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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
Co-Director, Translational Oncology Program and Associate Director for Clinical Research, Stanford Cancer Institute
Susy Yuan-Huey Hung Professor
Stanford School of Medicine

Current Research

In order to survive, grow and spread, breast cancer cells must produce an abundance of growth-promoting proteins. Many of these proteins–called oncoproteins–are present on the surface of the cancer cells, such as the HER2 receptor, and have been used as targets for therapy. Many others however are inside of the cells and are not easily targeted by current drugs. An alternative approach to breast cancer treatment would be to prevent or stop the production of these oncoproteins to make cancer cells more sensitive to anti-cancer drugs. Dr. Pegram and his colleagues discovered a unique feature in the way cancer cells produce oncoproteins, a process called alternative protein translation. They have devised a method to cripple the cells and prevent cancer growth by blocking the proteins that are involved in this process. In their 2014-2015 BCRF project, they will use advanced laboratory techniques to inhibit the proteins that regulate alternative translation and study the effects on breast cancer cells. In addition, they will analyze breast tumor tissue to determine the usefulness of this therapeutic idea for breast cancer patients. The research team will work closely with Breast Cancer Connections (BCC), a patient advocacy group in Palo Alto, CA, to disseminate results and discuss results. This study represents an entirely new strategy for the treatment of breast cancer and could lead to new therapeutic targets for drug development.

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

Mark D. Pegram, MD 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.