{"entity":{"id":"paper-destiny-breast04-nejm-2022","kind":"paper","name":"DESTINY-Breast04: trastuzumab deruxtecan works in HER2-low breast cancer, creating a new treatable group","aka":[],"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.","summary":"Open-label phase 3 trial of 557 patients with HER2-low (IHC 1+ or IHC 2+/ISH-negative) metastatic breast cancer after one or two lines of chemotherapy, randomised 2:1 to trastuzumab deruxtecan or physician's choice chemotherapy. About 89% were hormone-receptor positive. Primary endpoint was PFS in the HR-positive cohort.\n\nMedian PFS was 10.1 vs 5.4 months (HR 0.51) in the HR-positive cohort and overall survival 23.9 vs 17.5 months (HR 0.64); results in the whole population were similar. Roughly half of all breast cancers are HER2-low, so the trial redefined HER2 testing and opened ADC therapy to a very large population.","asOf":"2026-09-08","links":[{"label":"NEJM 2022","url":"https://doi.org/10.1056/NEJMoa2203690"},{"label":"ClinicalTrials.gov NCT03734029","url":"https://clinicaltrials.gov/study/NCT03734029"}],"tags":[],"related":["idea-payload-switching","her2-low-ihc"],"cancers":["breast-hr-positive","tnbc","tnbc-metastatic"],"sections":[],"technologies":["adc","histopathology-ihc","companion-diagnostic"],"targets":["her2"],"drugs":["trastuzumab-deruxtecan"],"companies":["daiichi-sankyo","astrazeneca"],"institutions":[],"pathways":[],"terms":["her2-low","ihc","bystander-effect","ild","pfs","os"],"trials":["destiny-breast04"],"people":["sohn-joohyuk","park-yeon-hee","xu-binghe","im-seock-ah","hope-rugo","kim-sung-bae","david-cameron"],"bottlenecks":["b-biomarker-validation","b-toxicity-qol"],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2022,"doi":"10.1056/NEJMoa2203690","authors":"Modi S, Jacot W, Yamashita T, et al.","paperType":"rct","findings":["HR-positive cohort: median PFS 10.1 vs 5.4 months, HR 0.51 (95% CI 0.40-0.64); median OS 23.9 vs 17.5 months, HR 0.64.","All patients: median PFS 9.9 vs 5.1 months (HR 0.50); median OS 23.4 vs 16.8 months (HR 0.64).","Benefit was similar for IHC 1+ and IHC 2+/ISH-negative tumours, questioning whether HER2 level is the true predictor.","The small HR-negative (triple-negative) cohort of about 58 patients showed a consistent trend (PFS HR 0.46).","Drug-related interstitial lung disease in 12.1% of T-DXd patients, including three deaths."],"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.","caveats":["HER2-low scoring by immunohistochemistry is poorly reproducible between pathologists, and the assay was never designed to distinguish 0 from 1+.","Fatal pneumonitis occurred; patients need CT surveillance and rapid steroid treatment of symptoms.","The triple-negative cohort was exploratory and small.","DESTINY-Breast06 later showed activity in HER2-ultralow (faint staining) tumours, suggesting the biomarker threshold is arbitrary."],"changedPractice":true,"participants":557},"route":"/key-papers/paper-destiny-breast04-nejm-2022/","neighbours":{"idea":[{"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/"},{"id":"idea-payload-switching","kind":"idea","name":"Payload-class switching as the rule for ADC sequencing","route":"/ideas/idea-payload-switching/"},{"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/"}],"biomarker":[{"id":"her2-low-ihc","kind":"biomarker","name":"HER2-low (IHC 1+ or IHC 2+/ISH-negative)","route":"/biomarkers/her2-low-ihc/"}],"cancer":[{"id":"breast-hr-positive","kind":"cancer","name":"HR-positive / HER2-negative breast cancer","route":"/cancers/breast-hr-positive/"},{"id":"tnbc-metastatic","kind":"cancer","name":"Metastatic triple-negative breast cancer","route":"/cancers/tnbc-metastatic/"},{"id":"tnbc","kind":"cancer","name":"Triple-negative breast cancer (TNBC)","route":"/cancers/tnbc/"}],"technology":[{"id":"adc","kind":"technology","name":"Antibody-drug conjugate (ADC)","route":"/technologies/adc/"},{"id":"companion-diagnostic","kind":"technology","name":"Companion diagnostics","route":"/technologies/companion-diagnostic/"},{"id":"histopathology-ihc","kind":"technology","name":"Histopathology & immunohistochemistry","route":"/technologies/histopathology-ihc/"}],"target":[{"id":"her2","kind":"target","name":"HER2","route":"/targets/her2/"}],"drug":[{"id":"trastuzumab-deruxtecan","kind":"drug","name":"Trastuzumab deruxtecan","route":"/drugs/trastuzumab-deruxtecan/"}],"company":[{"id":"astrazeneca","kind":"company","name":"AstraZeneca","route":"/companies/astrazeneca/"},{"id":"daiichi-sankyo","kind":"company","name":"Daiichi Sankyo","route":"/companies/daiichi-sankyo/"}],"term":[{"id":"bystander-effect","kind":"term","name":"Bystander effect (ADC)","route":"/terms/bystander-effect/"},{"id":"her2-low","kind":"term","name":"HER2-low and HER2-ultralow","route":"/terms/her2-low/"},{"id":"ihc","kind":"term","name":"Immunohistochemistry (IHC)","route":"/terms/ihc/"},{"id":"ild","kind":"term","name":"Interstitial lung disease (ILD) / pneumonitis","route":"/terms/ild/"},{"id":"os","kind":"term","name":"Overall survival (OS)","route":"/terms/os/"},{"id":"pfs","kind":"term","name":"Progression-free survival (PFS)","route":"/terms/pfs/"}],"trial":[{"id":"destiny-breast04","kind":"trial","name":"DESTINY-Breast04","route":"/trials/destiny-breast04/"}],"person":[{"id":"xu-binghe","kind":"person","name":"Binghe Xu","route":"/people/xu-binghe/"},{"id":"david-cameron","kind":"person","name":"David Cameron","route":"/people/david-cameron/"},{"id":"hope-rugo","kind":"person","name":"Hope S. Rugo","route":"/people/hope-rugo/"},{"id":"sohn-joohyuk","kind":"person","name":"Joohyuk Sohn","route":"/people/sohn-joohyuk/"},{"id":"im-seock-ah","kind":"person","name":"Seock-Ah Im","route":"/people/im-seock-ah/"},{"id":"shanu-modi","kind":"person","name":"Shanu Modi","route":"/people/shanu-modi/"},{"id":"kim-sung-bae","kind":"person","name":"Sung-Bae Kim","route":"/people/kim-sung-bae/"},{"id":"park-yeon-hee","kind":"person","name":"Yeon Hee Park","route":"/people/park-yeon-hee/"}],"bottleneck":[{"id":"b-biomarker-validation","kind":"bottleneck","name":"Biomarkers are not validated or standardised","route":"/bottlenecks/b-biomarker-validation/"},{"id":"b-toxicity-qol","kind":"bottleneck","name":"Toxicity and quality of life are undervalued","route":"/bottlenecks/b-toxicity-qol/"}],"journal":[{"id":"nejm","kind":"journal","name":"New England Journal of Medicine","route":"/journals/nejm/"}],"paper":[{"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/"}],"roadmap":[{"id":"tnbc-roadmap","kind":"roadmap","name":"Triple-negative breast cancer roadmap: from a remainder defined by three negative tests to immunotherapy, antibody-drug conjugates and the residual disease problem","route":"/roadmaps/tnbc-roadmap/"}]}}