BRCA2 Mutations in Ovarian Tumors Make Cancer Easier To Treat

Mutations of a tumor-suppressing gene that raise a woman's risk of developing ovarian cancer actually increase her chances of surviving the disease when they are present in her tumor.

This seemingly contradictory finding by scientists at The University of Texas MD Anderson Cancer Center about the BRCA2 gene is reported in this week's Journal of the American Medical Association.

They found that women with BRCA2 mutations in their tumors live longer and respond better to platinum-based drugs than those who have mutations in BRCA1, a sister tumor-suppressing gene, or regular versions of BRCA2 in their cancer.

Wei Zhang, Ph.D., professor in MD Anderson's Department of Pathology, and colleagues studied 316 cases of high-grade serous ovarian cancer - the most common form, which occurs on the surface of the ovaries. All patients had been treated with surgery followed by platinum-based chemotherapy.

Every patient with BRCA2 mutations in her tumor responded to platinum chemotherapy, compared to 80% with BRCA1 mutations and 82% with the normal BRCA2. Of those with BRCA2 mutations, 44% had progression-free survival at three years, compared with 16% of those with normal BRCA2 and 22% with BRCA1 mutations. "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.

BRCA2 normally helps repair double-strand DNA breaks. When BRCA2 is mutated, a cell is less capable of repairing DNA damage, which might then be passed on to other cells during cell division.

When these abnormal cells become cancerous, they in turn rely on DNA damage repair to defend themselves against DNA-damaging drugs, such as platinum-based agents. But with BRCA2 mutated, Zhang says, their defense is weakened.

A new class of drugs called PARP inhibitors block a separate DNA repair pathway, so adding them to DNA-damaging drugs to treat BRCA2-mutated tumors could make for a more effective attack, Zhang said.

An editorial in JAMA commenting on the study makes that very point:

"The study by Yang et al provides a major advance in the understanding of the use of new treatments for ovarian cancer among patients with BRCA mutations by demonstrating a difference in the response among patients with BRCA1 and BRCA2 mutations diagnosed with ovarian cancer. Newer studies may support the use of poly (ADP-ribose) polymerase inhibitors for the treatment of such patients. ... The next step would be to enroll these patients in randomized clinical trials to test whether BRCA1 or BRCA2 mutation carriers respond differently with regard to ovarian cancer, as Yang et al suggest."

Women who inherit BRCA1 mutations have a 39% to 54% lifetime risk of developing ovarian cancer. For those with BRCA2 mutations, that risk is 11 to 23%. The elevated risk is presumably caused by impaired DNA repair capability.

However, BRCA1 or BRCA2 mutations can accumulate in a tumor without being present in a woman's genome. Many tumors in this study, Zhang said, have these acquired mutations, also called somatic mutations.

Additional resources MD Anderson news release about this research.