,"whatItMeans":"The vocabulary used on the triple-negative page (basal-like 1 and 2, mesenchymal, luminal androgen receptor, immunomodulatory) comes from this paper; it made triple-negative breast cancer several diseases with several possible drugs rather than one disease with none."},{"id":"paper-lehmann-tnbctype-4-refinement-plos-one-2016","name":"Refinement of Triple-Negative Breast Cancer Molecular Subtypes: Implications for Neoadjuvant Chemotherapy Selection","route":"/key-papers/paper-lehmann-tnbctype-4-refinement-plos-one-2016/","journal":"PLoS One","year":2016,"whatItMeans":"The first evidence that molecular subtype predicts chemotherapy response in triple-negative disease, and the origin of the observation that the immune signal in these tumours is real and measurable, which tumour-infiltrating lymphocyte scoring later turned into a prognostic tool."},{"id":"paper-burstein-tnbc-genomic-subtypes-ccr-2015","name":"Comprehensive genomic analysis identifies novel subtypes and targets of triple-negative breast cancer","route":"/key-papers/paper-burstein-tnbc-genomic-subtypes-ccr-2015/","journal":"Clinical Cancer Research","year":2015,"whatItMeans":"Independently arrived at the same partition as the refined Lehmann scheme and added the insight that immune activation within basal-like tumours separates longer from shorter survival, the biology immunotherapy would exploit three years later."}]},{"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.","status":"current","refs":[{"id":"geparsixto","kind":"trial","name":"GeparSixto","route":"/trials/geparsixto/","status":"positive","tldr":"GeparSixto showed that adding carboplatin to chemotherapy given before surgery made triple-negative breast tumours disappear completely far more often, and in longer follow-up cut relapses, which put platinum into the standard neoadjuvant regimen for this type."},{"id":"paper-geparsixto-lancet-oncol-2014","kind":"paper","name":"Neoadjuvant carboplatin in patients with triple-negative and HER2-positive early breast cancer (GeparSixto; GBG 66): a randomised phase 2 trial","route":"/key-papers/paper-geparsixto-lancet-oncol-2014/","tldr":"Published report from the GeparSixto trial registered as NCT01426880, in The Lancet Oncology (2014), chosen as the most cited paper whose own text cites the registry id."},{"id":"paper-loibl-geparsixto-survival-hrd-ann-oncol-2018","kind":"paper","name":"Survival analysis of carboplatin added to an anthracycline/taxane-based neoadjuvant chemotherapy and HRD score as predictor of response-final results from GeparSixto","route":"/key-papers/paper-loibl-geparsixto-survival-hrd-ann-oncol-2018/","tldr":"The final GeparSixto report: adding carboplatin before surgery cut relapse in triple-negative disease by 44 percent, and a DNA-repair deficiency score predicted which tumours would disappear, though it did not predict who gained from the platinum."},{"id":"paper-sikov-calgb-40603-carboplatin-bevacizumab-jco-2015","kind":"paper","name":"Impact of the addition of carboplatin and/or bevacizumab to neoadjuvant once-per-week paclitaxel followed by dose-dense doxorubicin and cyclophosphamide on pathologic complete response rates in stage II to III triple-negative breast cancer: CALGB 40603 (Alliance)","route":"/key-papers/paper-sikov-calgb-40603-carboplatin-bevacizumab-jco-2015/","tldr":"The US trial of 443 women that showed adding carboplatin to pre-surgery paclitaxel, doxorubicin and cyclophosphamide raised complete tumour disappearance in breast and nodes from 41 to 54 percent, at the cost of more low blood counts and skipped doses; it and GeparSixto made platinum standard."},{"id":"brightness","kind":"trial","name":"BrighTNess","route":"/trials/brightness/","status":"completed","tldr":"BrighTNess showed that adding the platinum drug carboplatin to standard chemotherapy before surgery makes triple-negative breast tumours vanish completely more often, and later that fewer people relapsed, while the PARP inhibitor veliparib added on top made no difference."},{"id":"paper-brightness-lancet-oncol-2018","kind":"paper","name":"Addition of the PARP inhibitor veliparib plus carboplatin or carboplatin alone to standard neoadjuvant chemotherapy in triple-negative breast cancer (BrighTNess): a randomised, phase 3 trial","route":"/key-papers/paper-brightness-lancet-oncol-2018/","tldr":"Published report from the BrighTNess trial registered as NCT02032277, in The Lancet Oncology (2018), chosen as the most cited paper whose own text cites the registry id."},{"id":"paper-geyer-brightness-4-year-follow-up-ann-oncol-2022","kind":"paper","name":"Long-term efficacy and safety of addition of carboplatin with or without veliparib to standard neoadjuvant chemotherapy in triple-negative breast cancer: 4-year follow-up data from BrighTNess, a randomized phase III trial","route":"/key-papers/paper-geyer-brightness-4-year-follow-up-ann-oncol-2022/","tldr":"The 4.5-year follow-up of BrighTNess showing that adding carboplatin to pre-surgery chemotherapy in 634 women cut relapse or death by about 40 percent without more second cancers, while adding the PARP inhibitor veliparib added nothing."},{"id":"paper-tutt-nat-med","kind":"paper","name":"Carboplatin in BRCA1/2-mutated and triple-negative breast cancer BRCAness subgroups: the TNT Trial","route":"/key-papers/paper-tutt-nat-med/","tldr":"Paper cited by one pairing page, indexed on Europe PMC as PubMed record 29713086 and published in Nature Medicine; the citing page links this DOI, which is how the record was matched."},{"id":"paper-st-gallen-2025-consensus-ann-oncol-2025","kind":"paper","name":"Tailoring treatment to cancer risk and patient preference: the 2025 St Gallen International Breast Cancer Consensus Statement on individualizing therapy for patients with early breast cancer","route":"/key-papers/paper-st-gallen-2025-consensus-ann-oncol-2025/","tldr":"The 2025 international consensus on early breast cancer, which recommends platinum chemotherapy and immunotherapy for triple-negative disease, updated genetic testing guidance and shorter radiotherapy schedules."},{"id":"carboplatin","kind":"drug","name":"Carboplatin","route":"/drugs/carboplatin/","status":"approved","tldr":"Carboplatin is a platinum chemotherapy that crosslinks DNA; it is part of the standard pre-surgery regimen for triple-negative breast cancer."},{"id":"platinum","kind":"technology","name":"Platinum agents","route":"/technologies/platinum/","status":"standard-of-care","tldr":"Platinum agents such as cisplatin and carboplatin work by crosslinking DNA. They are curative in testicular cancer and central to lung, ovarian, bladder, head and neck, and TNBC treatment."},{"id":"hrd","kind":"term","name":"Homologous recombination deficiency (HRD)","route":"/terms/hrd/","tldr":"A tumour that cannot properly repair double-strand DNA breaks, usually because of BRCA or related gene loss."},{"id":"platinum-plus-hrd","kind":"pairing","name":"Platinum chemotherapy in HRD tumours","route":"/pairings/platinum-plus-hrd/","tldr":"DNA-crosslinking chemotherapy is especially effective in tumours that cannot repair double-strand breaks."},{"id":"sibylle-loibl","kind":"person","name":"Sibylle Loibl","route":"/people/sibylle-loibl/","tldr":"Leads the German Breast Group, whose GeparX trials defined neoadjuvant chemotherapy and immunotherapy in breast cancer."},{"id":"gbg","kind":"company","name":"German Breast Group (GBG)","route":"/companies/gbg/","tldr":"The German academic group whose GeparX trials established carboplatin and neoadjuvant strategies in triple-negative breast cancer."}],"trials":[{"id":"geparsixto","name":"GeparSixto","route":"/trials/geparsixto/","outcomes":[{"endpoint":"Pathological complete response (ypT0 ypN0), all patients","primary":true,"unit":"%","arms":[{"name":"Carboplatin added to neoadjuvant therapy","n":295,"value":43.7,"note":"Odds ratio 1.33 (95% CI 0.96 to 1.85)"},{"name":"No carboplatin","n":293,"value":36.9}],"p":"0.107","source":"https://doi.org/10.1016/s1470-2045(14)70160-3"},{"endpoint":"Pathological complete response, triple-negative breast cancer","unit":"%","arms":[{"name":"Carboplatin added to neoadjuvant therapy","n":158,"value":53.2},{"name":"No carboplatin","n":157,"value":36.9}],"p":"0.005","source":"https://doi.org/10.1016/s1470-2045(14)70160-3"},{"endpoint":"Pathological complete response, HER2-positive breast cancer","unit":"%","arms":[{"name":"Carboplatin added to neoadjuvant therapy","n":137,"value":32.8},{"name":"No carboplatin","n":136,"value":36.8}],"p":"0.581","source":"https://doi.org/10.1016/s1470-2045(14)70160-3"},{"endpoint":"Grade 3-4 neutropenia","unit":"%","arms":[{"name":"Carboplatin added to neoadjuvant therapy","n":295,"value":65},{"name":"No carboplatin","n":293,"value":27}],"source":"https://doi.org/10.1016/s1470-2045(14)70160-3"}],"setting":"Early triple-negative and HER2-positive breast cancer: neoadjuvant paclitaxel and non-pegylated liposomal doxorubicin (with bevacizumab in triple-negative and trastuzumab plus lapatinib in HER2-positive disease) with or without carboplatin","enrolled":595,"enrolledBasis":"registry"},{"id":"brightness","name":"BrighTNess","route":"/trials/brightness/","outcomes":[{"endpoint":"Pathological complete response (breast and lymph nodes)","primary":true,"unit":"%","arms":[{"name":"Paclitaxel + carboplatin + veliparib","n":316,"value":53},{"name":"Paclitaxel + carboplatin","n":160,"value":58},{"name":"Paclitaxel alone","n":158,"value":31}],"p":"<0.0001 (veliparib + carboplatin vs paclitaxel alone); 0.36 (vs paclitaxel + carboplatin)","source":"https://doi.org/10.1016/s1470-2045(18)30111-6"}],"setting":"Stage II to III triple-negative breast cancer before surgery: paclitaxel with carboplatin and the PARP inhibitor veliparib, paclitaxel with carboplatin and placebo, or paclitaxel alone, each followed by doxorubicin and cyclophosphamide","enrolled":634,"enrolledBasis":"registry"}],"papers":[{"id":"paper-geparsixto-lancet-oncol-2014","name":"Neoadjuvant carboplatin in patients with triple-negative and HER2-positive early breast cancer (GeparSixto; GBG 66): a randomised phase 2 trial","route":"/key-papers/paper-geparsixto-lancet-oncol-2014/","journal":"The Lancet Oncology","year":2014,"whatItMeans":"This is the paper Europe PMC returns for registry id NCT01426880 with the most citations, so it is the natural first reading for anyone following the GeparSixto trial. Read the abstract above alongside the trial page and the registry entry; the record was linked automatically and its figures have not been checked by hand."},{"id":"paper-loibl-geparsixto-survival-hrd-ann-oncol-2018","name":"Survival analysis of carboplatin added to an anthracycline/taxane-based neoadjuvant chemotherapy and HRD score as predictor of response-final results from GeparSixto","route":"/key-papers/paper-loibl-geparsixto-survival-hrd-ann-oncol-2018/","journal":"Annals of Oncology","year":2018,"whatItMeans":"The survival evidence behind platinum in early triple-negative disease, and the first large demonstration that most triple-negative tumours are DNA-repair deficient whether or not BRCA is mutated, which is why HRD scores have not become a platinum selection test."},{"id":"paper-sikov-calgb-40603-carboplatin-bevacizumab-jco-2015","name":"Impact of the addition of carboplatin and/or bevacizumab to neoadjuvant once-per-week paclitaxel followed by dose-dense doxorubicin and cyclophosphamide on pathologic complete response rates in stage II to III triple-negative breast cancer: CALGB 40603 (Alliance)","route":"/key-papers/paper-sikov-calgb-40603-carboplatin-bevacizumab-jco-2015/","journal":"Journal of Clinical Oncology","year":2015,"whatItMeans":"With GeparSixto, the trial that put carboplatin into the neoadjuvant triple-negative regimen; KEYNOTE-522's chemotherapy backbone is this one plus pembrolizumab. Bevacizumab, the other arm, left the field."},{"id":"paper-brightness-lancet-oncol-2018","name":"Addition of the PARP inhibitor veliparib plus carboplatin or carboplatin alone to standard neoadjuvant chemotherapy in triple-negative breast cancer (BrighTNess): a randomised, phase 3 trial","route":"/key-papers/paper-brightness-lancet-oncol-2018/","journal":"The Lancet Oncology","year":2018,"whatItMeans":"This is the paper Europe PMC returns for registry id NCT02032277 with the most citations, so it is the natural first reading for anyone following the BrighTNess trial. Read the abstract above alongside the trial page and the registry entry; the record was linked automatically and its figures have not been checked by hand."},{"id":"paper-geyer-brightness-4-year-follow-up-ann-oncol-2022","name":"Long-term efficacy and safety of addition of carboplatin with or without veliparib to standard neoadjuvant chemotherapy in triple-negative breast cancer: 4-year follow-up data from BrighTNess, a randomized phase III trial","route":"/key-papers/paper-geyer-brightness-4-year-follow-up-ann-oncol-2022/","journal":"Annals of Oncology","year":2022,"whatItMeans":"The third trial to show carboplatin's benefit persists beyond pathological complete response and the trial that closed the neoadjuvant PARP inhibitor route in unselected triple-negative disease; PARP inhibition survives only in germline BRCA carriers."},{"id":"paper-tutt-nat-med","name":"Carboplatin in BRCA1/2-mutated and triple-negative breast cancer BRCAness subgroups: the TNT Trial","route":"/key-papers/paper-tutt-nat-med/","journal":"Nature Medicine","year":2018,"whatItMeans":"One pairing page on OnCo cites this paper by its DOI; this record gives the citation a page of its own so a reader can follow it without leaving OnCo. Read the abstract above alongside the citing page listed under Related; the record was created automatically from the Europe PMC entry and its figures have not been checked by hand."},{"id":"paper-st-gallen-2025-consensus-ann-oncol-2025","name":"Tailoring treatment to cancer risk and patient preference: the 2025 St Gallen International Breast Cancer Consensus Statement on individualizing therapy for patients with early breast cancer","route":"/key-papers/paper-st-gallen-2025-consensus-ann-oncol-2025/","journal":"Annals of Oncology","year":2025,"whatItMeans":"Platinum and immunotherapy are now consensus for early triple-negative disease; the open votes have moved to who can safely receive less."}]},{"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.","status":"current","refs":[{"id":"paper-create-x-adjuvant-capecitabine-nejm-2017","kind":"paper","name":"Adjuvant Capecitabine for Breast Cancer after Preoperative Chemotherapy","route":"/key-papers/paper-create-x-adjuvant-capecitabine-nejm-2017/","tldr":"The Japanese and Korean trial of 910 women whose tumours had survived pre-surgery chemotherapy, in which six months of capecitabine tablets cut deaths by 41 percent, and by 48 percent in the triple-negative group; the first treatment ever shown to help after residual disease."},{"id":"capecitabine","kind":"drug","name":"Capecitabine","route":"/drugs/capecitabine/","status":"approved","tldr":"Capecitabine (Xeloda) is a tablet form of the chemotherapy fluorouracil. It is a backbone of treatment for bowel cancer and a standard option in advanced breast cancer."},{"id":"rcb","kind":"term","name":"Residual cancer burden (RCB)","route":"/terms/rcb/","tldr":"A pathology score for how much cancer remains in the breast and lymph nodes after pre-surgery treatment, from 0 (none) to III (a large amount), combining tumour bed size, cellularity and nodal involvement. RCB-II or III after neoadjuvant therapy predicts a high risk of relapse and defines who enters escalation trials."},{"id":"neoadjuvant-adjuvant","kind":"term","name":"Neoadjuvant / adjuvant / perioperative","route":"/terms/neoadjuvant-adjuvant/","tldr":"Neoadjuvant therapy is treatment given before surgery, adjuvant therapy is treatment given after it, and perioperative therapy is both. Neoadjuvant treatment shrinks tumours and shows whether the drug works in the living patient; adjuvant treatment aims to kill microscopic disease left behind."},{"id":"paper-esmo-early-breast-cancer-guideline-ann-oncol-2024","kind":"paper","name":"Early breast cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up","route":"/key-papers/paper-esmo-early-breast-cancer-guideline-ann-oncol-2024/","tldr":"The European oncology society's 2024 guideline for breast cancer that has not spread, covering diagnosis, surgery, radiotherapy, drug treatment before and after surgery, and follow-up; the reference standard for European and UK care of early triple-negative disease."},{"id":"idea-tnbc-ctdna-guided-adjuvant-decisions","kind":"idea","name":"ctDNA-guided adjuvant decisions after residual disease: escalate the positive, spare the negative","route":"/ideas/idea-tnbc-ctdna-guided-adjuvant-decisions/","tldr":"After pre-surgery chemotherapy leaves tumour behind, a blood test for tumour DNA triples the risk of distant relapse when positive. The one trial that acted on it found the DNA usually appeared too late. A trial that tests at surgery with a tumour-informed assay, escalates positives to an antibody-drug conjugate and observes negatives has not been run."}],"trials":[],"papers":[{"id":"paper-create-x-adjuvant-capecitabine-nejm-2017","name":"Adjuvant Capecitabine for Breast Cancer after Preoperative Chemotherapy","route":"/key-papers/paper-create-x-adjuvant-capecitabine-nejm-2017/","journal":"New England Journal of Medicine","year":2017,"whatItMeans":"Established that residual disease after neoadjuvant chemotherapy is a treatable state, the principle behind OlympiA and the post-neoadjuvant antibody-drug conjugate trials; capecitabine remains the option for residual triple-negative disease without a BRCA variant in ESMO, NCCN and UK practice."},{"id":"paper-esmo-early-breast-cancer-guideline-ann-oncol-2024","name":"Early breast cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up","route":"/key-papers/paper-esmo-early-breast-cancer-guideline-ann-oncol-2024/","journal":"Annals of Oncology","year":2024,"whatItMeans":"This is the European standard the UK page for triple-negative breast cancer is compared against; NICE guidance covers the same ground with a narrower set of funded drugs."}]},{"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.","status":"current","refs":[{"id":"olympiad","kind":"trial","name":"OlympiAD","route":"/trials/olympiad/","status":"positive","tldr":"OlympiAD was the first trial to show a PARP inhibitor tablet beats chemotherapy in breast cancer, delaying progression by about three months in women with an inherited BRCA mutation and with fewer side effects, though it did not lengthen life overall."},{"id":"paper-olympiad-nejm-2017","kind":"paper","name":"OlympiAD: olaparib versus chemotherapy in metastatic breast cancer with a germline BRCA mutation","route":"/key-papers/paper-olympiad-nejm-2017/","tldr":"In women with metastatic HER2-negative breast cancer and an inherited BRCA mutation, the PARP inhibitor tablet olaparib delayed progression by almost three months compared with chemotherapy and caused fewer severe side effects."},{"id":"embraca","kind":"trial","name":"EMBRACA","route":"/trials/embraca/","status":"positive","tldr":"EMBRACA showed that the PARP inhibitor talazoparib delays progression by about three months compared with chemotherapy in women with an inherited BRCA mutation and advanced breast cancer, with better quality of life but no gain in overall survival."},{"id":"paper-embraca-n-engl-j-med-2018","kind":"paper","name":"Talazoparib in Patients with Advanced Breast Cancer and a Germline BRCA Mutation","route":"/key-papers/paper-embraca-n-engl-j-med-2018/","tldr":"Published report from the EMBRACA trial registered as NCT01945775, in New England Journal of Medicine (2018), chosen as the most cited paper whose own text cites the registry id."},{"id":"olympia","kind":"trial","name":"OlympiA","route":"/trials/olympia/","status":"positive","tldr":"Showed that a year of a PARP inhibitor after standard treatment improves survival in women with inherited BRCA mutations."},{"id":"paper-olympia-nejm-2021","kind":"paper","name":"OlympiA: a year of olaparib after surgery for BRCA-mutated, high-risk early breast cancer","route":"/key-papers/paper-olympia-nejm-2021/","tldr":"In women born with a BRCA1 or BRCA2 mutation whose early breast cancer was high risk, a year of the PARP inhibitor olaparib after standard treatment cut relapses by more than 40% and later improved survival."},{"id":"paper-olympia-overall-survival-ann-oncol-2022","kind":"paper","name":"Overall survival in the OlympiA phase III trial of adjuvant olaparib in patients with germline pathogenic variants in BRCA1/2 and high-risk, early breast cancer","route":"/key-papers/paper-olympia-overall-survival-ann-oncol-2022/","tldr":"The second planned analysis of OlympiA, at 3.5 years, in which a year of olaparib tablets after standard treatment cut deaths by 32 percent in women with an inherited BRCA fault, the first time a PARP inhibitor had lengthened life in early breast cancer."},{"id":"paper-olympia-6-year-update-ann-oncol-2026","kind":"paper","name":"Sustained benefit of adjuvant olaparib in women with germline BRCA1- and BRCA2-associated high-risk HER2-negative early breast cancer: updated results from the OlympiA phase III trial","route":"/key-papers/paper-olympia-6-year-update-ann-oncol-2026/","tldr":"The six-year OlympiA update: the year of olaparib still cut relapse by 35 percent and death by 28 percent, six-year survival was 87.5 versus 83.2 percent, there were fewer new BRCA-related breast and ovarian cancers, and no excess of leukaemia."},{"id":"paper-asco-hereditary-breast-cancer-guideline-jco-2020","kind":"paper","name":"Management of Hereditary Breast Cancer: American Society of Clinical Oncology, American Society for Radiation Oncology, and Society of Surgical Oncology Guideline","route":"/key-papers/paper-asco-hereditary-breast-cancer-guideline-jco-2020/","tldr":"The 2020 joint US guideline for breast cancer in people who carry an inherited fault in BRCA1, BRCA2 or another risk gene: breast-conserving surgery is allowed, bilateral mastectomy should be discussed, platinum beats taxanes in advanced disease and PARP inhibitors beat single-agent chemotherapy."},{"id":"olaparib","kind":"drug","name":"Olaparib","route":"/drugs/olaparib/","status":"approved","tldr":"Olaparib was the first PARP inhibitor, and turned an inherited BRCA mutation from a risk factor into a drug target, including after surgery in breast cancer."},{"id":"talazoparib","kind":"drug","name":"Talazoparib","route":"/drugs/talazoparib/","status":"approved","tldr":"Talazoparib is a PARP inhibitor that traps PARP on DNA about 100 times more strongly than olaparib, which is why it works at a 1 mg daily dose. It is approved for germline BRCA-mutant HER2-negative breast cancer and, with enzalutamide, for HRR-mutant castration-resistant prostate cancer; anaemia is its dominant side effect."},{"id":"parp-inhibitor","kind":"technology","name":"PARP inhibitors","route":"/technologies/parp-inhibitor/","status":"approved","tldr":"Pills that block a DNA repair backup, killing cancer cells that already lost their main repair system (BRCA)."},{"id":"brca","kind":"target","name":"BRCA1 / BRCA2 (HRD)","route":"/targets/brca/","tldr":"DNA repair genes. Inheriting a broken copy raises breast and ovarian cancer risk, but tumours that lose them become uniquely vulnerable to PARP inhibitors and platinum."},{"id":"germline-testing","kind":"technology","name":"Germline (hereditary) testing","route":"/technologies/germline-testing/","status":"standard-of-care","tldr":"A test of the DNA you were born with, to find inherited risk genes such as BRCA or Lynch syndrome."},{"id":"germline-to-parp","kind":"pairing","name":"Germline BRCA test → adjuvant PARP inhibitor","route":"/pairings/germline-to-parp/","tldr":"A blood test for inherited BRCA mutations unlocks a year of olaparib after surgery, which improves survival."},{"id":"judy-garber","kind":"person","name":"Judy E. Garber","route":"/people/judy-garber/","tldr":"A leading authority on inherited cancer risk and how BRCA carriers should be treated and screened."},{"id":"andrew-tutt","kind":"person","name":"Andrew Tutt","route":"/people/andrew-tutt/","tldr":"Led OlympiA, the trial that showed a year of olaparib after surgery improves survival in BRCA-mutated breast cancer."},{"id":"mark-robson","kind":"person","name":"Mark E. Robson","route":"/people/mark-robson/","tldr":"New York breast oncologist and cancer geneticist who led OlympiAD, the trial that made olaparib the first PARP inhibitor approved for BRCA-mutated breast cancer."},{"id":"jennifer-litton","kind":"person","name":"Jennifer K. Litton","route":"/people/jennifer-litton/","tldr":"Jennifer Litton led the EMBRACA trial that brought talazoparib to BRCA-mutated breast cancer."},{"id":"astrazeneca","kind":"company","name":"AstraZeneca","route":"/companies/astrazeneca/","tldr":"AstraZeneca is the most ADC-committed large pharma, co-owner of Enhertu and Datroway, with deep targeted-therapy and radiopharma bets."},{"id":"pfizer","kind":"company","name":"Pfizer (incl. Seagen)","route":"/companies/pfizer/","tldr":"Bought Seagen for $43B to become an ADC leader; also makes Ibrance, Lorbrena, Braftovi, and the first PROTAC."}],"trials":[{"id":"olympiad","name":"OlympiAD","route":"/trials/olympiad/","outcomes":[{"endpoint":"Progression-free survival","primary":true,"unit":"months","arms":[{"name":"Olaparib","n":205,"value":7},{"name":"Chemotherapy","n":97,"value":4.2}],"hr":0.58,"ci":[0.43,0.8],"p":"<0.001","source":"https://doi.org/10.1056/NEJMoa1706450"},{"endpoint":"Overall survival","unit":"months","arms":[{"name":"Olaparib","value":19.3},{"name":"Chemotherapy","value":17.1}],"hr":0.9,"ci":[0.66,1.23],"source":"https://doi.org/10.1093/annonc/mdz012"}],"setting":"Germline BRCA-mutated, HER2-negative metastatic breast cancer after up to two chemotherapy lines: olaparib vs physician's choice chemotherapy","enrolled":302,"enrolledBasis":"registry"},{"id":"embraca","name":"EMBRACA","route":"/trials/embraca/","outcomes":[{"endpoint":"Progression-free survival","primary":true,"unit":"months","arms":[{"name":"Talazoparib","n":287,"value":8.6},{"name":"Chemotherapy","n":144,"value":5.6}],"hr":0.54,"ci":[0.41,0.71],"p":"<0.001","source":"https://doi.org/10.1056/NEJMoa1802905"},{"endpoint":"Overall survival (final)","arms":[{"name":"Talazoparib"},{"name":"Chemotherapy"}],"hr":0.85,"ci":[0.67,1.07],"source":"https://doi.org/10.1016/j.annonc.2020.08.2098"}],"setting":"Germline BRCA-mutated, HER2-negative locally advanced or metastatic breast cancer: talazoparib vs physician's choice chemotherapy","enrolled":431,"enrolledBasis":"registry"},{"id":"olympia","name":"OlympiA","route":"/trials/olympia/","outcomes":[{"endpoint":"Invasive disease-free survival at 3 years","primary":true,"unit":"%","arms":[{"name":"Olaparib","n":921,"value":85.9},{"name":"Placebo","n":915,"value":77.1}],"hr":0.58,"ci":[0.41,0.82],"p":"<0.001","source":"https://www.nejm.org/doi/full/10.1056/NEJMoa2105215"},{"endpoint":"Overall survival at 4 years","unit":"%","arms":[{"name":"Olaparib","value":89.8},{"name":"Placebo","value":86.4}],"hr":0.68,"ci":[0.47,0.97],"p":"0.009","source":"https://www.annalsofoncology.org/article/S0923-7534(22)04165-7/fulltext"},{"endpoint":"Overall survival at 6 years","unit":"%","arms":[{"name":"Olaparib","value":87.5},{"name":"Placebo","value":83.2}],"hr":0.72,"ci":[0.56,0.93],"source":"https://clinicaltrials.gov/study/NCT02032823"}],"setting":"Adjuvant olaparib for one year in germline BRCA-mutated, HER2-negative, high-risk early breast cancer","enrolled":1837,"enrolledBasis":"registry"}],"papers":[{"id":"paper-olympiad-nejm-2017","name":"OlympiAD: olaparib versus chemotherapy in metastatic breast cancer with a germline BRCA mutation","route":"/key-papers/paper-olympiad-nejm-2017/","journal":"New England Journal of Medicine","year":2017,"whatItMeans":"Germline BRCA testing became part of metastatic breast cancer work-up, and olaparib (with talazoparib after EMBRACA) is a standard option, especially for triple-negative disease."},{"id":"paper-embraca-n-engl-j-med-2018","name":"Talazoparib in Patients with Advanced Breast Cancer and a Germline BRCA Mutation","route":"/key-papers/paper-embraca-n-engl-j-med-2018/","journal":"New England Journal of Medicine","year":2018,"whatItMeans":"This is the paper Europe PMC returns for registry id NCT01945775 with the most citations, so it is the natural first reading for anyone following the EMBRACA trial. Read the abstract above alongside the trial page and the registry entry; the record was linked automatically and its figures have not been checked by hand."},{"id":"paper-olympia-nejm-2021","name":"OlympiA: a year of olaparib after surgery for BRCA-mutated, high-risk early breast cancer","route":"/key-papers/paper-olympia-nejm-2021/","journal":"New England Journal of Medicine","year":2021,"whatItMeans":"Everyone with HER2-negative early breast cancer that meets high-risk criteria should be offered germline BRCA testing, because a positive result now changes treatment: a year of olaparib after chemotherapy reduces relapse and death. It does not apply to low-risk tumours, HER2-positive disease, or somatic-only BRCA mutations."},{"id":"paper-olympia-overall-survival-ann-oncol-2022","name":"Overall survival in the OlympiA phase III trial of adjuvant olaparib in patients with germline pathogenic variants in BRCA1/2 and high-risk, early breast cancer","route":"/key-papers/paper-olympia-overall-survival-ann-oncol-2022/","journal":"Annals of Oncology","year":2022,"whatItMeans":"The survival result that moved adjuvant olaparib from a disease-free survival approval to an undisputed standard, and the reason germline testing at diagnosis of triple-negative breast cancer is now a treatment decision rather than a family history exercise."},{"id":"paper-olympia-6-year-update-ann-oncol-2026","name":"Sustained benefit of adjuvant olaparib in women with germline BRCA1- and BRCA2-associated high-risk HER2-negative early breast cancer: updated results from the OlympiA phase III trial","route":"/key-papers/paper-olympia-6-year-update-ann-oncol-2026/","journal":"Annals of Oncology","year":2026,"whatItMeans":"Answers the two questions that hung over adjuvant olaparib, durability and late leukaemia, in its favour; the remaining question is whether carriers who also received pembrolizumab or capecitabine, whom the trial did not study, get the same benefit."},{"id":"paper-asco-hereditary-breast-cancer-guideline-jco-2020","name":"Management of Hereditary Breast Cancer: American Society of Clinical Oncology, American Society for Radiation Oncology, and Society of Surgical Oncology Guideline","route":"/key-papers/paper-asco-hereditary-breast-cancer-guideline-jco-2020/","journal":"Journal of Clinical Oncology","year":2020,"whatItMeans":"Sets the surgical and systemic rules for the one in nine to one in six triple-negative patients who carry a germline BRCA variant (11 to 17 percent by cohort); the adjuvant gap it named was filled by OlympiA the following year."}]},{"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.","status":"current","refs":[{"id":"impassion130","kind":"trial","name":"IMpassion130","route":"/trials/impassion130/","status":"mixed","tldr":"IMpassion130 was the first immunotherapy success in breast cancer, later undermined when a sister trial failed and the approval was withdrawn."},{"id":"paper-impassion130-n-engl-j-med-2018","kind":"paper","name":"Atezolizumab and Nab-Paclitaxel in Advanced Triple-Negative Breast Cancer","route":"/key-papers/paper-impassion130-n-engl-j-med-2018/","tldr":"Published report from the IMpassion130 trial registered as NCT02425891, in New England Journal of Medicine (2018), chosen as the most cited paper whose own text cites the registry id."},{"id":"impassion131","kind":"trial","name":"IMpassion131","route":"/trials/impassion131/","status":"negative","tldr":"IMpassion131 was the sister trial to the first immunotherapy success in breast cancer. It failed, and the approval it was meant to confirm was withdrawn."},{"id":"paper-impassion131-ann-oncol-2021","kind":"paper","name":"Primary results from IMpassion131, a double-blind, placebo-controlled, randomised phase III trial of first-line paclitaxel with or without atezolizumab for unresectable locally advanced/metastatic triple-negative breast cancer","route":"/key-papers/paper-impassion131-ann-oncol-2021/","tldr":"Published report from the IMpassion131 trial registered as NCT03125902, in Annals of Oncology (2021), chosen as the most cited paper whose own text cites the registry id."},{"id":"paper-rugo-pd-l1-assay-comparison-impassion130-jnci-2021","kind":"paper","name":"PD-L1 Immunohistochemistry Assay Comparison in Atezolizumab Plus nab-Paclitaxel-Treated Advanced Triple-Negative Breast Cancer","route":"/key-papers/paper-rugo-pd-l1-assay-comparison-impassion130-jnci-2021/","tldr":"Three different PD-L1 tests run on the same 614 IMpassion130 tumours called 46, 75 and 73 percent of them positive and agreed with each other only about 69 percent of the time; the benefit of atezolizumab was concentrated in the tumours all three called positive."},{"id":"keynote-355","kind":"trial","name":"KEYNOTE-355","route":"/trials/keynote-355/","status":"positive","tldr":"Established immunotherapy plus chemotherapy as first-line treatment for metastatic triple-negative breast cancer with PD-L1 expression."},{"id":"paper-keynote-355-nejm-2022","kind":"paper","name":"KEYNOTE-355: pembrolizumab plus chemotherapy for PD-L1-positive advanced triple-negative breast cancer","route":"/key-papers/paper-keynote-355-nejm-2022/","tldr":"Adding pembrolizumab to first-line chemotherapy lengthened survival by almost seven months in advanced triple-negative breast cancer whose tumours had a PD-L1 combined positive score of 10 or more."},{"id":"keynote-522","kind":"trial","name":"KEYNOTE-522","route":"/trials/keynote-522/","status":"positive","tldr":"The trial that added immunotherapy to pre-surgery chemotherapy for triple-negative breast cancer and, uniquely, improved survival."},{"id":"paper-keynote-522-n-engl-j-med-2020","kind":"paper","name":"Pembrolizumab for Early Triple-Negative Breast Cancer","route":"/key-papers/paper-keynote-522-n-engl-j-med-2020/","tldr":"Published report from the KEYNOTE-522 trial registered as NCT03036488, in New England Journal of Medicine (2020), chosen as the most cited paper whose own text cites the registry id."},{"id":"paper-keynote-522-nejm-2022","kind":"paper","name":"KEYNOTE-522: adding pembrolizumab before and after surgery in early triple-negative breast cancer","route":"/key-papers/paper-keynote-522-nejm-2022/","tldr":"Adding the immunotherapy pembrolizumab to chemotherapy before surgery, then continuing it afterwards, cut the risk of relapse or death by about a third in stage II-III triple-negative breast cancer and later improved survival."},{"id":"paper-keynote-522-n-engl-j-med-2024-update","kind":"paper","name":"Overall Survival with Pembrolizumab in Early-Stage Triple-Negative Breast Cancer","route":"/key-papers/paper-keynote-522-n-engl-j-med-2024-update/","tldr":"Later report from the KEYNOTE-522 trial registered as NCT03036488, in New England Journal of Medicine (2024); its title describes an updated or longer-term analysis."},{"id":"paper-asco-pembrolizumab-early-tnbc-rapid-update-jco-2022","kind":"paper","name":"Use of Immune Checkpoint Inhibitor Pembrolizumab in the Treatment of High-Risk, Early-Stage Triple-Negative Breast Cancer: ASCO Guideline Rapid Recommendation Update","route":"/key-papers/paper-asco-pembrolizumab-early-tnbc-rapid-update-jco-2022/","tldr":"The 2022 fast-track amendment in which the US oncology society added pembrolizumab before and after surgery for high-risk early triple-negative breast cancer, a year after its main guideline had said the evidence was insufficient."},{"id":"paper-leon-ferre-tils-tnbc-no-chemotherapy-jama-2024","kind":"paper","name":"Tumor-Infiltrating Lymphocytes in Triple-Negative Breast Cancer","route":"/key-papers/paper-leon-ferre-tils-tnbc-no-chemotherapy-jama-2024/","tldr":"A pooled study of 1,966 women with early triple-negative breast cancer treated with surgery and radiotherapy but no chemotherapy, in which those whose tumours were half or more immune cells had 94 percent five-year freedom from distant relapse in stage I disease against 78 percent for immune-poor tumours."},{"id":"optimice-pcr","kind":"trial","name":"OptimICE-pCR (A012103)","route":"/trials/optimice-pcr/","status":"recruiting","tldr":"Asks whether patients whose cancer completely disappeared before surgery still need a year of immunotherapy afterwards."},{"id":"pembrolizumab","kind":"drug","name":"Pembrolizumab","route":"/drugs/pembrolizumab/","status":"approved","tldr":"Pembrolizumab is a PD-1 blocking antibody approved in more than 40 settings, from melanoma and lung cancer to the first tumour-agnostic approval for mismatch-repair-deficient tumours in 2017, and before and after surgery in triple-negative breast cancer. A subcutaneous form arrived in 2025, and it is the backbone partner for ADCs and personalised neoantigen vaccines."},{"id":"atezolizumab","kind":"drug","name":"Atezolizumab","route":"/drugs/atezolizumab/","status":"approved","tldr":"A PD-L1 blocker used in lung, liver, and bladder cancer. In 2026 it became the first drug approved based on a blood test showing leftover cancer after bladder surgery."},{"id":"checkpoint-inhibitor","kind":"technology","name":"Immune checkpoint inhibitors","route":"/technologies/checkpoint-inhibitor/","status":"standard-of-care","tldr":"Immune checkpoint inhibitors are antibodies against CTLA-4, PD-1 or PD-L1 that release the brakes on T cells so they attack the cancer. They are approved in more than 20 tumour types and produce lasting, sometimes curative responses that chemotherapy rarely does, but most patients do not respond and autoimmune side effects are the cost."},{"id":"cps","kind":"term","name":"Combined positive score (CPS)","route":"/terms/cps/","tldr":"A PD-L1 score that counts stained tumour cells and immune cells together."},{"id":"tils","kind":"term","name":"Tumour-infiltrating lymphocytes (TILs)","route":"/terms/tils/","tldr":"Immune cells that have got inside the tumour. More of them means better outcomes in triple-negative breast cancer."},{"id":"pdl1","kind":"target","name":"PD-L1","route":"/targets/pdl1/","tldr":"PD-L1 is the tumour's side of the PD-1 brake, and also the biomarker that decides who gets immunotherapy."},{"id":"peter-schmid","kind":"person","name":"Peter Schmid","route":"/people/peter-schmid/","tldr":"Led KEYNOTE-522 and IMpassion130, the trials that brought immunotherapy into triple-negative breast cancer."},{"id":"javier-cortes","kind":"person","name":"Javier Cortés","route":"/people/javier-cortes/","tldr":"Breast oncologist who led DESTINY-Breast03 and DESTINY-Breast09, the trials that made Enhertu the HER2-positive standard."},{"id":"hope-rugo","kind":"person","name":"Hope S. Rugo","route":"/people/hope-rugo/","tldr":"Breast oncologist who led key ADC and CDK4/6 trials and moved from UCSF to City of Hope in 2024."},{"id":"merck","kind":"company","name":"Merck & Co. (MSD)","route":"/companies/merck/","tldr":"Merck & Co. (MSD) makes Keytruda, the world's best-selling cancer drug, and is now building the next act around TROP2 ADCs and personalised vaccines."},{"id":"roche-genentech","kind":"company","name":"Roche / Genentech","route":"/companies/roche-genentech/","tldr":"Creator of Herceptin, Avastin, and Rituxan, and owner of Foundation Medicine; the company that defined antibody oncology."},{"id":"immunotherapy","kind":"section","name":"Immunotherapy","route":"/fronts/immunotherapy/","tldr":"Immunotherapy helps the patient's own immune system recognise and destroy the cancer."},{"id":"idea-tnbc-pd-l1-assay-harmonisation","kind":"idea","name":"Harmonise PD-L1 testing for triple-negative breast cancer around one scored assay, with external quality assurance","route":"/ideas/idea-tnbc-pd-l1-assay-harmonisation/","tldr":"Three PD-L1 tests run on the same tumours called 46, 75 and 73 percent of them positive and agreed only 69 percent of the time. With atezolizumab withdrawn, pembrolizumab's test (22C3, combined positive score of 10) is the only one that matters, yet laboratories still run whichever kit they have. One assay, one score and a proficiency scheme would end answers that vary by postcode."},{"id":"idea-tnbc-de-escalation-for-exceptional-responders","kind":"idea","name":"Give exceptional responders less: pembrolizumab omission after complete response, anthracycline-free regimens and chemotherapy omission in lymphocyte-rich stage I disease","route":"/ideas/idea-tnbc-de-escalation-for-exceptional-responders/","tldr":"Two thirds of women treated on the KEYNOTE-522 regimen have no tumour left at surgery and about 92 percent of them are alive without relapse at five years, yet all receive nine more cycles of pembrolizumab. Trials are now testing whether the best responders can stop early, skip the anthracycline, or in lymphocyte-rich stage I tumours skip chemotherapy altogether."}],"trials":[{"id":"impassion130","name":"IMpassion130","route":"/trials/impassion130/","outcomes":[{"endpoint":"Progression-free survival, PD-L1+ (SP142 IC ≥1%)","primary":true,"unit":"months","arms":[{"name":"Atezolizumab + nab-paclitaxel","n":185,"value":7.5},{"name":"Placebo + nab-paclitaxel","n":184,"value":5}],"hr":0.62,"ci":[0.49,0.78],"p":"<0.001","source":"https://www.nejm.org/doi/full/10.1056/NEJMoa1809615"},{"endpoint":"Overall survival, PD-L1+","unit":"months","arms":[{"name":"Atezolizumab + nab-paclitaxel","value":25.4,"note":"Not formally tested under the hierarchical design"},{"name":"Placebo + nab-paclitaxel","value":17.9}],"hr":0.67,"ci":[0.53,0.86],"source":"https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(19)30689-8/fulltext"},{"endpoint":"Overall survival, ITT","unit":"months","arms":[{"name":"Atezolizumab + nab-paclitaxel","value":21,"note":"Not significant"},{"name":"Placebo + nab-paclitaxel","value":18.7}],"hr":0.87,"ci":[0.75,1.02],"source":"https://doi.org/10.1056/NEJMoa1809615"}],"setting":"First-line metastatic TNBC: atezolizumab + nab-paclitaxel","enrolled":902,"enrolledBasis":"registry"},{"id":"impassion131","name":"IMpassion131","route":"/trials/impassion131/","outcomes":[{"endpoint":"Progression-free survival, PD-L1+ (investigator)","primary":true,"unit":"months","arms":[{"name":"Atezolizumab + paclitaxel","n":191,"value":6,"note":"Not significant"},{"name":"Placebo + paclitaxel","n":101,"value":5.7}],"hr":0.82,"ci":[0.6,1.12],"p":"0.20","source":"https://www.annalsofoncology.org/article/S0923-7534(21)02012-3/fulltext"},{"endpoint":"Overall survival, PD-L1+","unit":"months","arms":[{"name":"Atezolizumab + paclitaxel","value":22.1,"note":"Numerically unfavourable"},{"name":"Placebo + paclitaxel","value":28.3}],"hr":1.11,"ci":[0.76,1.64],"source":"https://www.annalsofoncology.org/article/S0923-7534(21)02012-3/fulltext"}],"setting":"First-line metastatic TNBC: atezolizumab + paclitaxel vs paclitaxel","enrolled":653,"enrolledBasis":"registry"},{"id":"keynote-355","name":"KEYNOTE-355","route":"/trials/keynote-355/","outcomes":[{"endpoint":"Overall survival, PD-L1 CPS ≥10","primary":true,"unit":"months","arms":[{"name":"Pembrolizumab + chemotherapy","n":220,"value":23},{"name":"Placebo + chemotherapy","n":103,"value":16.1}],"hr":0.73,"ci":[0.55,0.95],"p":"0.0185","source":"https://www.nejm.org/doi/full/10.1056/NEJMoa2202809"},{"endpoint":"Progression-free survival, PD-L1 CPS ≥10","primary":true,"unit":"months","arms":[{"name":"Pembrolizumab + chemotherapy","value":9.7},{"name":"Placebo + chemotherapy","value":5.6}],"hr":0.66,"ci":[0.5,0.88],"source":"https://www.nejm.org/doi/full/10.1056/NEJMoa2202809"},{"endpoint":"Overall survival, CPS ≥1","unit":"months","arms":[{"name":"Pembrolizumab + chemotherapy","value":17.6,"note":"Not significant"},{"name":"Placebo + chemotherapy","value":16}],"hr":0.86,"ci":[0.72,1.04],"source":"https://www.nejm.org/doi/full/10.1056/NEJMoa2202809"}],"setting":"First-line metastatic TNBC: pembrolizumab + chemotherapy vs chemotherapy","enrolled":882,"enrolledBasis":"registry"},{"id":"keynote-522","name":"KEYNOTE-522","route":"/trials/keynote-522/","outcomes":[{"endpoint":"Pathologic complete response (ypT0/Tis ypN0)","primary":true,"unit":"%","arms":[{"name":"Pembrolizumab + chemotherapy","n":401,"value":64.8},{"name":"Placebo + chemotherapy","n":201,"value":51.2}],"p":"0.00055","source":"https://www.nejm.org/doi/full/10.1056/NEJMoa1910549"},{"endpoint":"Event-free survival at 5 years","primary":true,"unit":"%","arms":[{"name":"Pembrolizumab + chemotherapy","n":784,"value":81.2},{"name":"Placebo + chemotherapy","n":390,"value":72.2}],"hr":0.65,"ci":[0.51,0.83],"source":"https://www.nejm.org/doi/full/10.1056/NEJMoa2409932"},{"endpoint":"Overall survival at 5 years","unit":"%","arms":[{"name":"Pembrolizumab + chemotherapy","value":86.6},{"name":"Placebo + chemotherapy","value":81.7}],"hr":0.66,"ci":[0.5,0.87],"p":"0.002","source":"https://www.nejm.org/doi/full/10.1056/NEJMoa2409932"},{"endpoint":"Event-free survival at 7 years","unit":"%","arms":[{"name":"Pembrolizumab + chemotherapy","value":78.3},{"name":"Placebo + chemotherapy","value":69.8}],"source":"https://www.lbbc.org/news/pivotal-progress-in-tnbc-asco-2026"},{"endpoint":"Overall survival at 7 years","unit":"%","arms":[{"name":"Pembrolizumab + chemotherapy","value":85.1},{"name":"Placebo + chemotherapy","value":77.2}],"source":"https://www.lbbc.org/news/pivotal-progress-in-tnbc-asco-2026"}],"setting":"Early-stage (II-III) TNBC: pembrolizumab + chemotherapy before surgery, pembrolizumab after","enrolled":1174,"enrolledBasis":"registry"}],"papers":[{"id":"paper-impassion130-n-engl-j-med-2018","name":"Atezolizumab and Nab-Paclitaxel in Advanced Triple-Negative Breast Cancer","route":"/key-papers/paper-impassion130-n-engl-j-med-2018/","journal":"New England Journal of Medicine","year":2018,"whatItMeans":"This is the paper Europe PMC returns for registry id NCT02425891 with the most citations, so it is the natural first reading for anyone following the IMpassion130 trial. Read the abstract above alongside the trial page and the registry entry; the record was linked automatically and its figures have not been checked by hand."},{"id":"paper-impassion131-ann-oncol-2021","name":"Primary results from IMpassion131, a double-blind, placebo-controlled, randomised phase III trial of first-line paclitaxel with or without atezolizumab for unresectable locally advanced/metastatic triple-negative breast cancer","route":"/key-papers/paper-impassion131-ann-oncol-2021/","journal":"Annals of Oncology","year":2021,"whatItMeans":"This is the paper Europe PMC returns for registry id NCT03125902 with the most citations, so it is the natural first reading for anyone following the IMpassion131 trial. Read the abstract above alongside the trial page and the registry entry; the record was linked automatically and its figures have not been checked by hand."},{"id":"paper-rugo-pd-l1-assay-comparison-impassion130-jnci-2021","name":"PD-L1 Immunohistochemistry Assay Comparison in Atezolizumab Plus nab-Paclitaxel-Treated Advanced Triple-Negative Breast Cancer","route":"/key-papers/paper-rugo-pd-l1-assay-comparison-impassion130-jnci-2021/","journal":"Journal of the National Cancer Institute","year":2021,"whatItMeans":"The clearest demonstration that PD-L1 positive in triple-negative breast cancer means different things depending on the kit; with atezolizumab withdrawn, pembrolizumab's 22C3 combined positive score of 10 is the surviving standard, and roughly a quarter of patients get a different answer depending on which assay their laboratory runs."},{"id":"paper-keynote-355-nejm-2022","name":"KEYNOTE-355: pembrolizumab plus chemotherapy for PD-L1-positive advanced triple-negative breast cancer","route":"/key-papers/paper-keynote-355-nejm-2022/","journal":"New England Journal of Medicine","year":2022,"whatItMeans":"PD-L1 testing with the combined positive score decides first-line treatment in metastatic triple-negative breast cancer; pembrolizumab-chemotherapy is the standard for scores of 10 or more."},{"id":"paper-keynote-522-n-engl-j-med-2020","name":"Pembrolizumab for Early Triple-Negative Breast Cancer","route":"/key-papers/paper-keynote-522-n-engl-j-med-2020/","journal":"New England Journal of Medicine","year":2020,"whatItMeans":"This is the paper Europe PMC returns for registry id NCT03036488 with the most citations, so it is the natural first reading for anyone following the KEYNOTE-522 trial. Read the abstract above alongside the trial page and the registry entry; the record was linked automatically and its figures have not been checked by hand."},{"id":"paper-keynote-522-nejm-2022","name":"KEYNOTE-522: adding pembrolizumab before and after surgery in early triple-negative breast cancer","route":"/key-papers/paper-keynote-522-nejm-2022/","journal":"New England Journal of Medicine","year":2022,"whatItMeans":"For stage II-III triple-negative breast cancer, chemotherapy plus pembrolizumab before surgery and pembrolizumab alone afterwards is now the standard approach worldwide, and the survival gain is real, not just a surrogate. It does not apply to stage I disease or to hormone-receptor-positive or HER2-positive cancers. The price is a year of immunotherapy with a meaningful chance of a permanent endocrine side effect such as hypothyroidism or adrenal insufficiency."},{"id":"paper-keynote-522-n-engl-j-med-2024-update","name":"Overall Survival with Pembrolizumab in Early-Stage Triple-Negative Breast Cancer","route":"/key-papers/paper-keynote-522-n-engl-j-med-2024-update/","journal":"New England Journal of Medicine","year":2024,"whatItMeans":"A second publication from the KEYNOTE-522 trial, later than the first and described in its title as an update or longer-term analysis. Read it with the primary publication linked from the trial page; the record was linked automatically and its figures have not been checked by hand."},{"id":"paper-asco-pembrolizumab-early-tnbc-rapid-update-jco-2022","name":"Use of Immune Checkpoint Inhibitor Pembrolizumab in the Treatment of High-Risk, Early-Stage Triple-Negative Breast Cancer: ASCO Guideline Rapid Recommendation Update","route":"/key-papers/paper-asco-pembrolizumab-early-tnbc-rapid-update-jco-2022/","journal":"Journal of Clinical Oncology","year":2022,"whatItMeans":"Shows how quickly the standard moved: the 2021 guideline and its reversal are 15 months apart."},{"id":"paper-leon-ferre-tils-tnbc-no-chemotherapy-jama-2024","name":"Tumor-Infiltrating Lymphocytes in Triple-Negative Breast Cancer","route":"/key-papers/paper-leon-ferre-tils-tnbc-no-chemotherapy-jama-2024/","journal":"JAMA","year":2024,"whatItMeans":"The evidence behind the stage I de-escalation statement on the triple-negative page: an ordinary haematoxylin and eosin slide identifies a fifth of patients whose outcome without chemotherapy matches treated cohorts. A prospective trial of chemotherapy omission is the missing step."}]},{"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.","status":"current","refs":[{"id":"ascent","kind":"trial","name":"ASCENT","route":"/trials/ascent/","status":"positive","tldr":"The trial that proved a TROP2 ADC could nearly double survival in heavily pretreated triple-negative breast cancer."},{"id":"paper-ascent-nejm-2021","kind":"paper","name":"ASCENT: sacituzumab govitecan doubles survival in heavily pretreated metastatic triple-negative breast cancer","route":"/key-papers/paper-ascent-nejm-2021/","tldr":"In triple-negative breast cancer that had already been through at least two treatments, the TROP2 antibody-drug conjugate sacituzumab govitecan roughly doubled the time patients lived compared with standard chemotherapy."},{"id":"destiny-breast04","kind":"trial","name":"DESTINY-Breast04","route":"/trials/destiny-breast04/","status":"positive","tldr":"Created a new category of breast cancer, HER2-low, by showing Enhertu works in tumours previously called HER2-negative."},{"id":"paper-destiny-breast04-nejm-2022","kind":"paper","name":"DESTINY-Breast04: trastuzumab deruxtecan works in HER2-low breast cancer, creating a new treatable group","route":"/key-papers/paper-destiny-breast04-nejm-2022/","tldr":"Breast cancers with only a little HER2 on their surface, long called HER2-negative, responded to trastuzumab deruxtecan and patients lived about six months longer than on chemotherapy. It created the HER2-low category."},{"id":"paper-schettini-her2-low-features-npj-breast-cancer-2021","kind":"paper","name":"Clinical, pathological, and PAM50 gene expression features of HER2-low breast cancer","route":"/key-papers/paper-schettini-her2-low-features-npj-breast-cancer-2021/","tldr":"A 3,689-patient study showing that 36.6 percent of triple-negative tumours are HER2-low, that in triple-negative disease HER2-low tumours are biologically no different from HER2-zero ones, and that pathologists agree poorly on the score; the label matters only because a drug now depends on it."},{"id":"ascent-03","kind":"trial","name":"ASCENT-03","route":"/trials/ascent-03/","status":"positive","tldr":"Moved Trodelvy into first-line use for triple-negative patients who cannot receive immunotherapy."},{"id":"paper-ascent-03-n-engl-j-med-2025","kind":"paper","name":"Sacituzumab Govitecan in Untreated, Advanced Triple-Negative Breast Cancer","route":"/key-papers/paper-ascent-03-n-engl-j-med-2025/","tldr":"Published report from the ASCENT-03 trial registered as NCT05382299, in New England Journal of Medicine (2025), chosen as the most cited paper whose own text cites the registry id."},{"id":"ascent-04","kind":"trial","name":"ASCENT-04 / KEYNOTE-D19","route":"/trials/ascent-04/","status":"positive","tldr":"Showed that pairing an ADC with immunotherapy beats chemotherapy plus immunotherapy in first-line PD-L1-positive TNBC."},{"id":"paper-ascent-04-n-engl-j-med-2026","kind":"paper","name":"Sacituzumab Govitecan plus Pembrolizumab for Advanced Triple-Negative Breast Cancer","route":"/key-papers/paper-ascent-04-n-engl-j-med-2026/","tldr":"Published report from the ASCENT-04 trial registered as NCT05382286, in New England Journal of Medicine (2026), chosen as the most cited paper whose own text cites the registry id."},{"id":"tropion-breast02","kind":"trial","name":"TROPION-Breast02","route":"/trials/tropion-breast02/","status":"positive","tldr":"The first trial to show an overall survival benefit for a first-line ADC in triple-negative breast cancer."},{"id":"paper-tropion-breast02-ann-oncol-2026","kind":"paper","name":"Datopotamab deruxtecan in patients with untreated, advanced triple-negative breast cancer (TROPION-Breast02): a randomised, open-label, international, phase III trial","route":"/key-papers/paper-tropion-breast02-ann-oncol-2026/","tldr":"The trial of 644 women with newly metastatic triple-negative breast cancer who could not have immunotherapy, in which the antibody-drug conjugate datopotamab deruxtecan held the cancer still for 10.8 months against 5.6 with chemotherapy and lengthened life from 18.7 to 23.7 months."},{"id":"bl-b01d1-307","kind":"trial","name":"BL-B01D1-307","route":"/trials/bl-b01d1-307/","status":"positive","tldr":"The first phase 3 win for a bispecific ADC, in triple-negative breast cancer, announced February 2026."},{"id":"nct03997123","kind":"trial","name":"Capivasertib+Paclitaxel as First Line Treatment for Patients With Locally Advanced or Metastatic TNBC","route":"/trials/nct03997123/","status":"active","tldr":"A phase 3 trial of Capivasertib in triple-negative breast cancer, run by AstraZeneca, active and no longer recruiting."},{"id":"paper-capitello-290-capivasertib-paclitaxel-ann-oncol-2026","kind":"paper","name":"Capivasertib plus paclitaxel as first-line treatment for metastatic triple-negative breast cancer: results from the randomised, global phase III CAPItello-290 trial","route":"/key-papers/paper-capitello-290-capivasertib-paclitaxel-ann-oncol-2026/","tldr":"The 812-patient trial in which adding the AKT inhibitor capivasertib to first-line paclitaxel did not lengthen life in metastatic triple-negative breast cancer (17.7 versus 18.0 months), even in the 31 percent of patients whose tumours carried the pathway alterations it targets."},{"id":"sacituzumab-govitecan","kind":"drug","name":"Sacituzumab govitecan","route":"/drugs/sacituzumab-govitecan/","status":"approved","tldr":"The first TROP2-targeted ADC. It delivers a strong chemotherapy directly to breast and bladder cancer cells and is now a first-line option in triple-negative breast cancer."},{"id":"datopotamab-deruxtecan","kind":"drug","name":"Datopotamab deruxtecan","route":"/drugs/datopotamab-deruxtecan/","status":"approved","tldr":"Datopotamab deruxtecan (Datroway) is the second TROP2 ADC and shares Enhertu's payload. In 2026 it became a first-line option for triple-negative breast cancer patients who cannot receive immunotherapy."},{"id":"trastuzumab-deruxtecan","kind":"drug","name":"Trastuzumab deruxtecan","route":"/drugs/trastuzumab-deruxtecan/","status":"approved","tldr":"Trastuzumab deruxtecan (Enhertu) is the most successful ADC ever. It redefined HER2 by working in tumours with only tiny amounts of the protein, and in 2026 moved into early-stage breast cancer."},{"id":"izalontamab-brengitecan","kind":"drug","name":"Izalontamab brengitecan","route":"/drugs/izalontamab-brengitecan/","status":"phase-3","tldr":"Izalontamab brengitecan is the first bispecific ADC to succeed in a phase 3 trial, hitting two growth receptors at once in triple-negative breast cancer."},{"id":"capivasertib","kind":"drug","name":"Capivasertib","route":"/drugs/capivasertib/","status":"approved","tldr":"Capivasertib (Truqap) is the first AKT inhibitor, for breast cancer with PI3K-pathway mutations and, since 2026, for prostate cancer with PTEN loss."},{"id":"trop2","kind":"target","name":"TROP2","route":"/targets/trop2/","tldr":"TROP2 is a surface glycoprotein present at high levels on most epithelial cancers (breast, lung, urothelial, gastric, pancreatic) and at low levels on normal tissue. It does not drive the cancer; it is a delivery address, used by the approved ADCs sacituzumab govitecan and datopotamab deruxtecan and by sacituzumab tirumotecan, with a TROP2 PET tracer in development to pick patients."},{"id":"her2-low","kind":"term","name":"HER2-low and HER2-ultralow","route":"/terms/her2-low/","tldr":"Tumours with a little HER2 (IHC 1+ or 2+ without amplification), or a trace (ultralow), which older HER2 drugs ignored but Enhertu can attack."},{"id":"adc","kind":"technology","name":"Antibody-drug conjugate (ADC)","route":"/technologies/adc/","status":"approved","tldr":"An antibody-drug conjugate is an antibody that homes to a protein on the tumour cell, is swallowed, and releases a chemotherapy payload inside it. That widens chemotherapy's safe dose window about a hundredfold, which is why payloads too toxic to give alone can be used, though lung inflammation, neutropenia and eye toxicity from the payload still occur."},{"id":"bispecific-adc","kind":"technology","name":"Bispecific ADC","route":"/technologies/bispecific-adc/","status":"phase-3","tldr":"A bispecific ADC is an ADC whose antibody grabs two different proteins on the cancer cell, so it sticks better to tumour and less to healthy tissue."},{"id":"trop2-adc-roadmap","kind":"roadmap","name":"TROP2 ADC roadmap: sacituzumab govitecan → Dato-DXd → sac-TMT → bispecifics and PET","route":"/roadmaps/trop2-adc-roadmap/","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."},{"id":"adc-generations","kind":"roadmap","name":"ADC roadmap: from Mylotarg to bispecific and dual-payload ADCs","route":"/roadmaps/adc-generations/","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."},{"id":"rebecca-dent","kind":"person","name":"Rebecca Dent","route":"/people/rebecca-dent/","tldr":"Breast medical oncologist and Deputy CEO for clinical operations at the National Cancer Centre Singapore, an international leader in triple-negative breast cancer trials."},{"id":"aditya-bardia","kind":"person","name":"Aditya Bardia","route":"/people/aditya-bardia/","tldr":"Led ASCENT, the trial that made sacituzumab govitecan the first ADC for triple-negative breast cancer, and the EMERALD trial of elacestrant."},{"id":"sara-tolaney","kind":"person","name":"Sara M. Tolaney","route":"/people/sara-tolaney/","tldr":"Leads Dana-Farber's breast oncology division and many of the trials that moved ADCs and de-escalated therapy into breast cancer care."},{"id":"gilead","kind":"company","name":"Gilead Sciences (incl. Kite)","route":"/companies/gilead/","tldr":"Gilead owns Trodelvy (via the $21B Immunomedics deal) and the Kite CAR-T franchise."},{"id":"astrazeneca","kind":"company","name":"AstraZeneca","route":"/companies/astrazeneca/","tldr":"AstraZeneca is the most ADC-committed large pharma, co-owner of Enhertu and Datroway, with deep targeted-therapy and radiopharma bets."},{"id":"daiichi-sankyo","kind":"company","name":"Daiichi Sankyo","route":"/companies/daiichi-sankyo/","tldr":"Daiichi Sankyo is the Japanese company whose DXd payload technology created the best ADC platform in the industry."},{"id":"adcs","kind":"section","name":"Antibody-Drug Conjugates","route":"/fronts/adcs/","tldr":"An antibody that finds the tumour, carrying a tiny dose of very strong chemotherapy that is released only inside it."},{"id":"idea-tnbc-adc-sequencing-trial","kind":"idea","name":"A randomised trial of antibody-drug conjugate sequence in metastatic triple-negative breast cancer","route":"/ideas/idea-tnbc-adc-sequencing-trial/","tldr":"Three antibody-drug conjugates now used in triple-negative breast cancer carry the same kind of chemotherapy warhead, a topoisomerase inhibitor. Nobody has randomised which to give first or whether the second works after the first; small series suggest it often does not. With two now approved first line, the question decides what a patient gets for the rest of her life."},{"id":"idea-tnbc-her2-ultralow-testing-uptake","kind":"idea","name":"Reflex re-scoring of HER2 0 versus 1+ with digital assistance so every eligible triple-negative patient reaches trastuzumab deruxtecan","route":"/ideas/idea-tnbc-her2-ultralow-testing-uptake/","tldr":"About a third of triple-negative tumours are HER2-low and so eligible for trastuzumab deruxtecan, but the difference between a HER2 score of 0 and 1+ is the one pathologists agree on least, and most triple-negative tumours were scored before the label mattered. Re-scoring archived slides with digital help when a patient relapses would find the eligible third."}],"trials":[{"id":"ascent","name":"ASCENT","route":"/trials/ascent/","outcomes":[{"endpoint":"Progression-free survival (patients without brain metastases)","primary":true,"unit":"months","arms":[{"name":"Sacituzumab govitecan","n":235,"value":5.6},{"name":"Chemotherapy (TPC)","n":233,"value":1.7}],"hr":0.41,"ci":[0.32,0.52],"p":"<0.001","source":"https://www.nejm.org/doi/full/10.1056/NEJMoa2028485"},{"endpoint":"Overall survival","unit":"months","arms":[{"name":"Sacituzumab govitecan","value":12.1},{"name":"Chemotherapy (TPC)","value":6.7}],"hr":0.48,"ci":[0.38,0.59],"p":"<0.001","source":"https://www.nejm.org/doi/full/10.1056/NEJMoa2028485"},{"endpoint":"Objective response rate","unit":"%","arms":[{"name":"Sacituzumab govitecan","value":35},{"name":"Chemotherapy (TPC)","value":5}],"source":"https://www.nejm.org/doi/full/10.1056/NEJMoa2028485"}],"setting":"Pretreated metastatic TNBC: sacituzumab govitecan vs chemotherapy","enrolled":529,"enrolledBasis":"registry"},{"id":"destiny-breast04","name":"DESTINY-Breast04","route":"/trials/destiny-breast04/","outcomes":[{"endpoint":"Progression-free survival, HR+ cohort (BICR)","primary":true,"unit":"months","arms":[{"name":"Trastuzumab deruxtecan","n":331,"value":10.1},{"name":"Chemotherapy (TPC)","n":163,"value":5.4}],"hr":0.51,"ci":[0.4,0.64],"p":"<0.001","source":"https://www.nejm.org/doi/full/10.1056/NEJMoa2203690"},{"endpoint":"Overall survival, all patients","unit":"months","arms":[{"name":"Trastuzumab deruxtecan","n":373,"value":23.4},{"name":"Chemotherapy (TPC)","n":184,"value":16.8}],"hr":0.64,"ci":[0.49,0.84],"p":"0.001","source":"https://www.nejm.org/doi/full/10.1056/NEJMoa2203690"},{"endpoint":"Progression-free survival, HR-negative (TNBC) cohort","unit":"months","arms":[{"name":"Trastuzumab deruxtecan","n":40,"value":8.5,"note":"Exploratory cohort"},{"name":"Chemotherapy (TPC)","n":18,"value":2.9}],"hr":0.46,"ci":[0.24,0.89],"source":"https://www.nejm.org/doi/full/10.1056/NEJMoa2203690"}],"setting":"HER2-low metastatic breast cancer after chemotherapy: T-DXd vs chemotherapy","enrolled":557,"enrolledBasis":"registry"},{"id":"ascent-03","name":"ASCENT-03","route":"/trials/ascent-03/","outcomes":[{"endpoint":"Progression-free survival (BICR)","primary":true,"unit":"months","arms":[{"name":"Sacituzumab govitecan","n":279,"value":9.7},{"name":"Chemotherapy (TPC)","n":279,"value":6.9}],"hr":0.62,"ci":[0.5,0.77],"p":"<0.0001","source":"https://dailyreporter.esmo.org/esmo-congress-2025/breast-cancer/survival-improvements-observed-with-first-line-antibody-drug-conjugates-in-triple-negative-breast-cancer"},{"endpoint":"Objective response rate","unit":"%","arms":[{"name":"Sacituzumab govitecan","value":48},{"name":"Chemotherapy (TPC)","value":44}]},{"endpoint":"Overall survival","unit":"months","arms":[{"name":"Sacituzumab govitecan","note":"Immature at the primary analysis; crossover to sacituzumab permitted on progression."},{"name":"Chemotherapy (TPC)"}]}],"setting":"First-line metastatic TNBC, not candidates for PD-1 inhibitors: sacituzumab govitecan vs chemotherapy","enrolled":558,"enrolledNote":"ClinicalTrials.gov lists 623 participants (actual); the NEJM 2025 primary analysis covered 558 randomised patients.","enrolledBasis":"randomised"},{"id":"ascent-04","name":"ASCENT-04 / KEYNOTE-D19","route":"/trials/ascent-04/","outcomes":[{"endpoint":"Progression-free survival (BICR)","primary":true,"unit":"months","arms":[{"name":"Sacituzumab govitecan + pembrolizumab","n":221,"value":11.2},{"name":"Chemotherapy + pembrolizumab","n":222,"value":7.8}],"hr":0.65,"ci":[0.51,0.84],"p":"0.0009","source":"https://dailyreporter.esmo.org/esmo-congress-2025/breast-cancer/survival-improvements-observed-with-first-line-antibody-drug-conjugates-in-triple-negative-breast-cancer"},{"endpoint":"Objective response rate","unit":"%","arms":[{"name":"Sacituzumab govitecan + pembrolizumab","value":60},{"name":"Chemotherapy + pembrolizumab","value":53}],"source":"https://doi.org/10.1056/NEJMoa2508959"},{"endpoint":"Overall survival","unit":"months","arms":[{"name":"Sacituzumab govitecan + pembrolizumab","note":"Immature; PFS2 favoured the ADC arm in the ASCO 2026 update."},{"name":"Chemotherapy + pembrolizumab"}],"source":"https://doi.org/10.1056/NEJMoa2508959"}],"setting":"First-line PD-L1+ (CPS ≥10) metastatic TNBC: sacituzumab govitecan + pembrolizumab vs chemotherapy + pembrolizumab","enrolled":443,"enrolledBasis":"registry"},{"id":"tropion-breast02","name":"TROPION-Breast02","route":"/trials/tropion-breast02/","outcomes":[{"endpoint":"Progression-free survival (BICR)","primary":true,"unit":"months","arms":[{"name":"Datopotamab deruxtecan","n":323,"value":10.8},{"name":"Chemotherapy (ICC)","n":321,"value":5.6}],"hr":0.57,"ci":[0.47,0.69],"p":"<0.0001","source":"https://www.annalsofoncology.org/article/S0923-7534(26)00130-4/fulltext"},{"endpoint":"Overall survival","primary":true,"unit":"months","arms":[{"name":"Datopotamab deruxtecan","value":23.7},{"name":"Chemotherapy (ICC)","value":18.7}],"hr":0.79,"ci":[0.64,0.98],"p":"0.0291","source":"https://www.astrazeneca.com/media-centre/press-releases/2025/datroway-demonstrated-an-unprecedented-median-overall-survival-improvement-of-five-months-vs-chemotherapy-as-1st-line-treatment-for-patients-with-metastatic-triple-negative-breast-cancer-for-whom-immunotherapy-was-not-an-option-in-tropion-breast02.html"}],"setting":"First-line metastatic TNBC, not candidates for PD-1/PD-L1: Dato-DXd vs chemotherapy","enrolled":644,"enrolledBasis":"registry"},{"id":"bl-b01d1-307","name":"BL-B01D1-307","route":"/trials/bl-b01d1-307/","outcomes":[{"endpoint":"Progression-free survival (BICR)","primary":true,"unit":"months","arms":[{"name":"Izalontamab brengitecan","n":207,"value":8.5},{"name":"Chemotherapy (TPC)","n":211,"value":3.1}],"hr":0.29,"ci":[0.22,0.38],"p":"<0.0001","source":"https://www.onclive.com/view/iza-bren-yields-pfs-and-os-benefits-vs-chemo-in-previously-treated-advanced-tnbc"},{"endpoint":"Overall survival (interim, median follow-up 11 months)","primary":true,"unit":"months","arms":[{"name":"Izalontamab brengitecan","value":15.9},{"name":"Chemotherapy (TPC)","value":12.5}],"hr":0.6,"ci":[0.42,0.85],"p":"0.0019","source":"https://www.onclive.com/view/iza-bren-yields-pfs-and-os-benefits-vs-chemo-in-previously-treated-advanced-tnbc"},{"endpoint":"Confirmed objective response rate (BICR)","unit":"%","arms":[{"name":"Izalontamab brengitecan","value":51.7},{"name":"Chemotherapy (TPC)","value":20.5}]}],"setting":"Previously treated locally advanced or metastatic TNBC: izalontamab brengitecan vs chemotherapy","enrolled":418,"enrolledBasis":"registry"},{"id":"nct03997123","name":"Capivasertib+Paclitaxel as First Line Treatment for Patients With Locally Advanced or Metastatic TNBC","route":"/trials/nct03997123/","outcomes":[{"endpoint":"Overall survival, all patients","primary":true,"unit":"months","arms":[{"name":"Capivasertib + paclitaxel","value":17.7},{"name":"Placebo + paclitaxel","value":18}],"hr":0.92,"ci":[0.78,1.08],"p":"0.3239","source":"https://doi.org/10.1016/j.annonc.2025.12.012"},{"endpoint":"Overall survival, PIK3CA/AKT1/PTEN-altered tumours","primary":true,"unit":"months","arms":[{"name":"Capivasertib + paclitaxel","value":20.4},{"name":"Placebo + paclitaxel","value":20.4}],"hr":1.05,"ci":[0.77,1.43],"p":"0.7602","source":"https://doi.org/10.1016/j.annonc.2025.12.012"},{"endpoint":"Progression-free survival (investigator), all patients","unit":"months","arms":[{"name":"Capivasertib + paclitaxel","value":5.6},{"name":"Placebo + paclitaxel","value":5.1}],"hr":0.72,"ci":[0.61,0.84],"source":"https://doi.org/10.1016/j.annonc.2025.12.012"}],"setting":"A Phase III Double-blind Randomised Study Assessing the Efficacy and Safety of Capivasertib/+Paclitaxel vs Placebo+Paclitaxel as First-line Treatment for Patients With Locally Advanced (Inoperable) or Metastatic TNBC.","enrolled":923,"enrolledNote":"ClinicalTrials.gov lists 923 participants (actual); the Annals of Oncology 2026 primary paper covers 812 randomised patients.","enrolledBasis":"randomised"}],"papers":[{"id":"paper-ascent-nejm-2021","name":"ASCENT: sacituzumab govitecan doubles survival in heavily pretreated metastatic triple-negative breast cancer","route":"/key-papers/paper-ascent-nejm-2021/","journal":"New England Journal of Medicine","year":2021,"whatItMeans":"Sacituzumab govitecan is a standard second-line or later treatment for metastatic triple-negative breast cancer, roughly doubling survival compared with the chemotherapies it was tested against. Patients should expect neutropenia and diarrhoea, which are manageable with growth factor support and loperamide. Trials are now testing it earlier, in first-line combinations with pembrolizumab and after surgery for residual disease."},{"id":"paper-destiny-breast04-nejm-2022","name":"DESTINY-Breast04: trastuzumab deruxtecan works in HER2-low breast cancer, creating a new treatable group","route":"/key-papers/paper-destiny-breast04-nejm-2022/","journal":"New England Journal of Medicine","year":2022,"whatItMeans":"Patients whose breast cancer was previously called HER2-negative may now be eligible for an effective HER2-directed drug if their tumour has even low-level HER2 staining, so pathology reports must now distinguish HER2-low (1+ or 2+/ISH-negative) from HER2-zero. This applies to metastatic disease after at least one line of chemotherapy; it does not mean these patients benefit from trastuzumab or other older HER2 drugs."},{"id":"paper-schettini-her2-low-features-npj-breast-cancer-2021","name":"Clinical, pathological, and PAM50 gene expression features of HER2-low breast cancer","route":"/key-papers/paper-schettini-her2-low-features-npj-breast-cancer-2021/","journal":"NPJ Breast Cancer","year":2021,"whatItMeans":"HER2-low is a drug eligibility label, not a biological subtype, in triple-negative disease; because a third of patients qualify for trastuzumab deruxtecan on a score pathologists disagree about, re-scoring and digital assistance for HER2 0 versus 1+ is a practical gap."},{"id":"paper-ascent-03-n-engl-j-med-2025","name":"Sacituzumab Govitecan in Untreated, Advanced Triple-Negative Breast Cancer","route":"/key-papers/paper-ascent-03-n-engl-j-med-2025/","journal":"New England Journal of Medicine","year":2025,"whatItMeans":"This is the paper Europe PMC returns for registry id NCT05382299 with the most citations, so it is the natural first reading for anyone following the ASCENT-03 trial. Read the abstract above alongside the trial page and the registry entry; the record was linked automatically and its figures have not been checked by hand."},{"id":"paper-ascent-04-n-engl-j-med-2026","name":"Sacituzumab Govitecan plus Pembrolizumab for Advanced Triple-Negative Breast Cancer","route":"/key-papers/paper-ascent-04-n-engl-j-med-2026/","journal":"New England Journal of Medicine","year":2026,"whatItMeans":"This is the paper Europe PMC returns for registry id NCT05382286 with the most citations, so it is the natural first reading for anyone following the ASCENT-04 trial. Read the abstract above alongside the trial page and the registry entry; the record was linked automatically and its figures have not been checked by hand."},{"id":"paper-tropion-breast02-ann-oncol-2026","name":"Datopotamab deruxtecan in patients with untreated, advanced triple-negative breast cancer (TROPION-Breast02): a randomised, open-label, international, phase III trial","route":"/key-papers/paper-tropion-breast02-ann-oncol-2026/","journal":"Annals of Oncology","year":2026,"whatItMeans":"The first-line overall survival result that made an antibody-drug conjugate the standard for PD-L1-negative or immunotherapy-ineligible metastatic triple-negative disease, and the reason the sequencing question (which TROP2 drug first, what after it) is now urgent."},{"id":"paper-capitello-290-capivasertib-paclitaxel-ann-oncol-2026","name":"Capivasertib plus paclitaxel as first-line treatment for metastatic triple-negative breast cancer: results from the randomised, global phase III CAPItello-290 trial","route":"/key-papers/paper-capitello-290-capivasertib-paclitaxel-ann-oncol-2026/","journal":"Annals of Oncology","year":2026,"whatItMeans":"The latest in a line of negative targeted-therapy trials in triple-negative disease (EGFR, VEGF, iniparib, now AKT): a modest delay in progression that did not translate into survival, in the same year that an antibody-drug conjugate did. It is why the roadmap treats pathway-targeted small molecules as the road not taken."}]},{"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).","status":"emerging","refs":[{"id":"paper-radovich-ctdna-ctc-bre12-158-jama-oncol-2020","kind":"paper","name":"Association of Circulating Tumor DNA and Circulating Tumor Cells After Neoadjuvant Chemotherapy With Disease Recurrence in Patients With Triple-Negative Breast Cancer: Preplanned Secondary Analysis of the BRE12-158 Randomized Clinical Trial","route":"/key-papers/paper-radovich-ctdna-ctc-bre12-158-jama-oncol-2020/","tldr":"In 196 women with triple-negative breast cancer left with residual tumour after pre-surgery chemotherapy, finding tumour DNA in the blood after surgery tripled the risk of distant relapse and quadrupled the risk of death; at two years 56 percent versus 81 percent were free of distant disease."},{"id":"paper-turner-c-trak-tn-ctdna-pembrolizumab-ann-oncol-2023","kind":"paper","name":"Results of the c-TRAK TN trial: a clinical trial utilising ctDNA mutation tracking to detect molecular residual disease and trigger intervention in patients with moderate- and high-risk early-stage triple-negative breast cancer","route":"/key-papers/paper-turner-c-trak-tn-ctdna-pembrolizumab-ann-oncol-2023/","tldr":"The UK trial that watched 161 women with early triple-negative breast cancer by three-monthly blood tests for tumour DNA: 27 percent tested positive within a year, but by then nearly three quarters already had visible metastases, and none of the five who started pembrolizumab cleared the DNA. The lesson was to test earlier and more sensitively."},{"id":"paper-yau-rcb-pooled-analysis-5161-lancet-oncol-2022","kind":"paper","name":"Residual cancer burden after neoadjuvant chemotherapy and long-term survival outcomes in breast cancer: a multicentre pooled analysis of 5161 patients","route":"/key-papers/paper-yau-rcb-pooled-analysis-5161-lancet-oncol-2022/","tldr":"A pooled analysis of 5,161 patients from 12 European and US institutions and trials confirming that the residual cancer burden score predicts relapse in every breast cancer subtype, and proposing it become part of standard pathology reporting after pre-surgery chemotherapy."},{"id":"ascent-05","kind":"trial","name":"ASCENT-05 / OptimICE-RD (AFT-65, GBG 119, NSABP B-63)","route":"/trials/ascent-05/","status":"recruiting","tldr":"Tests whether giving a TROP2 ADC after surgery can cure more of the triple-negative patients whose cancer survived pre-surgery chemo-immunotherapy."},{"id":"tropion-breast03","kind":"trial","name":"TROPION-Breast03","route":"/trials/tropion-breast03/","status":"active","tldr":"TROPION-Breast03 is the Dato-DXd counterpart to ASCENT-05: an ADC, with or without immunotherapy, for triple-negative patients with leftover cancer at surgery."},{"id":"ctdna","kind":"term","name":"Circulating tumour DNA (ctDNA)","route":"/terms/ctdna/","tldr":"Circulating tumour DNA (ctDNA) consists of fragments of DNA shed by tumour cells into the blood, detectable with sensitive sequencing."},{"id":"mrd","kind":"term","name":"Minimal / molecular residual disease (MRD)","route":"/terms/mrd/","tldr":"Cancer still present after treatment but too small to see on scans, detected by blood or marrow tests."},{"id":"rcb","kind":"term","name":"Residual cancer burden (RCB)","route":"/terms/rcb/","tldr":"A pathology score for how much cancer remains in the breast and lymph nodes after pre-surgery treatment, from 0 (none) to III (a large amount), combining tumour bed size, cellularity and nodal involvement. RCB-II or III after neoadjuvant therapy predicts a high risk of relapse and defines who enters escalation trials."},{"id":"liquid-biopsy","kind":"technology","name":"Liquid biopsy (ctDNA)","route":"/technologies/liquid-biopsy/","status":"standard-of-care","tldr":"A blood test that reads fragments of DNA shed by the tumour, so you can genotype or monitor cancer without a needle in the tumour."},{"id":"mrd-testing","kind":"technology","name":"MRD / molecular residual disease testing","route":"/technologies/mrd-testing/","status":"established","tldr":"An ultra-sensitive blood test after surgery that detects leftover cancer months before a scan would."},{"id":"signatera","kind":"drug","name":"Signatera","route":"/drugs/signatera/","status":"established","tldr":"Signatera is Natera's tumour-informed blood test that tracks 16 mutations from each patient's own tumour to detect residual or returning cancer after surgery. Medicare covers it in colorectal, breast, bladder, lung and ovarian cancer and for immunotherapy monitoring, and in 2026 it selected the bladder cancer patients for the first approval based on circulating tumour DNA."},{"id":"ctdna-tests","kind":"roadmap","name":"ctDNA tests roadmap: from a curiosity in plasma to blood tests that decide treatment","route":"/roadmaps/ctdna-tests/","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."},{"id":"nicholas-turner","kind":"person","name":"Nicholas Turner","route":"/people/nicholas-turner/","tldr":"Breast cancer researcher who turned ctDNA into a tool for choosing treatment, leading SERENA-6 and CAPItello-291."},{"id":"royal-marsden","kind":"institution","name":"The Royal Marsden","route":"/institutions/royal-marsden/","tldr":"The Royal Marsden was the world's first hospital dedicated to cancer (1851) and is paired with the Institute of Cancer Research."},{"id":"b-dormancy-mrd","kind":"bottleneck","name":"Dormant cells and minimal residual disease","route":"/bottlenecks/b-dormancy-mrd/","tldr":"After a 'successful' treatment, cells can sleep for years then relapse. We can barely detect them and cannot target them."},{"id":"idea-tnbc-ctdna-guided-adjuvant-decisions","kind":"idea","name":"ctDNA-guided adjuvant decisions after residual disease: escalate the positive, spare the negative","route":"/ideas/idea-tnbc-ctdna-guided-adjuvant-decisions/","tldr":"After pre-surgery chemotherapy leaves tumour behind, a blood test for tumour DNA triples the risk of distant relapse when positive. The one trial that acted on it found the DNA usually appeared too late. A trial that tests at surgery with a tumour-informed assay, escalates positives to an antibody-drug conjugate and observes negatives has not been run."}],"trials":[],"papers":[{"id":"paper-radovich-ctdna-ctc-bre12-158-jama-oncol-2020","name":"Association of Circulating Tumor DNA and Circulating Tumor Cells After Neoadjuvant Chemotherapy With Disease Recurrence in Patients With Triple-Negative Breast Cancer: Preplanned Secondary Analysis of the BRE12-158 Randomized Clinical Trial","route":"/key-papers/paper-radovich-ctdna-ctc-bre12-158-jama-oncol-2020/","journal":"JAMA Oncology","year":2020,"whatItMeans":"The proof that a blood test can split residual-disease patients into those likely to relapse and those likely cured, the premise of the ctDNA-guided adjuvant idea; no completed trial has yet acted on the result."},{"id":"paper-turner-c-trak-tn-ctdna-pembrolizumab-ann-oncol-2023","name":"Results of the c-TRAK TN trial: a clinical trial utilising ctDNA mutation tracking to detect molecular residual disease and trigger intervention in patients with moderate- and high-risk early-stage triple-negative breast cancer","route":"/key-papers/paper-turner-c-trak-tn-ctdna-pembrolizumab-ann-oncol-2023/","journal":"Annals of Oncology","year":2023,"whatItMeans":"The first prospective test of acting on ctDNA in triple-negative disease, and a negative one: with a quarterly, single-mutation assay the window between detectable DNA and visible metastasis was too short to intervene. Later designs use tumour-informed assays, earlier sampling and drugs with more single-agent activity."},{"id":"paper-yau-rcb-pooled-analysis-5161-lancet-oncol-2022","name":"Residual cancer burden after neoadjuvant chemotherapy and long-term survival outcomes in breast cancer: a multicentre pooled analysis of 5161 patients","route":"/key-papers/paper-yau-rcb-pooled-analysis-5161-lancet-oncol-2022/","journal":"The Lancet Oncology","year":2022,"whatItMeans":"The external validation the 2017 paper asked for; it is why residual cancer burden is reported in UK and European pathology and used as a trial entry criterion rather than an MD Anderson curiosity."}]},{"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.","status":"emerging","refs":[{"id":"optimice-pcr","kind":"trial","name":"OptimICE-pCR (A012103)","route":"/trials/optimice-pcr/","status":"recruiting","tldr":"Asks whether patients whose cancer completely disappeared before surgery still need a year of immunotherapy afterwards."},{"id":"scarlet-s2212","kind":"trial","name":"SCARLET (SWOG S2212)","route":"/trials/scarlet-s2212/","status":"recruiting","tldr":"Tests whether the anthracycline can be dropped from TNBC pre-surgery treatment without losing effect."},{"id":"ascent-05","kind":"trial","name":"ASCENT-05 / OptimICE-RD (AFT-65, GBG 119, NSABP B-63)","route":"/trials/ascent-05/","status":"recruiting","tldr":"Tests whether giving a TROP2 ADC after surgery can cure more of the triple-negative patients whose cancer survived pre-surgery chemo-immunotherapy."},{"id":"tropion-breast03","kind":"trial","name":"TROPION-Breast03","route":"/trials/tropion-breast03/","status":"active","tldr":"TROPION-Breast03 is the Dato-DXd counterpart to ASCENT-05: an ADC, with or without immunotherapy, for triple-negative patients with leftover cancer at surgery."},{"id":"tropion-breast05","kind":"trial","name":"TROPION-Breast05","route":"/trials/tropion-breast05/","status":"recruiting","tldr":"Tests whether Dato-DXd plus a PD-L1 blocker beats today's immunotherapy-chemotherapy standard."},{"id":"izabright-breast01","kind":"trial","name":"IZABRIGHT-Breast01","route":"/trials/izabright-breast01/","status":"recruiting","tldr":"IZABRIGHT-Breast01 is the global first-line trial of the EGFR×HER3 bispecific ADC in triple-negative breast cancer."},{"id":"nct06419621","kind":"trial","name":"PM8002 or Placebo Plus Nab-Paclitaxel as First-line Treatment in Inoperable Locally Advanced/Metastatic TNBC","route":"/trials/nct06419621/","status":"active","tldr":"A phase 3 trial testing PM8002 in triple-negative breast cancer, active and no longer recruiting."},{"id":"keynote-522","kind":"trial","name":"KEYNOTE-522","route":"/trials/keynote-522/","status":"positive","tldr":"The trial that added immunotherapy to pre-surgery chemotherapy for triple-negative breast cancer and, uniquely, improved survival."},{"id":"olympia","kind":"trial","name":"OlympiA","route":"/trials/olympia/","status":"positive","tldr":"Showed that a year of a PARP inhibitor after standard treatment improves survival in women with inherited BRCA mutations."},{"id":"de-escalation","kind":"term","name":"De-escalation, escalation and response-adapted therapy","route":"/terms/de-escalation/","tldr":"Giving less treatment to patients who are doing well and more to those who are not, using a marker such as scan response, ctDNA or MRD to decide. The aim is to cure the same number of people with less harm."},{"id":"idea-tnbc-de-escalation-for-exceptional-responders","kind":"idea","name":"Give exceptional responders less: pembrolizumab omission after complete response, anthracycline-free regimens and chemotherapy omission in lymphocyte-rich stage I disease","route":"/ideas/idea-tnbc-de-escalation-for-exceptional-responders/","tldr":"Two thirds of women treated on the KEYNOTE-522 regimen have no tumour left at surgery and about 92 percent of them are alive without relapse at five years, yet all receive nine more cycles of pembrolizumab. Trials are now testing whether the best responders can stop early, skip the anthracycline, or in lymphocyte-rich stage I tumours skip chemotherapy altogether."},{"id":"idea-tnbc-ctdna-guided-adjuvant-decisions","kind":"idea","name":"ctDNA-guided adjuvant decisions after residual disease: escalate the positive, spare the negative","route":"/ideas/idea-tnbc-ctdna-guided-adjuvant-decisions/","tldr":"After pre-surgery chemotherapy leaves tumour behind, a blood test for tumour DNA triples the risk of distant relapse when positive. The one trial that acted on it found the DNA usually appeared too late. A trial that tests at surgery with a tumour-informed assay, escalates positives to an antibody-drug conjugate and observes negatives has not been run."}],"trials":[{"id":"keynote-522","name":"KEYNOTE-522","route":"/trials/keynote-522/","outcomes":[{"endpoint":"Pathologic complete response (ypT0/Tis ypN0)","primary":true,"unit":"%","arms":[{"name":"Pembrolizumab + chemotherapy","n":401,"value":64.8},{"name":"Placebo + chemotherapy","n":201,"value":51.2}],"p":"0.00055","source":"https://www.nejm.org/doi/full/10.1056/NEJMoa1910549"},{"endpoint":"Event-free survival at 5 years","primary":true,"unit":"%","arms":[{"name":"Pembrolizumab + chemotherapy","n":784,"value":81.2},{"name":"Placebo + chemotherapy","n":390,"value":72.2}],"hr":0.65,"ci":[0.51,0.83],"source":"https://www.nejm.org/doi/full/10.1056/NEJMoa2409932"},{"endpoint":"Overall survival at 5 years","unit":"%","arms":[{"name":"Pembrolizumab + chemotherapy","value":86.6},{"name":"Placebo + chemotherapy","value":81.7}],"hr":0.66,"ci":[0.5,0.87],"p":"0.002","source":"https://www.nejm.org/doi/full/10.1056/NEJMoa2409932"},{"endpoint":"Event-free survival at 7 years","unit":"%","arms":[{"name":"Pembrolizumab + chemotherapy","value":78.3},{"name":"Placebo + chemotherapy","value":69.8}],"source":"https://www.lbbc.org/news/pivotal-progress-in-tnbc-asco-2026"},{"endpoint":"Overall survival at 7 years","unit":"%","arms":[{"name":"Pembrolizumab + chemotherapy","value":85.1},{"name":"Placebo + chemotherapy","value":77.2}],"source":"https://www.lbbc.org/news/pivotal-progress-in-tnbc-asco-2026"}],"setting":"Early-stage (II-III) TNBC: pembrolizumab + chemotherapy before surgery, pembrolizumab after","enrolled":1174,"enrolledBasis":"registry"},{"id":"olympia","name":"OlympiA","route":"/trials/olympia/","outcomes":[{"endpoint":"Invasive disease-free survival at 3 years","primary":true,"unit":"%","arms":[{"name":"Olaparib","n":921,"value":85.9},{"name":"Placebo","n":915,"value":77.1}],"hr":0.58,"ci":[0.41,0.82],"p":"<0.001","source":"https://www.nejm.org/doi/full/10.1056/NEJMoa2105215"},{"endpoint":"Overall survival at 4 years","unit":"%","arms":[{"name":"Olaparib","value":89.8},{"name":"Placebo","value":86.4}],"hr":0.68,"ci":[0.47,0.97],"p":"0.009","source":"https://www.annalsofoncology.org/article/S0923-7534(22)04165-7/fulltext"},{"endpoint":"Overall survival at 6 years","unit":"%","arms":[{"name":"Olaparib","value":87.5},{"name":"Placebo","value":83.2}],"hr":0.72,"ci":[0.56,0.93],"source":"https://clinicaltrials.gov/study/NCT02032823"}],"setting":"Adjuvant olaparib for one year in germline BRCA-mutated, HER2-negative, high-risk early breast cancer","enrolled":1837,"enrolledBasis":"registry"}],"papers":[]},{"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.","status":"current","refs":[{"id":"paper-rugo-pd-l1-assay-comparison-impassion130-jnci-2021","kind":"paper","name":"PD-L1 Immunohistochemistry Assay Comparison in Atezolizumab Plus nab-Paclitaxel-Treated Advanced Triple-Negative Breast Cancer","route":"/key-papers/paper-rugo-pd-l1-assay-comparison-impassion130-jnci-2021/","tldr":"Three different PD-L1 tests run on the same 614 IMpassion130 tumours called 46, 75 and 73 percent of them positive and agreed with each other only about 69 percent of the time; the benefit of atezolizumab was concentrated in the tumours all three called positive."},{"id":"paper-lin-tnbc-cns-metastases-dfci-cancer-2008","kind":"paper","name":"Sites of distant recurrence and clinical outcomes in patients with metastatic triple-negative breast cancer: high incidence of central nervous system metastases","route":"/key-papers/paper-lin-tnbc-cns-metastases-dfci-cancer-2008/","tldr":"A 2008 Dana-Farber series of 116 women with metastatic triple-negative breast cancer in which 46 percent developed brain metastases before death, median survival after spread was 13.3 months and after a brain diagnosis 4.9 months."},{"id":"paper-scott-tnbc-disparities-uscs-cancer-2019","kind":"paper","name":"Update on triple-negative breast cancer disparities for the United States: A population-based study from the United States Cancer Statistics database, 2010 through 2014","route":"/key-papers/paper-scott-tnbc-disparities-uscs-cancer-2019/","tldr":"A count of 1.15 million US breast cancers from 2010 to 2014 in which Black women had 2.27 times the odds of a triple-negative diagnosis and women under 40 nearly twice the odds, confirming the disparity at national scale."},{"id":"paper-copson-posh-ethnicity-young-breast-cancer-uk-bjc-2014","kind":"paper","name":"Ethnicity and outcome of young breast cancer patients in the United Kingdom: the POSH study","route":"/key-papers/paper-copson-posh-ethnicity-young-breast-cancer-uk-bjc-2014/","tldr":"The UK cohort of 2,915 women diagnosed with breast cancer at 40 or younger in which Black women had more triple-negative tumours (26 versus 19 percent) and worse survival despite the same access to care and the same use of chemotherapy."},{"id":"adc-sequencing","kind":"term","name":"ADC sequencing","route":"/terms/adc-sequencing/","tldr":"The open question of whether a second ADC works after the first one fails, especially when both carry the same type of payload."},{"id":"adc-after-adc-caution","kind":"pairing","name":"Caution: TOP1 ADC immediately after TOP1 ADC","route":"/pairings/adc-after-adc-caution/","tldr":"Giving a second ADC with the same kind of payload straight after the first often does not work well."},{"id":"brain-metastases","kind":"term","name":"Brain metastases (intracranial disease)","route":"/terms/brain-metastases/","tldr":"Tumour deposits that have travelled to the brain from a cancer elsewhere, ten times more common than cancers that start in the brain, mostly from lung, breast, melanoma and kidney cancer. Because the blood-brain barrier excludes most drugs, whether a medicine reaches and shrinks them now decides which drug is chosen, and trials report intracranial progression separately."},{"id":"b-biomarker-validation","kind":"bottleneck","name":"Biomarkers are not validated or standardised","route":"/bottlenecks/b-biomarker-validation/","tldr":"Tests that decide who gets a drug are often not validated prospectively and are measured differently in every lab."},{"id":"b-resistance","kind":"bottleneck","name":"Acquired resistance to every therapy","route":"/bottlenecks/b-resistance/","tldr":"Nearly every targeted therapy stops working within months to a few years as the tumour adapts."},{"id":"b-brain-delivery","kind":"bottleneck","name":"The brain: barrier and sanctuary","route":"/bottlenecks/b-brain-delivery/","tldr":"The blood-brain barrier's tight junctions and efflux pumps keep antibodies, antibody-drug conjugates and most kinase inhibitors out of the brain, so glioblastoma treatment has barely changed since 2005 and brain metastases, which develop in about a fifth of adults with cancer, are usually left to radiotherapy alone."},{"id":"b-trial-diversity","kind":"bottleneck","name":"Trials do not represent the people who get cancer","route":"/bottlenecks/b-trial-diversity/","tldr":"Older, Black, Hispanic, Asian, rural, poor and multimorbid patients are under-represented, so results may not apply to them."},{"id":"idea-tnbc-pd-l1-assay-harmonisation","kind":"idea","name":"Harmonise PD-L1 testing for triple-negative breast cancer around one scored assay, with external quality assurance","route":"/ideas/idea-tnbc-pd-l1-assay-harmonisation/","tldr":"Three PD-L1 tests run on the same tumours called 46, 75 and 73 percent of them positive and agreed only 69 percent of the time. With atezolizumab withdrawn, pembrolizumab's test (22C3, combined positive score of 10) is the only one that matters, yet laboratories still run whichever kit they have. One assay, one score and a proficiency scheme would end answers that vary by postcode."},{"id":"idea-tnbc-adc-sequencing-trial","kind":"idea","name":"A randomised trial of antibody-drug conjugate sequence in metastatic triple-negative breast cancer","route":"/ideas/idea-tnbc-adc-sequencing-trial/","tldr":"Three antibody-drug conjugates now used in triple-negative breast cancer carry the same kind of chemotherapy warhead, a topoisomerase inhibitor. Nobody has randomised which to give first or whether the second works after the first; small series suggest it often does not. With two now approved first line, the question decides what a patient gets for the rest of her life."},{"id":"idea-tnbc-brain-metastasis-trials","kind":"idea","name":"Trials that include, and report, brain metastases in triple-negative breast cancer","route":"/ideas/idea-tnbc-brain-metastasis-trials/","tldr":"Nearly half of women with metastatic triple-negative breast cancer develop brain metastases and survive under five months after the diagnosis, yet the trials that set the standard mostly exclude active brain disease. Requiring a brain metastasis cohort in every phase 3, with intracranial response as an endpoint, would answer whether the new drugs reach the brain."},{"id":"idea-tnbc-disparities-in-access-and-outcomes","kind":"idea","name":"Close the gap between who gets triple-negative breast cancer and who is in its trials","route":"/ideas/idea-tnbc-disparities-in-access-and-outcomes/","tldr":"Black women in the United States have about twice the odds of a triple-negative diagnosis and, in the UK POSH cohort, worse survival than White women despite equal chemotherapy use. The pivotal trials enrolled few of them. Enrolment targets tied to incidence, reported by ethnicity in every primary paper, would make the evidence match the disease."},{"id":"idea-tnbc-uk-ethnicity-stratified-outcome-reporting","kind":"idea","name":"Ethnicity-stratified outcome reporting for triple-negative breast cancer in NHS cancer statistics","route":"/ideas/idea-tnbc-uk-ethnicity-stratified-outcome-reporting/","tldr":"The one UK study to look found young Black women had more triple-negative breast cancer and worse survival than White women despite equal chemotherapy, but it ended in 2008 and covered women under 41. Routine cancer statistics could report triple-negative incidence, stage and survival by ethnicity every year; at present they do not."}],"trials":[],"papers":[{"id":"paper-rugo-pd-l1-assay-comparison-impassion130-jnci-2021","name":"PD-L1 Immunohistochemistry Assay Comparison in Atezolizumab Plus nab-Paclitaxel-Treated Advanced Triple-Negative Breast Cancer","route":"/key-papers/paper-rugo-pd-l1-assay-comparison-impassion130-jnci-2021/","journal":"Journal of the National Cancer Institute","year":2021,"whatItMeans":"The clearest demonstration that PD-L1 positive in triple-negative breast cancer means different things depending on the kit; with atezolizumab withdrawn, pembrolizumab's 22C3 combined positive score of 10 is the surviving standard, and roughly a quarter of patients get a different answer depending on which assay their laboratory runs."},{"id":"paper-lin-tnbc-cns-metastases-dfci-cancer-2008","name":"Sites of distant recurrence and clinical outcomes in patients with metastatic triple-negative breast cancer: high incidence of central nervous system metastases","route":"/key-papers/paper-lin-tnbc-cns-metastases-dfci-cancer-2008/","journal":"Cancer","year":2008,"whatItMeans":"The 13.3-month median is the pre-immunotherapy, pre-antibody-drug conjugate benchmark against which first-line trials now reporting medians near two years are measured; the brain metastasis rate is why trials that exclude active brain disease leave the question unanswered."},{"id":"paper-scott-tnbc-disparities-uscs-cancer-2019","name":"Update on triple-negative breast cancer disparities for the United States: A population-based study from the United States Cancer Statistics database, 2010 through 2014","route":"/key-papers/paper-scott-tnbc-disparities-uscs-cancer-2019/","journal":"Cancer","year":2019,"whatItMeans":"The most recent national figure behind the statement that Black women in the United States have about twice the incidence of triple-negative breast cancer; trial enrolment has not matched it."},{"id":"paper-copson-posh-ethnicity-young-breast-cancer-uk-bjc-2014","name":"Ethnicity and outcome of young breast cancer patients in the United Kingdom: the POSH study","route":"/key-papers/paper-copson-posh-ethnicity-young-breast-cancer-uk-bjc-2014/","journal":"British Journal of Cancer","year":2014,"whatItMeans":"The UK's own evidence that the disparity is not only American and not only about access: within the NHS, with equal chemotherapy use, young Black women had more triple-negative disease and worse survival. It anchors the disparities idea on the triple-negative page and the UK and NHS page."}]}],"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":[{"id":"tropion-breast02","kind":"trial","name":"TROPION-Breast02","route":"/trials/tropion-breast02/","status":"positive","tldr":"The first trial to show an overall survival benefit for a first-line ADC in triple-negative breast cancer."},{"id":"datopotamab-deruxtecan","kind":"drug","name":"Datopotamab deruxtecan","route":"/drugs/datopotamab-deruxtecan/","status":"approved","tldr":"Datopotamab deruxtecan (Datroway) is the second TROP2 ADC and shares Enhertu's payload. In 2026 it became a first-line option for triple-negative breast cancer patients who cannot receive immunotherapy."}]},{"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":[{"id":"nct03997123","kind":"trial","name":"Capivasertib+Paclitaxel as First Line Treatment for Patients With Locally Advanced or Metastatic TNBC","route":"/trials/nct03997123/","status":"active","tldr":"A phase 3 trial of Capivasertib in triple-negative breast cancer, run by AstraZeneca, active and no longer recruiting."},{"id":"capivasertib","kind":"drug","name":"Capivasertib","route":"/drugs/capivasertib/","status":"approved","tldr":"Capivasertib (Truqap) is the first AKT inhibitor, for breast cancer with PI3K-pathway mutations and, since 2026, for prostate cancer with PTEN loss."},{"id":"paper-capitello-290-capivasertib-paclitaxel-ann-oncol-2026","kind":"paper","name":"Capivasertib plus paclitaxel as first-line treatment for metastatic triple-negative breast cancer: results from the randomised, global phase III CAPItello-290 trial","route":"/key-papers/paper-capitello-290-capivasertib-paclitaxel-ann-oncol-2026/","tldr":"The 812-patient trial in which adding the AKT inhibitor capivasertib to first-line paclitaxel did not lengthen life in metastatic triple-negative breast cancer (17.7 versus 18.0 months), even in the 31 percent of patients whose tumours carried the pathway alterations it targets."}]},{"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":[{"id":"ascent-05","kind":"trial","name":"ASCENT-05 / OptimICE-RD (AFT-65, GBG 119, NSABP B-63)","route":"/trials/ascent-05/","status":"recruiting","tldr":"Tests whether giving a TROP2 ADC after surgery can cure more of the triple-negative patients whose cancer survived pre-surgery chemo-immunotherapy."},{"id":"sacituzumab-govitecan","kind":"drug","name":"Sacituzumab govitecan","route":"/drugs/sacituzumab-govitecan/","status":"approved","tldr":"The first TROP2-targeted ADC. It delivers a strong chemotherapy directly to breast and bladder cancer cells and is now a first-line option in triple-negative breast cancer."},{"id":"pembrolizumab","kind":"drug","name":"Pembrolizumab","route":"/drugs/pembrolizumab/","status":"approved","tldr":"Pembrolizumab is a PD-1 blocking antibody approved in more than 40 settings, from melanoma and lung cancer to the first tumour-agnostic approval for mismatch-repair-deficient tumours in 2017, and before and after surgery in triple-negative breast cancer. A subcutaneous form arrived in 2025, and it is the backbone partner for ADCs and personalised neoantigen vaccines."},{"id":"rcb","kind":"term","name":"Residual cancer burden (RCB)","route":"/terms/rcb/","tldr":"A pathology score for how much cancer remains in the breast and lymph nodes after pre-surgery treatment, from 0 (none) to III (a large amount), combining tumour bed size, cellularity and nodal involvement. RCB-II or III after neoadjuvant therapy predicts a high risk of relapse and defines who enters escalation trials."}]},{"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":[{"id":"tropion-breast05","kind":"trial","name":"TROPION-Breast05","route":"/trials/tropion-breast05/","status":"recruiting","tldr":"Tests whether Dato-DXd plus a PD-L1 blocker beats today's immunotherapy-chemotherapy standard."},{"id":"datopotamab-deruxtecan","kind":"drug","name":"Datopotamab deruxtecan","route":"/drugs/datopotamab-deruxtecan/","status":"approved","tldr":"Datopotamab deruxtecan (Datroway) is the second TROP2 ADC and shares Enhertu's payload. In 2026 it became a first-line option for triple-negative breast cancer patients who cannot receive immunotherapy."},{"id":"cps","kind":"term","name":"Combined positive score (CPS)","route":"/terms/cps/","tldr":"A PD-L1 score that counts stained tumour cells and immune cells together."}]},{"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":[{"id":"nct06419621","kind":"trial","name":"PM8002 or Placebo Plus Nab-Paclitaxel as First-line Treatment in Inoperable Locally Advanced/Metastatic TNBC","route":"/trials/nct06419621/","status":"active","tldr":"A phase 3 trial testing PM8002 in triple-negative breast cancer, active and no longer recruiting."},{"id":"nab-paclitaxel","kind":"drug","name":"Nab-paclitaxel","route":"/drugs/nab-paclitaxel/","status":"approved","tldr":"Paclitaxel bound to albumin so it needs no solvent and no steroid premedication. Adding it to gemcitabine and cisplatin looked promising in a small study of bile duct and gallbladder cancer but did not lengthen life in the 452-patient SWOG S1815 trial."}]},{"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":[{"id":"tropion-breast03","kind":"trial","name":"TROPION-Breast03","route":"/trials/tropion-breast03/","status":"active","tldr":"TROPION-Breast03 is the Dato-DXd counterpart to ASCENT-05: an ADC, with or without immunotherapy, for triple-negative patients with leftover cancer at surgery."},{"id":"datopotamab-deruxtecan","kind":"drug","name":"Datopotamab deruxtecan","route":"/drugs/datopotamab-deruxtecan/","status":"approved","tldr":"Datopotamab deruxtecan (Datroway) is the second TROP2 ADC and shares Enhertu's payload. In 2026 it became a first-line option for triple-negative breast cancer patients who cannot receive immunotherapy."},{"id":"rcb","kind":"term","name":"Residual cancer burden (RCB)","route":"/terms/rcb/","tldr":"A pathology score for how much cancer remains in the breast and lymph nodes after pre-surgery treatment, from 0 (none) to III (a large amount), combining tumour bed size, cellularity and nodal involvement. RCB-II or III after neoadjuvant therapy predicts a high risk of relapse and defines who enters escalation trials."}]},{"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":[{"id":"bl-b01d1-307","kind":"trial","name":"BL-B01D1-307","route":"/trials/bl-b01d1-307/","status":"positive","tldr":"The first phase 3 win for a bispecific ADC, in triple-negative breast cancer, announced February 2026."},{"id":"izalontamab-brengitecan","kind":"drug","name":"Izalontamab brengitecan","route":"/drugs/izalontamab-brengitecan/","status":"phase-3","tldr":"Izalontamab brengitecan is the first bispecific ADC to succeed in a phase 3 trial, hitting two growth receptors at once in triple-negative breast cancer."}]},{"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":[{"id":"izabright-breast01","kind":"trial","name":"IZABRIGHT-Breast01","route":"/trials/izabright-breast01/","status":"recruiting","tldr":"IZABRIGHT-Breast01 is the global first-line trial of the EGFR×HER3 bispecific ADC in triple-negative breast cancer."},{"id":"izalontamab-brengitecan","kind":"drug","name":"Izalontamab brengitecan","route":"/drugs/izalontamab-brengitecan/","status":"phase-3","tldr":"Izalontamab brengitecan is the first bispecific ADC to succeed in a phase 3 trial, hitting two growth receptors at once in triple-negative breast cancer."},{"id":"bispecific-adc","kind":"technology","name":"Bispecific ADC","route":"/technologies/bispecific-adc/","status":"phase-3","tldr":"A bispecific ADC is an ADC whose antibody grabs two different proteins on the cancer cell, so it sticks better to tumour and less to healthy tissue."}]},{"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":[{"id":"olympia","kind":"trial","name":"OlympiA","route":"/trials/olympia/","status":"positive","tldr":"Showed that a year of a PARP inhibitor after standard treatment improves survival in women with inherited BRCA mutations."},{"id":"olaparib","kind":"drug","name":"Olaparib","route":"/drugs/olaparib/","status":"approved","tldr":"Olaparib was the first PARP inhibitor, and turned an inherited BRCA mutation from a risk factor into a drug target, including after surgery in breast cancer."},{"id":"paper-olympia-6-year-update-ann-oncol-2026","kind":"paper","name":"Sustained benefit of adjuvant olaparib in women with germline BRCA1- and BRCA2-associated high-risk HER2-negative early breast cancer: updated results from the OlympiA phase III trial","route":"/key-papers/paper-olympia-6-year-update-ann-oncol-2026/","tldr":"The six-year OlympiA update: the year of olaparib still cut relapse by 35 percent and death by 28 percent, six-year survival was 87.5 versus 83.2 percent, there were fewer new BRCA-related breast and ovarian cancers, and no excess of leukaemia."}]},{"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":[{"id":"scarlet-s2212","kind":"trial","name":"SCARLET (SWOG S2212)","route":"/trials/scarlet-s2212/","status":"recruiting","tldr":"Tests whether the anthracycline can be dropped from TNBC pre-surgery treatment without losing effect."},{"id":"keynote-522","kind":"trial","name":"KEYNOTE-522","route":"/trials/keynote-522/","status":"positive","tldr":"The trial that added immunotherapy to pre-surgery chemotherapy for triple-negative breast cancer and, uniquely, improved survival."},{"id":"anthracycline","kind":"term","name":"Anthracyclines (doxorubicin, epirubicin)","route":"/terms/anthracycline/","tldr":"A family of red chemotherapy drugs derived from a soil bacterium that damage cancer DNA. Cornerstones of breast cancer, lymphoma, leukaemia and sarcoma treatment, but they weaken the heart in a dose-dependent way, so there is a lifetime limit."},{"id":"de-escalation","kind":"term","name":"De-escalation, escalation and response-adapted therapy","route":"/terms/de-escalation/","tldr":"Giving less treatment to patients who are doing well and more to those who are not, using a marker such as scan response, ctDNA or MRD to decide. The aim is to cure the same number of people with less harm."}]},{"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":[{"id":"optimice-pcr","kind":"trial","name":"OptimICE-pCR (A012103)","route":"/trials/optimice-pcr/","status":"recruiting","tldr":"Asks whether patients whose cancer completely disappeared before surgery still need a year of immunotherapy afterwards."},{"id":"pembrolizumab","kind":"drug","name":"Pembrolizumab","route":"/drugs/pembrolizumab/","status":"approved","tldr":"Pembrolizumab is a PD-1 blocking antibody approved in more than 40 settings, from melanoma and lung cancer to the first tumour-agnostic approval for mismatch-repair-deficient tumours in 2017, and before and after surgery in triple-negative breast cancer. A subcutaneous form arrived in 2025, and it is the backbone partner for ADCs and personalised neoantigen vaccines."},{"id":"pcr","kind":"term","name":"Pathologic complete response (pCR)","route":"/terms/pcr/","tldr":"No invasive cancer left in the breast and lymph nodes when the surgeon removes the tissue after pre-surgery treatment."},{"id":"de-escalation","kind":"term","name":"De-escalation, escalation and response-adapted therapy","route":"/terms/de-escalation/","tldr":"Giving less treatment to patients who are doing well and more to those who are not, using a marker such as scan response, ctDNA or MRD to decide. The aim is to cure the same number of people with less harm."}]},{"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":[{"id":"adc-sequencing","kind":"term","name":"ADC sequencing","route":"/terms/adc-sequencing/","tldr":"The open question of whether a second ADC works after the first one fails, especially when both carry the same type of payload."},{"id":"idea-tnbc-adc-sequencing-trial","kind":"idea","name":"A randomised trial of antibody-drug conjugate sequence in metastatic triple-negative breast cancer","route":"/ideas/idea-tnbc-adc-sequencing-trial/","tldr":"Three antibody-drug conjugates now used in triple-negative breast cancer carry the same kind of chemotherapy warhead, a topoisomerase inhibitor. Nobody has randomised which to give first or whether the second works after the first; small series suggest it often does not. With two now approved first line, the question decides what a patient gets for the rest of her life."}]},{"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":[{"id":"ctdna","kind":"term","name":"Circulating tumour DNA (ctDNA)","route":"/terms/ctdna/","tldr":"Circulating tumour DNA (ctDNA) consists of fragments of DNA shed by tumour cells into the blood, detectable with sensitive sequencing."},{"id":"mrd-testing","kind":"technology","name":"MRD / molecular residual disease testing","route":"/technologies/mrd-testing/","status":"established","tldr":"An ultra-sensitive blood test after surgery that detects leftover cancer months before a scan would."},{"id":"idea-tnbc-ctdna-guided-adjuvant-decisions","kind":"idea","name":"ctDNA-guided adjuvant decisions after residual disease: escalate the positive, spare the negative","route":"/ideas/idea-tnbc-ctdna-guided-adjuvant-decisions/","tldr":"After pre-surgery chemotherapy leaves tumour behind, a blood test for tumour DNA triples the risk of distant relapse when positive. The one trial that acted on it found the DNA usually appeared too late. A trial that tests at surgery with a tumour-informed assay, escalates positives to an antibody-drug conjugate and observes negatives has not been run."}]}]}