James M. Ford, MD

2009-2010 BCRF Project:
Approximately 15% of all breast cancers, as well as the majority of BRCA1 associated breast cancers, are 'triple negative', lacking expression of estrogen and progesterone receptors, and lacking over-expression or amplification of the HER2/neu oncogene. This is a very aggressive type of breast cancer that disproportionately affects young women and African-Americans, and the best way to treat women with these high-risk breast cancers is still unknown. Dr. Ford's laboratory has recently shown that triple-negative breast cancer is especially sensitive to specific drugs that target defects in the DNA repair capacity of these cancer cells, including the chemotherapy agents cisplatin and gemcitabine, and a novel class of biologic agents that inhibit the poly-ADP ribose polymerase (PARP) enzyme. The hypothesis of this study is that a combination treatment regimen of gemcitabine, carboplatin, and the PARP inhibitor BSI-201 (produced by a research collaborator, BiPAR Sciences) will yield significant improvement in tumor response among women with early-stage triple negative breast cancer; notably, improved breast tumor response has been proven to predict better survival.

During the initial year of this project, Dr. Ford and colleagues designed and opened a Phase II clinical trial to study the effectiveness of a combination of chemotherapy and a novel PARP inhibitor drug that targets DNA repair defects, for the pre-operative (neoadjuvant) treatment of women with Stage I - II triple-negative breast cancer. In the two months that this trial has been open to accrual, they have enrolled three participants, who have had very promising clinical responses to this experimental regimen. They have also performed correlative laboratory studies on biospecimens from these participants to predict their clinical outcomes, based on mechanisms for DNA repair that they study in the laboratory. The researchers expect to accelerate patient accrual in the second year of this clinical and laboratory research project.

Mid-Year Progress Report:
With the support of BCRF, in early 2009, Dr. Ford opened a single-institution Phase II clinical trial to study the effectiveness of a combination of gemcitabine, carboplatin, and the PARP inhibitor BSI-201 (manufactured by BiPar Sciences, Inc, a wholly-owned subsidiary of Sanofi-Aventis) for women with Stage I - III, newly-diagnosed, triple-negative breast cancer. The study hypothesis is that this combination treatment regimen acts synergistically and will yield significant improvement in tumor response among these early-stage cancers.

The researchers' primary objective is to evaluate the improvement in breast tumor shrinkage in women treated with this regimen, and their secondary translational objectives are to identify biomarkers that predict for response, by measuring levels of candidate DNA repair and DNA damage response genes in tumor biopsies obtained prior to therapy, performing gene expression studies in tumor samples and in circulating tumor cells, and identifying germline polymorphisms or rare genetic variants that may prove predictive of response to targeted therapy for triple-negative breast cancer.

As of January 2010, accrual to this study has been much better than anticipated, with one-half of the 36 patient goal achieved. Patients have tolerated this regimen very well, with no withdrawals from the study. All patients have had an objective clinical response, with most achieving a complete clinical response, and no progression of disease. Pre-treatment core biopsy samples and blood samples both pre- and post-treatment have been obtained on each subject and are being evaluated for gene expression of candidate biomarkers that may predict sensitivity or resistance to this therapeutic regimen. Dr. Ford and his team are hopeful that this project will help them to understand the role of DNA repair pathways in this disease and help the nearly 30,000 women who develop triple-negative breast cancer each year in the United States by developing an effective targeted therapy.

Bio:
Jim Ford is a medical oncologist and geneticist at Stanford, devoted to studying the genetic basis of breast cancer development, treatment and prevention. Dr. Ford graduated in 1984 Magna Cum Laude (Biology) from Yale University where he later received his M.D. degree from the School of Medicine in 1989. He has been intern (1989-90) and resident (1990-91) of internal medicine, Clinical Fellow in Medical Oncology (1991-94), Research Fellow of Biological Sciences (1993-97), Assistant Professor of Medicine (Oncology) and Genetics (1998-2006), Director of the Stanford Oncology Fellowship Training Program, and Director of the Stanford Cancer Genetics Clinic, at the Stanford University Medical Center. Dr. Ford is currently Associate Professor of Medicine, Pediatrics and Genetics, and Director, Stanford Program for Clinical Cancer Genetics.

Dr. Ford's goals are to understand the role of genetic changes in cancer genes in the risk and development of common cancers. He discovered that the p53 and BRCA1 tumor suppressor genes regulate DNA repair, and has developed novel assays to examine DNA repair activity in primary human tissues. He is developing techniques for high-throughput genomic analyses of cancer to identify molecular signatures for targeted therapies.

Dr. Ford's honors and awards include the Etta S. Chidsey Award in Cancer Research from the Yale Comprehensive Cancer Center (1987), NIH K08 Clinical Investigator Award (1995), Second Annual Gerald B. Grindey Memorial Young Investigator Award - AACR (1997), Sidney Kimmel Foundation for Cancer Research Scholar Award (1999), Doris Duke Foundation Clinical Scientist Award in Cancer Etiology and Pathogenesis (1999), Burroughs-Wellcome Fund New Investigator Award in Toxicology (2000), and the V Foundation Translational Research Award. Dr. Ford is an Editor for the journals Cancer Research and DNA Repair, is on the Scientific Review Committee for the V Foundation for Cancer Research, and a Council Member of the California Breast Cancer Research Program.