Women with high-grade ovarian cancer live longer and respond better to platinum-based chemotherapy when their tumors have BRCA2 genetic mutations, researchers at The University of Texas MD Anderson Cancer Center and the Institute for Systems Biology report in the Oct. 12 issue of the Journal of the American Medical Association.
“BRCA2-mutated tumors are more vulnerable to these DNA-damaging agents, which is really exciting because there are a number of drugs in clinical trials now that block DNA repair that might prove effective against these tumors in combinations,” said senior author Wei Zhang, Ph.D., professor in MD Anderson’s Department of Pathology.
BRCA2 and its cousin, BRCA1, are tumor-suppressing genes involved in DNA repair that, when mutated, raise a woman’s risk for having breast or ovarian cancer.
“Uncovering the separate potential effects of BRCA1 and BRCA2 mutations takes us a step towards a more personalized approach to treating ovarian cancer, and perhaps other cancers,” Zhang said. “This paper suggests those two genes, and the many others involved in DNA repair, are prime targets for further research.”
Past studies of the possible clinical impact of BRCA1 and BRCA2 mutations tended to look at the two genes together and were limited by small sample sizes.
First author Da Yang, Ph.D., an Odyssey Fellow in MD Anderson’s Department of Pathology, said their in-depth study was made possible by The Cancer Genome Atlas project. TCGA published a study of 489 cases of high-grade serous ovarian cancer, the most common form of the disease, that combined an exhaustive analysis of each tumor’s genome with comprehensive clinical data on each patient.
“TCGA gave us enough analytical power to differentiate between BRCA1 and BRCA2 mutations and conduct a survival analysis,” Yang said.
Improved overall survival
Of 316 cases, 29 tumors had BRCA2 mutations tumors and 37 had BRCA1 mutations. Tumors were similar in grade and stage. Findings include:
* 61 percent of patients with BRCA2 mutations survived for five years, compared with 25 percent of those with normal BRCA2 in their tumors.
* 44 percent of those with BRCA2 mutations lived three years after surgery and platinum treatment without disease progression, compared with 16 percent of those with normal BRCA2.
* BRCA1 mutations in tumors were not associated with survival.
* All of those with BRCA2 mutations responded to platinum chemotherapy, compared to 82 percent with the normal gene and 80 percent whose tumors had BRCA1 mutations.
* Their response to chemotherapy lasted 18 months, compared with 11.7 months for normal BRCA2 and 12.5 months for BRCA1 mutations.
* Tumors with BRCA2 variations also are hypermutants - they had more genetic mutations - with 84 mutations per tumor sample compared to 52 for normal BRCA2
Zhang said this last aspect - called the hypermutator phenotype - might be both a factor in the development and growth of the tumor and a sign of its vulnerability.
The ovaries are part of a woman’s reproductive system. They are in the pelvis. Each ovary is about the size of an almond.
The ovaries make the female hormones - estrogen and progesterone. They also release eggs. An egg travels from an ovary through a fallopian tube to the womb (uterus).
When a woman goes through her “change of life” (menopause), her ovaries stop releasing eggs and make far lower levels of hormones.
BRCA2 is normally involved in the repair of double-strand DNA breaks. Cells with BRCA2 mutants are less capable of repair, allowing other genetic mutations to survive and grow, the type of genomic instability that cancer thrives upon.
However, cancer cells in turn rely on DNA repair to defend themselves against DNA-damaging drugs, such as platinum-based agents. So adding drugs that inhibit DNA repair could increase the effectiveness of chemotherapy, Zhang noted. PARP-inhibitors, a new class of drug in clinical trials, block DNA repair and may also be effective in treating BRCA2 mutated ovarian cancer.
Ovarian cancer risk factors
Doctors cannot always explain why one woman develops ovarian cancer and another does not. However, we do know that women with certain risk factors may be more likely than others to develop ovarian cancer. A risk factor is something that may increase the chance of developing a disease.
Studies have found the following risk factors for ovarian cancer:
Family history of cancer: Women who have a mother, daughter, or sister with ovarian cancer have an increased risk of the disease. Also, women with a family history of cancer of the breast, uterus, colon, or rectum may also have an increased risk of ovarian cancer.
If several women in a family have ovarian or breast cancer, especially at a young age, this is considered a strong family history. If you have a strong family history of ovarian or breast cancer, you may wish to talk to a genetic counselor. The counselor may suggest genetic testing for you and the women in your family. Genetic tests can sometimes show the presence of specific gene changes that increase the risk of ovarian cancer.
Personal history of cancer: Women who have had cancer of the breast, uterus, colon, or rectum have a higher risk of ovarian cancer.
Age over 55: Most women are over age 55 when diagnosed with ovarian cancer.
Never pregnant: Older women who have never been pregnant have an increased risk of ovarian cancer.
Menopausal hormone therapy: Some studies have suggested that women who take estrogen by itself (estrogen without progesterone) for 10 or more years may have an increased risk of ovarian cancer.
Scientists have also studied whether taking certain fertility drugs, using talcum powder, or being obese are risk factors. It is not clear whether these are risk factors, but if they are, they are not strong risk factors.
Having a risk factor does not mean that a woman will get ovarian cancer. Most women who have risk factors do not get ovarian cancer. On the other hand, women who do get the disease often have no known risk factors, except for growing older. Women who think they may be at risk of ovarian cancer should talk with their doctor.
Additional studies of the function of BRCA1 and BRCA2 mutations are needed to more fully understand and exploit their findings to treat cancer, Zhang and colleagues note.
The Cancer Genome Atlas is a joint project of the National Cancer Institute and the National Human Genome Research Institute, both of the National Institutes of Health, to comprehensively characterize changes in genetic mutation and regulation of various cancers.
Co-authors with Zhang and Yang are Sofia Kahn, Ph.D., and Yan Sun, M.D., Ph.D., of MD Anderson’s Department of Pathology; Kenneth Hess, Ph.D., of MD Anderson’s Department of Biostatistics, Anil Sood, M.D., of MD Anderson Departments of Cancer Biology and Gynecologic Oncology and Reproductive Medicine and the Center for RNAi and Non-Coding RNA; and Ilya Shmulevich, Ph.D., Institute for Systems Biology in Seattle.
This research was funded by the National Cancer Institute; the Blanton-Davis Ovarian Cancer Research Program, MD Anderson’s NCI Specialized Program in Research Excellence in Ovarian Cancer; MD Anderson’s Odyssey Fellows Program; and an ASLA-Fulbright Research Grant.
About MD Anderson
The University of Texas MD Anderson Cancer Center in Houston ranks as one of the world’s most respected centers focused on cancer patient care, research, education and prevention. MD Anderson is one of only 40 comprehensive cancer centers designated by the National Cancer Institute. For eight of the past 10 years, including 2011, MD Anderson has ranked No. 1 in cancer care in “Best Hospitals,” a survey published annually in U.S. News & World Report.
University of Texas M. D. Anderson Cancer Center