Mark E. Robson, MD

Drs. Robson and Offit have completed the major aims of this project, which led to the identification of a new locus associated with a low risk for breast cancer in individuals of Ashkenazi Jewish background who have tested negative for BRCA mutations. Through ongoing studies they have identified new regions of the gene (on chromosomes 5, 6 and 16) associated with an increase in breast cancer of approximately 1.2-1.4 fold. Over the past year they have replicated findings of the chromosome 6 risk marker in Caucasian Ashkenazi Jewish as well as non-Ashkenazi women, and have noted the risk is greater for estrogen receptor positive breast cancer. They have started to unravel the possible genes involved and the relationship to estrogen. In the coming year they will focus on new (de novo) copy number variations in breast cancer susceptibility by comparing the genomes of parents and their offspring affected by breast cancer. This will enhance understanding of the genetic basis of seemingly "sporadic" early-onset breast cancers. Finding new breast cancer susceptibility genes could have broad applications in terms of improved breast cancer risk assessment and breast cancer prevention. If shown to play a role in breast cancer, copy-number variations may represent a new paradigm in our understanding of not only breast cancer, but all of cancer genetics.

In a related continuing project they are studying the validity of genomic testing for breast cancer risk, which is being offered by some commercial companies, but whose readiness for routine use the researchers have questioned. They have studied over 1000 women in their clinic who have tested negative for BRCA mutations and who have consented to prospective research to quantify new markers of genetic risk. They have compared genomic risk to traditional risk models in these women. This study will continue to evaluate the best way to use genomic markers for individual risk assessment and set the stage for offering the results of genomic risk information to women in the setting of a behavioral study.

Dr. Offit is also leading a project, in collaboration with the Broad Institute, supported by BCRF. A decade after the initial identification of BRCA1 and BRCA2 there remains considerable uncertainty regarding cancer risks associated with inherited mutations of these genes. The basis of this variation of risk is most striking for BRCA2, and affects clinical management: patients with the same BRCA mutation will develop breast, ovarian, or other cancers at different ages or not at all (Offit, 2006). It is the hypothesis of this proposal that there exist genetic "protective factors" (alleles) which interact with known genetic risk markers, and which may serve as breast cancer or ovarian cancer protective factors in the general population. Over the past year, this project has succeeded in the assembly of DNA samples from over 6,000 women with BRCA2 mutations around the world. This collection of DNA samples has involved close coordination with colleagues at the Broad Institute at Harvard/MIT. Dr. Offit and team have completed half of the first phase of whole genome analysis, with genotyping to be finished by the end of the summer of 2009. They are coordinating our analysis with BCRF colleagues at the Mayo Clinic, who are looking at modifiers of BRCA1 mutations.

Bio:
Mark Robson, MD, is an Associate Attending Physician of the Clinical Genetics and Breast Cancer Medicine Services in the Department of Medicine at Memorial Sloan-Kettering Cancer Center. He received his B.Sc. from Washington and Lee University and his M.D. from the University of Virginia. He performed residency and fellowship training at Walter Reed Army Medical center before coming to Memorial Sloan-Kettering in 1996. He is currently the Clinic Director of the Clinical Genetics Service and the chair of the Cancer Genetics Subcommittee of the American Society of Clinical Oncology.

Dr. Robson's research is directed toward the improving the integration of genetic information into the clinical management of women with breast cancer. He and his colleagues have conducted a number of studies examining outcomes in women with hereditary breast cancer to better define the risks and benefits of treatments such as breast conserving therapy and adjuvant chemotherapy in this group. He and his coworkers have also conducted a number of studies examining the effectiveness of screening interventions such as breast MRI or ovarian cancer screening in women at hereditary risk. He is currently conducting studies to evaluate the impact of intensive screening or surgical prevention upon women's quality of life, and to develop new screening tools, such as serum peptide profiling.