Abstract Background: PARP inhibitors (PARPi) are a standard of care for breast cancer (BC) patients (pts) with germline BRCA (gBRCA) mutation, with benefit demonstrated also in patients with somatic (s) BRCA1/2 mutations. The use of circulating tumor (ct) DNA testing allows to detect resistant and actionable alterations in BC, but it could be associated with the incidental identification of germinal mutations. The aim of this study was to describe the incidence of both, somatic and germinal BRCA1/2 alterations, and the impact on the therapeutic outcomes in a retrospective BC cohort with clinical ctDNA testing for their BC. Materials and methods: A retrospective cohort of 245 BC pts that underwent ctDNA analysis (Guardant 360) between August 2014 and May 2023 at Weill Cornell Medical College was identified. Pts with at least a BRCA1/2 alteration, including variant of uncertain significant (VUS) and synonymous, were enrolled in the study. A descriptive analysis was performed. Results: Among 35 patients included, 34 had metastatic disease, the median age was 61 years old (IQR 40-67), and 65.7% were post-menopausal at diagnosis. 57.1% of pts had hormone receptor positive/HER2 negative (HR+/HER2-) BC, 20% had HER2 positive disease and 22.9% were triple-negative (TN) BC. Ten (28.6%) and 20 (57.1%) pts had a sBRCA1 or a sBRCA2 alteration on ctDNA, respectively; 5 pts (14.3%) had a coexisting sBRCA1/2 mutation. The median variant allele frequency (VAF) was 1.2% for BRCA1 and 2.7% for BRCA2 alterations. Furthermore, 53.3% and 6.7% of sBRCA1 and 40% and 8% of sBRCA2 mutations were identified as VUS and synonymous, respectively. The most common associated genomic alterations included TP53 (62.9%), ESR1 (20%) and PI3KCA (52%) with a median number of 4 variants (IQR 2-7). Next generation sequencing (NGS) testing on tissue was available for 3 patients: two demonstrated concordance with BRCA alterations detected by ctDNA, whereas no alteration in BRCA1/2 genes was found for the third patient despite the tissue analysis was performed at the same time of the ctDNA. Germline testing was available for 24 (69%) pts; a corresponding gBRCA1 mutation was found for 3 pts (VAF 48.6%-84.3%), and a gBRCA2 for 8 pts (VAF 26.7%-49.5%). Due to the small sample size, a univocal VAF cut-off to detect gBRCA1/2 mutations could not be calculated. Twenty-nine pts had a sBRCA1/2 mutation detected by ctDNA test before starting a new therapy; of these 55.2% had HR+/HER2- disease, while 17.2% and 27.6% were HER2 positive and TN BC, respectively. The median progression free survival (mPFS) was 10.3 (3.2-17.4) months (ms) and the 1-year and 2-year overall survival (OS) rates were 82.3% and 70.5%, respectively. The mPFS was 10.3 ms (0-25.0) for patients (n=16) that underwent chemotherapy, 5.6 ms (0-15.1) for those who had received endocrine therapy (n=9), and not reached for patients treated with PARPi (n=4). Conclusions: ctDNA analysis allows the detection of sBRCA1/2 mutations that could be missed by tissue-based testing. The identification of BRCA alterations on ctDNA could guide the use of germline testing even when these are present at a lower VAF than expected, with relevant impact on the therapeutic choices and family screening. Further evaluation to establish the impact of sBRCA1/2 detected by ctDNA on the therapeutic algorithm decision are needed. Citation Format: Letizia Pontolillo, Eleonora Nicolò, Laura Munoz Arcos, Carolina Reduzzi, Mara Serena Serafini, Amanda Kaylan Strickland, Nadia Bayou, Jeannine Donahue, Elisabetta Molteni, Lorenzo Gerratana, Diana Giannarelli, Eleni Andreopoulou, Emilio Bria, Massimo Cristofanilli. Association between BRCA alterations detected by circulating tumor DNA and germline mutations in breast cancer patients: a retrospective mono-institutional analysis [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-14-11.
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