Abstract PS3-13-12: Parp inhibition augments response to anti-pd1 therapy in hrd mutated breast cancer

Abstract Introduction: Over 2 million women develop breast cancer globally every year despite immense advances in disease biology, genomic assessment and novel treatment options. Many preclinical and clinical studies suggest a benefit of combining PARP inhibitors (PARPi) and immune checkpoint inhibitors (ICi) in patients with homologous recombination intact and mutated cancers. However, similar to the varied benefits of either drug class as single agent, the benefits of such combinations are strongly dependent on tumor type, tissue and mutational context. In this study, we explored the association of immune cell composition in the tumor tissues for driving the responses. Methods: To study how select homologous recombination deficiency (HRD) mutations respond to a combination of a PARPi with an ICi, we used CRISPR engineering to repress BRCA1, BRCA2, ATM, CHEK2, PALB2 in different murine and human breast cancer cell lines. The CRISPR engineered cells were implanted in mice and treated with PARPi and ICi to determine whether the ICi, PARPi and their combination induced response. Using spectral flow-cytometry, immunohistochemistry and RNA sequencing, the different immune cell population in the tumor microenvironment were analyzed. Results: In vitro, induced suppression of BRCA1 and PALB2 in the EMT6 cell lines showed higher sensitivity to PARPi (IC50 0.01 uM and 0.098 uM) than suppression of BRCA2 and ATM (IC50 0.16 uM and IC50 0.28 uM). In contrast, induced suppression of CHEK2 showed resistance to PARPi compared to their parental EMT6 cells (IC50 13.9 uM versus 5.3 uM). We further validated these findings in MDA-MB231 and observed similar trends. Expression levels of PDL1 and select chemokines (CCL2, CCL5, CXCL9, CXCL10 and CXCL11) were associated with sensitivity to PARPi. We investigated the efficacy of combining PARPi with ICi in our in vivo models. In EMT6 background, presence of BRCA1 or BRCA2 mutations showed sensitivity to either single agent or the combination. The response correlates with higher CD8+ T cells infiltration. Presence of ATM mutation has shown benefit to either single agent but not enhanced by the combination. This mirrors the findings in the clinic. Conclusion: Using inducible suppression of HRD function in an immune competent mouse breast cancer model helps to understand the differential role of individual HRD mutations (BRCA1, BRCA2, ATM, CHEK2, PALB2) in altering inflammatory signals in response to PARPi and ICi. This data may guide the clinical development of such combination in breast and other cancers. Citation Format: S. Chaudhuri, A. Emata, J. Camara Serrano, V. Steri, S. Thomas, P. Munster. Parp inhibition augments response to anti-pd1 therapy in hrd mutated breast cancer [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 PS3-13-12.