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BCRF Grantee Since

2013

Donor Recognition

The Celebrity Cruises Award

Area(s) of Focus

Mark Pegram, MD

Director, Breast Cancer Program, Stanford Cancer Institute
Co-Director, Solid Tumor Therapeutics Program, Stanford Cancer Institute
Susy Yuan-Huey Hung Professor
Stanford University School of Medicine

Current Research

Co-Investigator: James M. Ford, MD, Stanford University School of Medicine, Stanford, CA

Sporadic triple negative breast cancers (TNBCs) share many pathologic and molecular features with breast cancers due to hereditary BRCA1 gene mutations, including sensitivity to platinum chemotherapy drugs. Several clinical trials have tested cisplatin or carboplatin as pre-operative therapy for surgically resectable TNBCs. Not all patients respond to this regimen, and predictive molecular signatures are needed to better select patients for this approach to therapy. Drs. Ford and Pegram have independently collected patient tumor samples from clinical trials of pre-operative platinum based chemotherapy. They will now collaborate to measure expression of all genes in these samples and attempt to identify profiles that best predict for chemosensitivity. Ultimately, they hope to use such a predictive gene expression signature to prospectively select patients most likely to benefit from platinum based therapies, as well as others that target DNA repair pathways, such as PARP inhibitors.

Mid-Year Summary

Project 1: Improving Breast Cancer Genetic Risk Assessment:
Currently available tests for the genetic risk of developing breast cancer are uninformative for most patients, even those with family histories strongly suggestive of cancer susceptibility. Emerging technologies allow inexpensive sequencing of multiple genes, but we do not know whether these tests will improve patient care. Using more than 400 research blood samples provided by patients referred to the Stanford Cancer Genetics Program for clinical BRCA1/2 gene mutation testing, the researchers performed high-throughput, multi-gene sequencing to identify risk-associated variants in 42 cancer-related genes. Extensive clinical, demographic and epidemiologic data was gathered for all study participants and analyzed together with results of multi-gene panel testing. Their initial results in both a discovery set of 198 samples and a validation set of 240 samples found that approximately 10% of non-BRCA1/2 carriers carry a potentially pathogenic germline variant in another cancer susceptibility gene. Per participant, the average number of variants of uncertain significance (VUS) across all genes was 2.1. The researchers are currently analyzing their risk profiles based on genetic and family information. Patients with newly identified pathogenic variants were invited for confirmatory clinical testing, genetic counseling and screening recommendations. Disclosure of research testing results to participants who donated specimens several years previously appears feasible and well-tolerated. The results of this study have strong potential to guide the translation of emerging genetic tests for clinical use, and to inform the design of a large population-based registry study.

Project 2: Gene Expression Profiles in Triple-Negative Breast Cancer: Predicting Platinum Sensitivity
Sporadic triple-negative breast cancers (TNBCs) share many pathologic and molecular features with breast cancers due to hereditary BRCA1 gene mutations, including sensitivity to platinum chemotherapy drugs. Several clinical trials have tested cisplatin or carboplatin as pre-operative therapy for surgically resectable TNBCs. Not all patients respond to this regimen, and predictive molecular signatures are needed to better select patients for this approach to therapy. Drs. Ford and Pegram have independently collected patient tumor samples from clinical trials of pre-operative platinum based chemotherapy. In the first six months of this project the Pegram laboratory has performed extensive gene expression studies on 125 samples from their cohort of platinum treated TNBC patients and analyzed them with regard to clinical response. Specific sets of genes have been identified that predict for response and survival. They will now collaborate with Dr. Ford to measure expression of all genes in their respective sample sets and to identify profiles that best predict for chemosensitivity. Ultimately, they hope to use such a predictive gene expression signature to prospectively select patients most likely to benefit from platinum based therapies, as well as others that target DNA repair pathways, such as PARP inhibitors.

Bio

Dr. Mark D. Pegram is the first director of the Breast Cancer Oncology Program at Stanford Women’s Cancer Center. He is also the co-director of Stanford’s Molecular Therapeutics Program. He is a renowned clinician and scholar in breast cancer research and a leader in translational medicine. Dr. Pegram played a major role in developing the drug Herceptin as a treatment for HER2-positive breast cancer, which constitutes about 20 percent of all cases. His laboratory experiments demonstrated that combining Herceptin with chemotherapy effectively killed cancer cells that overproduced the growth factor HER2. Dr. Pegram and others then conducted clinical trials showing that Herceptin improved survival rates and even cured some breast cancer patients. This remains one of the premier examples of bench-to-bedside translational research. Dr. Pegram’s current research efforts include a continued focus on the cancer-associated gene that encodes HER2 and developing new ways to target cancer cells expressing this protein. He is also pursuing strategies to target estrogen receptors, implicated in some 70 percent of all breast cancer cases.

Dr. Pegram earned his undergraduate and medical degrees from the University of North Carolina before joining the faculty of the University of California, Los Angeles. He spent five years at the University of Miami Miller School of Medicine, where he was a Sylvester Chair professor of medicine in the Braman Family Breast Cancer Institute and associate director for clinical research in the University’s Sylvester Comprehensive Cancer Center. He joined the Stanford faculty in 2012.

Co-Investigators