Judy E. Garber, MD, MPH

2007-2008 BCRF Project:
Mutations in the BRCA1 and BRCA2 breast/ovarian cancer susceptibility genes confer a remarkable risk of hereditary breast cancer. However, 60% of breast cancer families do not have mutations in the BRCA genes. For more than 10 years, scientists have been searching for other genes that confer a high risk of breast cancer, but none has yet been found. In addition, BRCA1 mutation carriers have been shown to preferentially develop basal-like breast cancers, a specific subtype of invasive ductal breast cancers that is often negative for ER, PR and HER2.

In contrast, non-BRCA1/2 breast cancer families are more likely to develop invasive lobular breast cancers, for which susceptibility genes have not been identified. The E-cadherin gene (CDH1) has been shown to be heritable in mutant form. Germline mutations in CDH1 have been primarily associated with inherited susceptibility to diffuse gastric cancer, a rare tumor. Recently, many families with hereditary diffuse gastric cancer have also been noted to have an increased incidence of lobular breast cancer as well. Many of these lobular breast cancer patients carry mutations in the CDH1 gene.

In preliminary work, Dr. Garber and her colleagues have observed CDH1 mutations in women with invasive lobular breast cancer and a family history of breast cancer. They are now extending these early observations in familiar lobular breast cancers in collaboration with a consortium of investigators also funded by BCRF. They believe that this could lead to the identification of CDH1 as a novel marker for a subset of hereditary breast cancers, with important implications for the management of women at increased risk for lobular breast cancers, an understudied breast cancer subtype.

Dr. Garber reports that all procedures are finalized and IRB-approved for subject identification and enrollment (including informed consent), specimen collection and processing, laboratory analysis and the construction and management of a confidential web-based data collection and management system. The Dana-Farber team and their collaborators are assembling participants and specimens for the composition of the cohorts, and laboratory analysis has begun. They are finalizing a manuscript reporting their initial finding of a CDH1 mutation in a family with only lobular breast cancers but no gastric cancers for the Journal of Medical Genetics.

Dr. Garber's new BCRF-funded project will build on a recent observation from other investigators that the normal breast tissue in laboratory models with one altered copy of BRCA1 genes (very like humans) has a high level of progesterone receptor in the tissue, and that the administration of an anti-progesterone agent prevented mammary tumors from developing. She proposes to study prophylactic mastectomy specimens from women with BRCA1 and BRCA2 mutations, and a control group, and to compare PR levels. Concurrently, they will be evaluating a series of biomarkers in specimens from women with mutations about to undergo prophylactic mastectomies. The goals are to confirm or definitively refute the finding of PR dysregulation in BRCA1 carriers, and if confirmed, then to interrogate a series of targets downstream of PR to develop some biomarkers for validation for a larger study of anti-progestrogens.

Mid-Year Progress Report:
Dr. Garber reports that trial of platinum as treatment for women with triple negative breast cancer has given rise to a second trial that has more than half of its planned accrual, and plans for an exciting multi-center trial comparing platinum to platinum plus the new PARP inhibitors, a class of drugs that have early efficacy in women with BRCA1 and BRCA2 mutations and advanced ovarian and breast cancers. The Dana Farber investigators are conducting this trial with a number of other BCRF investigators (Drs. Baselga, Carey, Tung, Livingston, and Perou).

They also continue to study the breast tumors from women in the platinum trials to search for new targets for therapy, and new markers with which to predict response to current treatments. They have been studying familial lobular breast cancer, and have assembled 40% of more than 100 specimens promised for analysis of the CDH1 gene, which has been linked to lobular breast cancers and hereditary gastric cancers. Their specimens again come from BCRF collaborators (Offit, Domchek, Brown, Ford, Olopade). They should have an answer later this year as to whether this gene identifies another group of women at hereditary risk for lobular breast cancers, which should be easier to prevent than to detect!

For their most recent project, studying progesterone receptor in the normal breast tissue of women with BRCA1 mutations as a target for preventive therapies, Dr. Garber and her team are awaiting final IRB approval to permit collection of the specimens, have worked out all of the procedures and conditions for the assays, and have identified sources of normal breast tissue for the comparison studies. With all of the approvals in place, they anticipate beginning collection in March.

Bio:
Dr. Garber is Director of the Cancer Risk and Prevention Program at the Gillette Center for Women's Cancers at Dana-Farber Cancer Institute. She is also an attending physician at Dana-Farber's Breast Evaluation Center, an associate physician at Brigham and Women’s Hospital and an associate professor of Medicine at the Harvard Medical School. Dr. Garber's research is focused on genetic susceptibility to breast, ovarian and other cancers, and the development of novel medical strategies to prevent cancer. She uses the tools of cancer epidemiology and biostatistics, genetics and molecular biology to identify women at high risk for breast cancer.

Dr. Garber has been at Dana-Farber Cancer Institute since 1988 when she joined the faculty after completing a fellowship in Medical Oncology at DFCI and fellowships in Cancer Epidemiology and Biostatistics at the National Cancer Institute and DFCI.

A graduate of the University of Virginia, Dr. Garber earned her medical degree and her master's degree in public health from Yale University School of Medicine and completed her internship and residency at Brigham and Women's Hospital and the Brockton-West Roxbury Veteran's Administration Medical Center.