Abstract PS4-03-18: Homologous Recombination Deficiency and DNA-Damage Response in Breast Invasive Lobular Carcinoma

Abstract Background: Identification of genetic alterations in homologous recombination deficiency (HRD) and DNA damage response (DDR) genes in breast cancer (BC) is key for prognostication and potential selection for targeted therapies, such as PARPi. While HRD/DDR somatic oncogenic alterations are generally associated with ductal BCs, their roles in invasive lobular carcinoma (ILC) remain unclear. Here, we sought to investigate the spectrum of HRD/DDR somatic genetic alterations in ILC and their histologic features of these BCs. Design: We interrogated 1,076 ILC previously subjected to paired tumor-normal targeted sequencing (MSK-IMPACT) for oncogenic somatic genetic alterations in 22 HRD/DDR genes. Loss of heterozygosity (LOH) was assessed using FACETS, and mutational signatures using SigMA. HRD status was evaluated using an algorithm optimized for MSK-IMPACT. Histologic assessment was performed as per the WHO. ER/HER2 status was determined per ASCO/CAP guidelines, and follow-up data retrieved from medical records. Results: We identified 53 ILC, including 14 primary ILCs and 39 recurrent/metastatic ILCs harboring somatic oncogenic alterations in HRD/DDR genes, with BRCA2 (38%) and ATM (23%) being the most frequently affected. Other recurrently altered (≥2 cases) HRD/DDR genes were CHEK2, PALB2, BRCA1, BARD1, RAD50, RAD51C, NBN, RECQL and ABRAXAS1. LOH analysis revealed that 53% of HRD/DDR genetic alterations in ILCs were bi-allelic, including 75% of BRCA2 and 70% of ATM cases. Most (71%) primary ILCs were of pleomorphic type or exhibited pleomorphic features (Pleo-ILC), histologic grade 2/3 (93%) and ER+/HER2- (93%). Of the metastatic ILCs, 59% were pleomorphic, and most were ER+/HER2- (74%), followed by HER2+ (18%). Median follow-up for the HRD/DDR-mutant primary ILC cohort was 72 months (range 21-150); 6 patients (43%) had no evidence of disease, 5 were deceased (36%), and 3 were alive with disease (21%). Median follow-up time for the HRD/DDR-mutant metastatic ILC cohort was 84 months (range 19-288); 62% of patients were deceased. ILCs with biallelic inactivation of BRCA2 were classified as HRD by our algorithm in 60% of cases, and half of them showed a dominant HRD mutational signature, whereas the majority of those with ATM biallelic alterations (83%) were classified as non-HRD and exhibited either dominant APOBEC or clock signature (60%). The most frequent non-HRD/DDR affected genes in the cohort were CDH1 (76%), PIK3CA (48%), and FOXA1 (21%). Conclusion: Our findings show that, although at a lower frequency than that reported for ductal BC, DNA repair deficiency including HRD/DDR defects can occur in a subset of ILC. Somatic alterations affecting HRD/DDR genes in ILC are often biallelic, with BRCA2 and ATM being the most altered genes. While these tumors are phenotypically diverse, they often display pleomorphic histology and appear to be associated with more aggressive clinical behavior. These findings highlight the potential clinical relevance of HRD/DDR profiling in ILC, which may help inform treatment strategies. Citation Format: C. J. Schwartz, D. Muldoon, H. Dopeso, A. Gazzo, P. Terraf, M. Repetto, B. Weigelt, D. Mandelker, L. Norton, H. Y. Wen, H. Zhang, D. Ross, B. Edi, A. Mamtani, S. Shen, C. Bandlamudi, F. Pareja. Homologous Recombination Deficiency and DNA-Damage Response in Breast Invasive Lobular Carcinoma [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 PS4-03-18.