Abstract PS1-11-28: Prognostic impact of type and location of germline BRCA2 pathogenic or likely pathogenic variants in patients with HR+/HER2- advanced breast cancer: results from the multicenter real-world PAMBRACA study

Abstract Background: The type and location of germline likely pathogenic or pathogenic variants (LP/PVs) in the BRCA1 and BRCA2 genes influence the risk of developing ovarian and breast cancer (BC) and their prognosis. However, their clinical impact in patients (pts) with advanced BC (aBC) remains to be fully elucidated. Methods: The PAMBRACA study is a multicenter, hospital-based, retrospective cohort study including BRCA1 and BRCA2 LP/PV carriers with hormone receptor positive/HER2-negative (HR+/HER2-) aBC treated with endocrine therapy (ET) plus cyclin-dependent kinase 4/6 inhibitors (CDK4/6i). Some pts also received PARP inhibitors (PARPi) after progression on CDK4/6i plus ET. For this specific analysis, BRCA1 carriers were excluded due to limited sample size. We collected information on type [insertion-deletion mutation (INDEL), single nucleotide variant (SNV), or copy number variation (CNV)], coding consequences (frameshift, nonsense, splicing, or missense), truncating versus non-truncating status, and exon location]. OS was defined as the time between metastatic disease diagnosis and pt death. Pts without an event were censored at the date of last follow-up. To account for potential immortal time bias, observation times were left truncated at the time of BRCA testing. Moreover, association between BRCA LP/PV type/location and pt progression free survival (PFS) during CDK4/6i plus ET or subsequent PARPi was explored. Multivariate Cox regression modelling was used to assess the association between LP/PV type/location, clinically relevant variables and pt outcomes. Results: Seventy-two pts with BRCA2 LP/PV diagnosed with HR+/HER2- aBC between Jan 1998 and Dec 2023 in six Italian Institutions were included. All pts received CDK4/6i plus ET and 36 (50.0%) received PARPi in the advanced setting. Detailed mutation type and location information was available for 57 cases (79.2%). Regarding BRCA2 LP/PV types, 37 (64.9%) INDELs and 20 (35.1%) SNVs were identified. The coding consequences included 33 (57.9%) frameshift, 16 (28.1%) nonsense, 5 (8.8%) splicing and 3 (5.2%) missense LP/PVs. Protein impact analysis showed 49 (85.9%) truncating, 3 (5.3%) non-truncating, and 5 (8.8%) unclassifiable LP/PV. Regarding LP/PV location, 32 (56.1%) LP/PV were located in exon 11, while 25 (43.9%) in other exons. No significant differences in baseline clinicopathologic variables (including age at BC diagnosis, menopausal status, pathological stage at BC diagnosis, tumor grading, estrogen/progesterone receptor levels, Ki67 levels, HER2 expression, presence of de novo metastatic disease, metastatic sites involvement) and LP/PV type/location (INDEL vs. SNV, frameshift vs. nonsense vs. splicing vs. missense, truncating vs. not truncating, and exon location) were observed. 5-year OS rate was 51% [95% confidence interval (CI) 37-72]. No BRCA2 LP/PV type or location was associated with OS, even after adjusting for clinically relevant covariates. At multivariable analysis, a number of metastatic higher than 3 [adjusted hazard ratio (aHR) 14.2, 95% CI 2.9-69.4, p = 0.001] and post-menopausal status at BC diagnosis (aHR 2.7, 95% CI 1.0-7.3, p = 0.056) were independently associated with poorer OS. No significant association was observed between BRCA2 LP/PV type/location and PFS with CDK4/6i plus ET or PFS with PARPi. Conclusions: In this cohort of pts with HR+/HER2- aBC harboring germline BRCA2 LP/PV, neither the type nor the location of the LP/PV was associated with OS. Furthermore, the effectiveness of CDK4/6i and PARPi appeared to be independent of the BRCA2 LP/PV type or location. Larger, prospective studies are warranted to further clarify the clinical impact of BRCA LP/PV types and locations on BC phenotype and outcome. Citation Format: E. Zattarin, E. Tenedini, A. Marra, A. Palazzo, G. Griguolo, C. Vernieri, J. Etessami, L. Pontolillo, G. Landa, A. Daneri, M. De Monte, R. Cuoghi Costantini, O. Ponzoni, M. Razeti, C. Sposetti, E. Barbieri, M. Manni, L. Cortesi, G. Curigliano, E. Bria, V. Guarneri, M. Dominici, M. Lambertini, A. Toss. Prognostic impact of type and location of germline BRCA2 pathogenic or likely pathogenic variants in patients with HR+/HER2- advanced breast cancer: results from the multicenter real-world PAMBRACA study [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 PS1-11-28.