PS4-05-29: Homologous Recombination Deficiency in Breast Cancer: Exploratory Analysis of a Brazilian Cohort with Germline Genetic Testing

Abstract Introduction: Breast cancer (BC) is the most prevalent malignancy among women, and 5-10% are associated with germline pathogenic/likely pathogenic variants (PVs) in high-penetrance BC genes, mostly BRCA1/2. These genes encode proteins involved in the homologous recombination repair (HRR) pathway, whose dysfunction leads to homologous recombination deficiency (HRD). Germline PVs, somatic alterations, and/or epigenetic modifications in HRR pathway genes can induce the HRD tumor phenotype. While HRD is well-characterized in ovarian cancer and is a predictive biomarker for Parp inhibitors in this setting, data in BC remains scarce, especially in the Brazilian population. Objective: To evaluate HRD status in breast cancer samples from a Brazilian cohort. Methods: This retrospective single-center study included women with BC treated between 2020-2023 whose formalin-fixed paraffin-embedded tumor samples were available for analysis at Oncoclínicas Precision Medicine laboratory (OCPM). The laboratory database was used to identify eligible samples. All tumor samples were submitted to pathology review. HRD analysis assessed genomic scars (loss of heterozygosity, telomeric allelic imbalance, and large-scale state transitions) by sequencing 13,809 single nucleotide polymorphisms, plus mutational profiling of 15 genes involved in the HRR pathway. HRD status was defined using a validated assay by OCPM. Genomic instability score cutoff of 65 or higher. HRD profiles were described in relation to clinicopathological and molecular features. Results: Among 134 identified samples, 55 patients were consecutively selected for tumor analysis according to the study budget. Eight samples were excluded due to inadequate material for molecular analysis. Among 47 cases eligible for HRD analysis, 9 samples were excluded due to post-analytical failures. HRD profile was performed in 38 samples. The mean age of BC diagnosis was 51.4 years (range 49,8-52,2 years); 52.6% were premenopausal. Regarding molecular subtype distribution: 47.4% were Luminal B-like, 31.6% triple-negative, 15.8% Luminal A-like, and 2.6% HER2-positive. Half of the samples were from primary tumor sites and the remaining from metastatic sites. Most tumors were stage III (31.6%) at diagnosis followed by stage II (26.3%), IV (18.4%), and I (15.8%). Regarding germline status, 26.3% of patients harbored germline PVs, among these, 40% in BRCA1/2, 40% in other HRR genes, and 20% in non-HRR genes. The overall HRD prevalence was 31.6% (12/38). TNBC had a higher rate of HRD (66.7%; 8/12), followed by Luminal B-like (25%) and Luminal A-like (8.3%). None of the HER2-positive tumors had HRD phenotype. Patients with HRD tumors (n=12) were predominantly premenopausal (75%), had a younger age at BC diagnosis (mean age 49.8 years), presented more locally advanced disease (41.7% stage III), and in 75% of these cases, tumor samples were from the primary site. Thirty-three percent of patients with HRD tumors harbored germline PVs in HRR genes (2BRCA1,1BLM;1RAD51C); 60% of those were truncating variants (nonsense and frameshifts). Conclusions: This is the first Brazilian study to evaluate HRD in breast cancer, revealing a 31.6% prevalence consistent with international data. HRD was more common in aggressive tumors subtypes, younger patients, and those with germline PVs in HRR genes. The identification of alterations beyond classical BRCA1/2 mutations expands the molecular spectrum of HRD. Citation Format: A. K. Souto, F. C. Koyama, S. S. Koide, B. B. Souza, J. D. Massaro, L. J. Oliveira, L. Yamamoto, T. A. Santana, M. L. Bulcão, C. B. Fernandes, C. A. Resende, M. S. Mano, L. C. Landeiro, G. O. Bretas, C. B. Miranda, R. Dienstmann, R. L. Sandoval. Homologous Recombination Deficiency in Breast Cancer: Exploratory Analysis of a Brazilian Cohort with Germline Genetic Testing [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 PS4-05-29.