Ross Berkowitz, MD

2012-2013 BCRF Project:
(made possible by generous support from Play for P.I.N.K.)
Co-Investigators: Ursula Matulonis, MD, and Zhigang Charles Wang, MD, PhD, Dana-Farber Cancer Institute, and Brigham and Women's Hospital/Harvard Medical School, Boston, MA

The goal of this research team at the Dana-Farber Cancer Institute and Brigham and Women's Hospital is to discover genomic predictors for response to therapy and potential therapeutic target(s) shared by high-grade serous ovarian tumors and triple-negative breast cancer. In the past year, Drs. Berkowitz, Matulonis, and Wang investigated mutations in a dataset using a genome-wide assay in a group of ovarian cancer patients treated in Boston, and they extended their analyses to a publically available genome sequencing dataset. The results suggest that the number of genome-wide gene mutations may reflect the degree of genomic instability and may also be useful to predict sensitivity to platinum-based chemotherapy in high-grade serous ovarian cancer. This genomic feature may also be applicable to triple negative breast cancer since these cancers possess DNA repair deficiencies that are observed in high-grade serous ovarian cancer. Drs. Berkowitz, Matulonis, and Wang generated a genomic dataset of the new genome-wide assay from ovarian cancer tissues from ongoing clinical trials with PARP inhibitors, which are drugs that stop repair of DNA in tumor. They have also included genome sequencing for mutation analysis in these studies.

Mid-year Progress: This team continues to work on the discovery of predictors for response to therapy and potential therapeutic targets shared by high-grade serous ovarian tumors and triple negative breast cancer. Recently, a mutation analysis was done using a publically available set of data from the National Cancer Institute. This dataset contains a large amount of genetic information, which was scrutinized with the hypothesis that the number of genetic mutations predicts response to treatment and the outcome of patients with breast and ovarian cancer. This group found that total mutation number in tumor genomes reflects the amount of genomic instability in both ovarian and breast cancers. As the mutation burden increases, so does the sensitivity to ovarian cancer chemotherapy, and patient survival increases as well. Surprisingly, this measure seems to predict chemotherapy response and survival in the subset of ovarian cancer patients with deficiency in one of the two key DNA repair genes called BRCA1 and BRCA2. These two genes are also the inherited causes of breast and ovarian cancer. Drs. Berkowitz, Matulonis, and Wang are analyzing data from breast cancer patients to see if the same relationship between good outcome and higher mutation burden is maintained. The working hypothesis is mutation burden reflects fidelity of DNA repair, which in turn predicts the outcome of certain chemotherapies and new agents like PARP inhibitors in both breast and ovarian cancer. The breast and ovarian group in Boston published an influential manuscript describing some of their work in ovarian cancer, acknowledging BCRF support, and already is talking to industrial partners about using their findings in upcoming clinical trials.

Bio:
Ross Berkowitz, MD is the William H. Baker Professor of Gynecology at Harvard Medical School and the Director of Gynecology and Gynecologic Oncology at Dana-Farber Cancer Institute and Brigham and Women's Hospital. In addition, he is also the Co-Director of the Women's Cancers Program at Dana-Farber and the Director of the Gynecologic Cancer Program at Dana-Farber/Partners Cancercare and Dana-Farber/Harvard Cancer Center.

During the past twenty years, the focus of his research has been in the areas of gestational trophoblastic disease and ovarian neoplasia. Investigations in gestational trophoblastic disease have dealt with identifying risk factors for development of these tumors as well as advancing understanding of the natural history of these diseases including subsequent reproductive experience. His research in ovarian neoplasia has concerned both the development of innovative and novel therapies as well as molecular biologic studies to identify genetic changes in ovarian neoplasia and differences in the pathways of development of borderline ovarian tumors, invasive ovarian cancers, and peritoneal cancers.

Dr. Berkowitz earned his MD from Boston University and had his residency training in surgery at the Peter Bent Brigham Hospital and then in obstetrics and gynecology at the Boston Hospital for Women. He completed his fellowship in gynecologic oncology at the Boston Hospital for Women and joined the faculty at Brigham and Women's Hospital thereafter.