Abstract PS4-03-26: Cell-free DNA BRCA copy number loss and/or deletions in patients with metastatic breast cancer: incidence and association with clinical and genomic features

Abstract Background: BRCA mutations may impact outcomes in metastatic breast cancer (MBC). While germline and somatic BRCA mutations have been studied, the incidence and impact of cell-free DNA (cfDNA) BRCA copy number loss and/or deletions (CNL/D) are not known. We evaluated cfDNA BRCA CNL/D, and the association with clinical/genomic features in MBC. Methods: Patients with MBC with cfDNA (Guardant360 next-generation sequencing) results at 3 academic centers in the Precision Medicine Action for Cancer consortium from 12/2021 (when Guardant360 began reporting BRCA CNL/D) to 1/2024 were identified. A retrospective analysis was conducted to identify clinical/genomic features associated with cfDNA BRCA1 and/or 2 CNL/D. Median therapy durations and overall survival (OS) after detection of cfDNA BRCA CNL/D were estimated with the Kaplan-Meier method. Results: Among 1,198 patients with MBC who had cfDNA testing, 65 (5.4%) had cfDNA BRCA CNL/D. In the cohort with cfDNA BRCA CNL/D, median age at MBC diagnosis was 60 years. Subtypes included 47/65 (72%) hormone receptor (HR)+/HER2-, 15/65 (23%) triple negative, and 3/65 (4.6%) HER2+. Prior to cfDNA testing, patients received a median of 1 hormone therapy (HR+/HER2-) and 0 chemotherapy agents (all subtypes) for MBC. Table 1 shows the types of cfDNA BRCA CNL/D that were detected. Of patients with cfDNA BRCA CNL/D, 16/65 (25%) were BRCA1, 37/65 (57%) BRCA2, and 12/65 (18%) BRCA1&2. Thirteen of 65 (20%) patients had a co-existing pathogenic cfDNA BRCA mutation, 40/65 (62%) had a cfDNA TP53 mutation, and 43/65 (66%) had cfDNA high tumor mutation burden (TMB) >/= 10 mut/Mb. Ten of 32 (31%) patients with tumor tissue genotyping results had a concomitant tissue BRCA1/2 mutation. Five of 45 (11%) patients with germline genetic testing results had a concomitant germline BRCA1/2 mutation. Median duration on first therapy post detection of cfDNA BRCA CNL/D was 94 days (95% confidence interval (CI): 54-134 days). Post detection of cfDNA BRCA CNL/D, 5 patients received platinum chemotherapy with a median response duration of 168 days (range 32-582 days), and 4 patients received a PARP inhibitor with a median response duration of 105 days (range 26-231). Median OS after detection of BRCA CNL/D was 490 days (95% CI: 232-748 days). Conclusions: CfDNA BRCA CNL/D were detectable in a subset of patients with MBC, with most present in non-germline BRCA carriers. CfDNA BRCA CNL/D co-occurred frequently with TP53 mutations and elevated TMB, suggesting the possibility that cfDNA BRCA CNL/D could arise from increased mutagenesis in MBC. Further research is needed to define the impact of platinum and PARP inhibitor therapy in this cohort. Citation Format: N. Vidula, D. Giannarelli, A. Putur, L. Pontollilo, E. Nicolo, C. Reduzzi, E. Podany, G. Cunningham, A. Davis, E. Blouch, M. Cristofanilli. Cell-free DNA BRCA copy number loss and/or deletions in patients with metastatic breast cancer: incidence and association with clinical and genomic features [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 PS4-03-26.