Mark E. Robson, MD

Over the past year, Dr. Robson, Dr. Offit and their team have 1) assembled DNA samples from 250 Ashkenazi Jewish families with 3 or more cases of breast cancer but no BRCA mutations and 300 samples from women free of breast cancer; 2) carried out a "whole genome analysis" using a 500,000 marker "gene chip"; 3) pinpointed the location of approximately 300 sites that may harbor new breast cancer susceptibility genes, and 4) completed the first "genome wide" analysis of Ashkenazi Jewish individuals, casting new light in its genetic history and evolution.

This analysis will now confirm and validate the findings of new breast cancer susceptibility genes in 2,000 breast cancer cases and normal samples from the U.S. and Israel. The final phase of the project will entail validation of novel breast cancer susceptibility alleles in a large sample of at least 2,000 Ashkenazi women with breast cancer and 2000 healthy controls, with 500 additional cases and controls now also being added from Israel. This additional genotyping is important to be able to generalize finding in the Ashkenazim to the broader population.

Drs. Robson and Offic will also undertake a pilot project this year. Women who develop breast cancer as the result of an inherited mutation in either BRCA1 or BRCA2 are at a high risk of developing a new second primary cancer in the opposite (contralateral) breast as well as ovarian cancer. Although not currently offered, for both technical as well as psychological reasons, immediate genetic testing could allow an early decision about whether or not to undergo preventive surgery of the breasts and ovaries at time of initial treatment.

In this study the researchers will offer 100 women who have been newly diagnosed with breast cancer, and who have a significant risk of carrying a BRCA mutation, the option of either immediate BRCA testing, receiving results within a week of diagnostic visit, or delayed testing after the completion of surgical treatment (post-surgical). The purpose of this exploratory study is to assess the feasibility of pre-surgical testing, as measured by uptake, and the safety of pre-surgical testing, as measured by later psychological regret with respect to the decision. If successful, this study will be expanded and could have a major impact on the way in which genetic testing is offered in clinical practice.

Dr. Offit is also leading a new project, in collaboration with the Broad Institute, to be supported by BCRF. A decade after the initial identification of BRCA1 and BRCA2, there remains considerable uncertainty regarding cancer risks ("variable penetrance") associated with inherited mutations of these genes. The basis of this variable penetrance is most striking for BRCA2, and affects clinical management: patients with the same BRCA2 mutation will develop breast, ovarian or other cancers at different ages or not at all. 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 protective factors in the general population.

This study will leverage two unique resources: 1) the large number of Ashkenazi Jewish women in the U.S. and Israel harboring a single mutation in BRCA2, with data on age at onset and clinical presentation, and 2) DNA samples from more than 5,000 carriers of BRCA2 mutations assembled by an international consortium. The researchers will take a whole genome approach, searching for common variants and for de novo copy number alterations, that might be associated with cancer resistance (modifier) effects. This study will bring together a group of leaders in cancer genetics around the world.

Mid-Year Progress Report:
To discover new genetic markers, Drs. Robson and Offit and their team have completed a collaborative study involving centers in the US, Canada and Israel. They have performed a whole genome scan on 250 Ashkenazi Jewish families with three of more cases of breast cancer but who do not have known mutations in BRCA1 or BRCA2 genes, and have compared these findings to healthy individuals. They have carried out an additional second phase of the study comparing approximately 1,000 Jewish individuals with breast cancer and 1,000 individuals of the same age who are not affected by breast cancer. Finally, the researchers have carried out a third stage comparing approximately 300 individuals with breast cancer and 300 individuals without breast cancer.

In the first phase of this analysis they used a "whole genome" approach looking at approximately 150,000 genetic markers across the entire human genome, and in subsequent phases we have zeroed in on the most promising markers. The results of this finding have pinpointed a new genetic region associated with breast cancer in Ashkenazi Jewish individuals. This region is located on chromosome 6. Individuals with this "risk marker" have from a 13-40% increased chance of developing breast cancer compared with individuals without this genetic marker. While this level of risk is much less than that associated with the BRCA genes, it is nonetheless of great scientific interest. It will lead to further studies that will better identify the genetic mechanisms of breast cancer.

By the completion of the BRCF grant, the researchers will have carried out a study in non-Ashkenazi individuals with breast cancer to show how that these risk markers also exist in the "general" population as well. The results of their initial findings will soon be published in the Proceedings of the National Academy of Sciences.

For the new project in collaboration with the Broad Institute, Drs. Robson and Offit report that since submission of the BRCF application, additional funding has been obtained from the Starr Foundation that will allow genotyping to take place in the third and fourth quarters of 2008. It is planned that genotyping will be carried out on thousands of individuals with BRCA2 mutations to discover genetic factors that protect individuals from breast cancer or increase their risk in the setting of a BRCA2 mutation. While no genotyping is planned until the end of the year, considerable progress has been made to date. An IRB protocol has been written and submitted. This will guarantee the human subjects oversight of the study.

In addition, the team has carried out a series of technical meetings with research collaborators at the Broad Institute in Cambridge. Mechanisms for transporting thousands of samples around the world and for guaranteeing quality assurance have been worked out. The details of the study will be presented to an international gathering of European collaborators with the aim of beginning the collection of DNA samples by the end of the year and the carrying out of genotyping as well by the end of the year.

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.