Molecular and clinical insights of trastuzumab deruxtecan efficacy in advanced breast cancer

BACKGROUND: Trastuzumab deruxtecan (T-DXd) has transformed the treatment paradigm for HER2-expressing breast cancer, including HER2-low disease. However, biomarkers associated with T-DXd activity remain poorly defined. We conducted a comprehensive analysis of clinical, genomic, and immune correlates of T-DXd outcomes to identify molecular determinants of therapeutic benefit and resistance. METHODS: We retrospectively analyzed 2 independent cohorts of patients with advanced breast cancer treated with T-DXd at Dana-Farber Cancer Institute and Yale Cancer Center between 2018 and 2024. We included patients with ≥2 tumor blocks with HER2 immunohistochemistry (IHC) assessments prior to T-DXd. Clinical data on 524 patients were manually reviewed, and genomic profiling and immune microenvironment assessments were performed on a subset of patients. Multivariable Cox proportional hazards models evaluated associations between molecular features and overall survival (OS) and time to next treatment (TTNT). RESULTS: Among 524 patients, HER2 IHC discordance between sequential tumor biopsies was observed in 20% of patients and was independently associated with significantly worse OS (hazard ratio [HR] = 0.67; P = .012) and TTNT (HR = 0.65; P = .002), resembling outcomes seen in HER2 0 tumors. Genomic analysis revealed that PTEN mutations correlated with inferior TTNT (HR = 2.2; q = 0.068), whereas ERBB2 amplifications predicted improved OS and TTNT. An inflamed tumor microenvironment determined by digital pathology was associated with significantly poorer TTNT outcomes (median TTNT = 5.5 months) compared with immune-desert phenotypes (median OS = 9.6 months, P = .03). CONCLUSIONS: This study identifies HER2 IHC discordance and specific genomic and immune features as prognostic biomarkers of T-DXd efficacy. These findings warrant prospective validation and may inform biomarker-driven strategies to optimize T-DXd therapy in HER2-expressing malignancies.