Abstract PS4-02-06: Analysis of BRCA1 and 2 mutations as predictive biomarkers of response to trastuzumab deruxtecan in hormone receptor-positive, HER2-low metastatic breast cancer: a systematic review and meta-analysis

Abstract Background: Trastuzumab deruxtecan (T-DXd), an antibody-drug conjugate targeting HER2, has shown significant clinical benefit in patients with HER2-low metastatic breast cancer. The DESTINY-Breast04 trial led to its approval in this setting, particularly among hormone receptor-positive (HR+) patients. Given its topoisomerase I inhibitor payload and DNA-damaging mechanism, tumors with homologous recombination deficiency, such as those harboring BRCA1/2 mutations, may be particularly sensitive to T-DXd. While prior studies have explored this hypothesis, the predictive role of BRCA mutations in the efficacy of T-DXd in HR+/HER2-low disease remains unclear and has not been systematically quantified. Objectives: To evaluate whether BRCA1/2 mutations are associated with improved efficacy of trastuzumab deruxtecan in patients with hormone receptor-positive, HER2-low metastatic breast cancer, by comparing objective response rate (ORR) and progression-free survival (PFS) between BRCA-mutated and BRCA wild-type populations. Methods: A systematic review and meta-analysis were conducted on June 23, 2025 according to PRISMA guidelines. Literature searches were performed in PubMed, Embase, Cochrane Library, and ASCO and ESMO websites databases. Eligible studies reported T-DXd outcomes stratified by BRCA mutation status in HR+/HER2-low metastatic breast cancer. Two reviewers independently performed study selection and data extraction. The primary endpoints were objective response rate (ORR) and progression-free survival (PFS). Analyses were performed using R software (v.4.2.2) with random-effects models. The protocol for this systematic review and meta-analysis was registered in the PROSPERO international prospective register of systematic reviews (ID: CRD420251089678). Results: A total of 3,194 records were retrieved, and after deduplication, 2,461 unique records were screened. Three studies were included: two randomized trials (DESTINY-Breast04 and DESTINY-Breast06) and one large real-world cohort (Tarantino et al., 2025). Patients with BRCA1/2 mutations demonstrated a significantly higher ORR compared to BRCA wild-type counterparts, with a pooled odds ratio of 4.48 (95% CI 1.66-12.09; I2 = 0%). For PFS, the pooled hazard ratio favored BRCA-mutated patients (HR 0.56, 95% CI 0.15-2.04), although with substantial heterogeneity (I2 = 90.3%). Conclusions: This is the first meta-analysis to evaluate the predictive impact of BRCA1/2 mutations on the efficacy of T-DXd specifically in HR+/HER2-low metastatic breast cancer. BRCA mutations appear to be associated with significantly higher response rates and a potential progression-free survival advantage. These results highlight the need to consider BRCA status as a predictive biomarker in future clinical trials of T-DXd and support its role in guiding therapeutic decisions in HER2-low disease. Citation Format: L. P. Genovez, H. J. Kim, S. M. Sanches, M. G. Cesca. Analysis of BRCA1 and 2 mutations as predictive biomarkers of response to trastuzumab deruxtecan in hormone receptor-positive, HER2-low metastatic breast cancer: a systematic review and meta-analysis abstract. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS4-02-06.