DESTINY-Breast04: trastuzumab deruxtecan works in HER2-low breast cancer, creating a new treatable group
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.
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.
Median 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.
- 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.
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.
- 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.
Pages like this
not linked directly; found by shared links- Key paperDESTINY-Breast03: trastuzumab deruxtecan beats T-DM1 as second-line treatment of HER2-positive metastatic breast cancer
Shares Sung-Bae Kim, Yeon Hee Park, Seock-Ah Im, Binghe Xu.
- Key paperDESTINY-Breast06: trastuzumab deruxtecan before any chemotherapy in hormone-receptor-positive, HER2-low or ultralow breast cancer
Shares Joohyuk Sohn, Seock-Ah Im, Immunohistochemistry (IHC), Interstitial lung disease (ILD) / pneumonitis.
- Key paperTROPION-Breast01: datopotamab deruxtecan versus chemotherapy in pretreated hormone-receptor-positive breast cancer, and why a PFS win did not translate to survival
Shares Seock-Ah Im, Binghe Xu, Immunohistochemistry (IHC), Payload-class switching as the rule for ADC sequencing.
- IdeaCalibrated reference slides so every lab scores HER2-low the same way
Shares DESTINY-Breast04, Immunohistochemistry (IHC), HER2-low and HER2-ultralow, Histopathology & immunohistochemistry.
- PairingHER2-low scoring → T-DXd
Shares DESTINY-Breast04, HER2-low and HER2-ultralow, Histopathology & immunohistochemistry, Trastuzumab deruxtecan.
- IdeaAI quantification of HER2-low and HER2-ultralow
Shares Immunohistochemistry (IHC), HER2-low and HER2-ultralow, Histopathology & immunohistochemistry, Trastuzumab deruxtecan.
- Key paperSPOTLIGHT: zolbetuximab, the first Claudin 18.2 antibody, added to chemotherapy in gastric cancer
Shares Immunohistochemistry (IHC), Companion diagnostics, Histopathology & immunohistochemistry, Overall survival (OS).
- IdeaRe-test the metastasis, not the old primary, before every change of treatment
Shares Immunohistochemistry (IHC), HER2-low and HER2-ultralow, Histopathology & immunohistochemistry, HR-positive / HER2-negative breast cancer.