The evolutionary landscape of BRCA-associated breast cancer and its impact on endocrine therapy resistance

/SUMMARY Most breast cancer deaths occur in women with estrogen-driven (i.e., estrogen receptor-positive [ER+]) cancer that has become resistant to standard treatments, such as endocrine therapy. Although most ER+ breast cancers are initially sensitive to endocrine therapy, 15-20% of patients do not respond, and another 30-50% acquire resistance. The mechanism of endocrine therapy resistance is unknown in ≥60% of cases. There is accumulating evidence that estrogen signaling and response to endocrine therapy are affected by alterations that cause homologous recombination deficiency (HRD), such as BRCA mutations. Clinical data suggest that BRCA2 carriers with ER+ breast cancer have a significantly worse prognosis than noncarriers and do not benefit as much from endocrine therapy. In vitro studies suggest that HRD causes hormone- independent growth. Approximately 24% of primary breast cancers display HRD. Leveraging our cell line and patient-derived models of HRD, ER+ breast cancer, this project aims to understand the mechanism by which HRD affects responsiveness to endocrine therapy, which promises to explain a significant proportion of therapy resistance. Specifically, we will: 1. Comprehensively characterize changes in BRCA2-associated ER+ breast cancers on endocrine therapy. Using patient tumor specimens collected following 2 weeks of preoperative endocrine therapy, we will compare tumor proliferative index (Ki67) in response to endocrine therapy between BRCA2 carriers and noncarriers. We will also compare their genomic and transcriptional profiles to determine if BRCA2 deficiency leads to accumulation of alterations in pathways that affect ER signaling. 2. Test for direct effects of HR pathway alterations on ER function. We will compare ER-driven growth and response to endocrine therapy between BRCA2-knockout vs. wildtype ER+ breast cancer cell lines. To define global changes in ER response, we will subject the above models to integrative analyses of gene expression (including RNA-seq, ATAC-seq, WES, and ChIP-seq). 3. Determine how BRCA2 mutations affect ER function and response to endocrine therapy and clinically relevant combination therapies in a panel of patient-derived models. We will assess response to estrogen stimulation and deprivation in matched normal and tumor PDOs from BRCA2 carriers and noncarriers to understand the spectrum of changes in ER signaling in each setting (including BRCA2 haploinsufficiency in normal tissue from BRCA2 carriers and complete inactivation in tumors). With tumor PDOs, we will assess response to currently approved and clinically relevant therapies for BRCA2 carriers with ER+ breast cancers, including endocrine therapy, CDK4/6 inhibitors, and PARP inhibitors. Taken together, the proposed investigations and new multimodal models of HRD, ER+ breast cancer will provide valuable insight into unique mechanisms and new targets of endocrine therapy resistance. Project Number: 1K08CA301096-01A1 | Fiscal Year: 2026 | NIH Institute/Center: National Cancer Institute (NCI) | Principal Investigator: Minna Lee | Institution: SLOAN-KETTERING INST CAN RESEARCH, NEW YORK, NY | Award Amount: $246,362 | Activity Code: K08 | Study Section: Special Emphasis Panel[ZRG1 CTH-K (83)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11302018