Judy E. Garber, MD, MPH

Assessing the biology of BRCA-associated, estrogen receptor-positive breast cancers.

Impact

Little is known about the biology of BRCA1 or BRCA2-driven breast cancers that are estrogen receptor (ER)-positive, which may be associated with intrinsically less favorable biology and higher risk of recurrence. This subset of breast cancers appears pathologically “intermediate” between BRCA-associated ER-negative breast cancers and more common ER-positive breast cancers. This observation could mean that there is a unique mechanism by which some ER-positive breast cancers develop in BRCA mutation carriers. Dr. Garber is working to understand the biology of BRCA-associated, ER-positive breast cancers more deeply to ultimately improve treatment for these patients.

Progress Thus Far

While PARP inhibitors are commonly used to treat BRCA-associated breast cancers independently of ER status, uncovering what drives ER-positive, BRCA-associated cancers is necessary for effective treatment. Dr. Garber has assembled a cohort of patients with ER-positive breast cancer who have mutations in BRCA1, BRCA2, or PALB2, another breast cancer susceptibility gene. Overall, she and her team have successfully sequenced 39 BRCA1-associated, 90 BRCA2-associated, and 17 PALB2-associated tumor samples and digitized images of these samples.

The team analyzed these data and compared their biology with ER-positive tumors from patients without known pathogenic variants from one publicly available dataset, The Cancer Genome Atlas (TCGA). The team found that ER-positive breast cancers in individuals with BRCA1, BRCa2 or PALB2 pathogenic variants share many features with sporadic ER-positive tumors but differ in other genetic alterations that are associated with tumor growth. These distinctions may have important implications for treatment and prevention strategies and warrant further investigation.

What’s next

In the coming year, Dr. Garber and her team plan to expand their analysis to include 20 additional BRCA-associated ER-positive breast tumors and 120 BRCA-associated triple-negative breast cancer (TNBC) tumors. They will compare the findings from the BRCA-associated ER-positive cohort to 270 samples from TCGA. Finally, the team will evaluate tumor infiltrating lymphocytes in BRCA-associated ER-positive breast tumors and compare with the TCGA data.