Abstract 6332: Targeting PARP for the prevention of BRCA1-deficient triple-negative breast cancers

Abstract Background: Triple-negative breast cancer (TNBC) tumors frequently harbor BRCA1 gene mutations especially in women with a family history of breast cancer. It has been shown that BRCA1-deficient cells are highly sensitive to Poly ADP ribose polymerase (PARP) inhibitors as PARP inhibition and trapping leads to synthetic lethality due to increased genomic instability. PARP inhibitors are therefore effective treatments for breast cancers with BRCA1 or BRCA2 mutations and may have potential utility for cancer prevention and risk reduction strategies, in particular for women with germline BRCA1 or BRCA2 pathogenic variants. For this study, we hypothesized that PARP inhibitors will prevent the development of TNBCs in a mouse model of mammary tumorigenesis with BRCA1 deficiency. Methods: Two studies were conducted in immune competent models: (1) a dose and schedule finding study using syngeneic BRCA1-deficient graft model, and (2) a long-term study to determine whether a PARP inhibitor can prevent de novo tumor formation. In the dose-finding study, mammary tumor fragments from MMTV-Cre+/+/BRCA1co/co/p53+/- mice were transplanted into the mammary fat pads of MMTV-Cre+/+/BRCA1co/co/p53+/+ mice. When these mice developed palpable tumors, they were treated by oral gavage with talazoparib or AZD5305. In the second series of experiments designed to determine the preventative efficacy of the PARP inhibitors, mice were treated with PARP inhibitors from 4 months of age until tumors reached 1, 500 mm3. Mice were observed daily for tumor formation and toxicity. Tumor incidence and time to tumor formation were visualized using Kaplan Meier curves and analyzed using the log-rank test. Results: All three doses and schedules of talazoparib and AZD5305 significantly suppressed the growth of MMTV-Cre/BRCA1co/co/p53+/- tumors in the syngraft model. Our current results from the long-term study show that (a) treatment with AZD5305 (at 0.5mg/kg; 5X/week for one week followed by 3 weeks off) significantly (p=0.0001) delays mammary tumor formation in MMTV-Cre/BRCA1co/co/p53+/- mice with median survival increasing from 213 days to 383 days, and (b) daily treatment of AZD5305 (5 days treatment, followed by 2 days off) at a lower dose (0.125mg/kg) also significantly delays mammary tumor formation in MMTV-Cre/BRCA1co/co/p53+/- mice with median survival increasing from 266 days to 320 days (p=0.004). Long term treatment with AZD5305 at these doses was not associated with any observable toxicity in this study. Conclusions: Both talazoparib and AZD5305 greatly suppress the growth of syngrafted BRCA1-deficient tumors in mice. AZD5305 also delayed the development of TNBC mammary tumors in MMTV-Cre/BRCA1co/co/p53+/- mice. Based on these results, in the future, PARP inhibitors may be effective drugs to reduce the risk of BRCA1-deficient breast cancer. (Supported by NCI-PREVENT to PB & AM) Citation Format: Amanda Lanier, John Clifford, Jamal Hill, Darian Coleman, Cassandra Moyer, Alejandro Contreras, Mark Albertella, Anna Staniszewska, Andrew Reynolds, Shizuko Sei, Powel Brown, Abhijit Mazumdar. Targeting PARP for the prevention of BRCA1-deficient triple-negative breast cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6332.