Titles and Affiliations
Chief, Division of Cancer Genetics and Prevention
Susan F. Smith Chair
Dana-Farber Cancer Institute
Professor of Medicine
Harvard Medical School
BCRF Scientific Director
Research area
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. Dr. Garber and her team completed one of the largest multi-omic analyses to date of untreated, hereditary ER-positive breast cancers, sequencing tumors from more than 200 patients carrying BRCA1, BRCA2, or PALB2 mutations and comparing them against sporadic ER-positive tumors. The results confirmed that hereditary ER-positive breast cancers are not simply variants of common ER-positive disease, but a biologically distinct entity. Across the hereditary cohort, the team found evidence of homologous recombination deficiency, the same DNA repair defect associated with sensitivity to PARP inhibitors, differences in estrogen receptor signaling, and a tumor microenvironment substantially richer in immune activity than sporadic ER-positive tumors. Notably, within the hereditary cohort, patients whose tumors had lower immune infiltration had worse clinical outcomes, a finding that could help identify which patients are most in need of more aggressive or alternative treatment approaches. Together, these findings provide strong support for pursuing PARP inhibitor-based strategies and immunotherapy combinations specifically tailored to hereditary ER-positive breast cancer, rather than treating it identically to its sporadic counterpart.
What’s next
In the coming year, Dr. Garber and her team will expand their multi-omic analysis to include additional BRCA1, BRCA2, PALB2, and TP53-associated tumors, as well as more non-carrier ER-positive cases, integrating genomic, transcriptomic, and immune profiling data across this larger cohort. The team will also perform detailed spatial immune profiling to precisely characterize how tumor and immune cells interact within these tumors, work that is expected to reveal new biomarkers capable of guiding precision treatment decisions. Because ER-positive breast cancer is the most common subtype of the disease overall, clarifying which of these features are unique to hereditary cases and which are shared more broadly stands to improve risk assessment, treatment selection, and clinical trial design for a large population of patients with inherited cancer susceptibility.
Biography
Judy E. Garber, MD, MPH is the Director of the Center for Cancer Genetics and Prevention at Dana-Farber Cancer Institute, an attending physician at the Brigham and Women’s Hospital, and a professor of medicine at Harvard Medical School.
Her interests focus on breast cancer genetics, risk reduction and the development of therapeutics for the treatment and prevention of breast and related cancers in individuals carrying predisposing mutations. Her research includes the study of basal-like breast cancer, common in women with BRCA1 mutations. Her first neo-adjuvant trial of cisplatin in patients based on the role of BRCA1 in DNA repair demonstrated a significant complete response rate that has led to a series of trials, including a randomized phase II international, multicenter trial. Her research also includes the evaluation of novel agents targeting DNA repair defects in the treatment and prevention of triple negative or basal-like breast cancer, particularly platinums, PARP inhibitors and RANK ligand inhibitors.
Dr. Garber was elected to the National Academy of Medicine in 2013. She is a past president of the American Association for Cancer Research and a member of the National Cancer Advisory Board. She also served on the Board of Scientific Counselors of the National Cancer Institute. She has been a member of the BCRF Scientific Advisory Board since 2008.
