{"entity":{"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","aka":[],"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.","summary":"Schettini's 3,689-patient study found HER2-low in 36.6 percent of triple-negative tumours, no biological difference between HER2-low and HER2 0 triple-negative disease, and suboptimal reproducibility of the HER2-low call among pathologists; DESTINY-Breast04 showed trastuzumab deruxtecan lengthens survival in HER2-low metastatic disease including the triple-negative cohort. The HER2 score was designed to find amplification, so the 0 versus 1+ distinction was never quality-assured, and the HER2-ultralow category (0 with faint staining in 10 percent or fewer cells) that DESTINY-Breast06 validated in hormone receptor-positive disease has no triple-negative evidence yet. Digital scoring algorithms for HER2 low expression are in validation.","asOf":"2026-09-24","links":[{"label":"Schettini et al.: clinical, pathological and PAM50 features of HER2-low breast cancer (NPJ Breast Cancer 2021)","url":"https://europepmc.org/article/MED/33397968"}],"tags":["tnbc-evidence"],"related":[],"cancers":["tnbc","her2-low-metastatic-breast-cancer"],"sections":[],"technologies":["digital-pathology-ai","adc"],"targets":["her2"],"drugs":["trastuzumab-deruxtecan"],"companies":["astrazeneca","daiichi-sankyo"],"institutions":[],"pathways":[],"terms":["her2-low","her2-ultralow","ihc"],"trials":["destiny-breast04"],"people":[],"bottlenecks":["b-biomarker-validation","b-knowledge-diffusion"],"keyPapers":["paper-schettini-her2-low-features-npj-breast-cancer-2021","paper-destiny-breast04-nejm-2022","paper-destiny-breast04-nat-med-2025-update"],"journals":[],"dependsOn":[],"notes":[],"hypothesis":"Pathology-initiated re-scoring of HER2 on the diagnostic or metastatic specimen at relapse, using a standardised low-expression protocol with digital assistance, will raise the proportion of metastatic triple-negative patients recorded as HER2-low from under 25 percent to the 35 percent prevalence measured in cohorts and double the number receiving trastuzumab deruxtecan within two years.","rationale":"The drug and the approval exist; the limiting step is a score that was not designed for the decision it now makes, and the fix is a protocol and a re-read rather than a new test.","test":"Before-and-after audit across a pathology network: proportion of metastatic triple-negative cases with a documented HER2-low or HER2 0 status, concordance of re-scored versus original calls, proportion treated with trastuzumab deruxtecan; a nested validation of digital HER2 low-expression scoring against a reference panel; a prospective HER2-ultralow triple-negative cohort within the next trastuzumab deruxtecan trial.","maturity":"early-clinical","actor":"clinic","cost":"small","horizonYears":2},"route":"/ideas/idea-tnbc-her2-ultralow-testing-uptake/","neighbours":{"cancer":[{"id":"her2-low-metastatic-breast-cancer","kind":"cancer","name":"HER2-low and HER2-ultralow metastatic breast cancer","route":"/cancers/her2-low-metastatic-breast-cancer/"},{"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":"digital-pathology-ai","kind":"technology","name":"Digital pathology & AI","route":"/technologies/digital-pathology-ai/"}],"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":"her2-low","kind":"term","name":"HER2-low and HER2-ultralow","route":"/terms/her2-low/"},{"id":"ihc","kind":"term","name":"Immunohistochemistry (IHC)","route":"/terms/ihc/"}],"biomarker":[{"id":"her2-ultralow","kind":"biomarker","name":"HER2-ultralow (IHC 0 with membrane staining)","route":"/biomarkers/her2-ultralow/"}],"trial":[{"id":"destiny-breast04","kind":"trial","name":"DESTINY-Breast04","route":"/trials/destiny-breast04/"}],"bottleneck":[{"id":"b-biomarker-validation","kind":"bottleneck","name":"Biomarkers are not validated or standardised","route":"/bottlenecks/b-biomarker-validation/"},{"id":"b-knowledge-diffusion","kind":"bottleneck","name":"Knowledge reaches practice too slowly","route":"/bottlenecks/b-knowledge-diffusion/"}],"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/"},{"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/"},{"id":"paper-destiny-breast04-nat-med-2025-update","kind":"paper","name":"Trastuzumab deruxtecan in HER2-low metastatic breast cancer: long-term survival analysis of the randomized, phase 3 DESTINY-Breast04 trial","route":"/key-papers/paper-destiny-breast04-nat-med-2025-update/"}],"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/"}]}}