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Mutant Gene That Ups Risk for Ovarian Cancer May Aid Survival
Date:10/11/2011

By Jenifer Goodwin
HealthDay Reporter

TUESDAY, Oct. 11 (HealthDay News) -- Women who have the BRCA2 gene mutation that raises the risk for both breast and ovarian cancer are more likely to survive ovarian cancer than other women, a new study indicates.

Those other women include both women with the BRCA1 mutation, also linked to a heightened risk of breast and ovarian cancer, and women without either mutation.

Researchers said the explanation for the better survival rates with BRCA2 is that women with that mutation respond better to chemotherapy.

"BRCA2 has a better survival compared to BRCA1 and wild type [typical] patients," said study author Da Yang, a postdoctoral fellow at the University of Texas M.D. Anderson Cancer Center. "When we further looked at the chemotherapy response, we find BRCA2 has a more beneficial response compared to the BRCA1 and wild type."

The study is published in the Oct. 12 issue of the Journal of the American Medical Association.

Both the BRCA1 and BRCA2 mutations substantially raise the risk of developing both breast and ovarian cancer, leading many women to opt for preventive mastectomies and removal of their ovaries and fallopian tubes.

Over the course of a lifetime, women with BRCA1 have a 39 percent to 54 percent risk of developing ovarian cancer, while women with BRCA2 mutations have an 11 percent to 23 percent risk, according to background information in the study.

It's also been observed that women who have the mutations and who develop ovarian cancer tend to live longer than those without the mutations, Yang said. The new research not only confirms that, but gets at the differences between the two types of BRCA mutations.

Using data on 316 women with ovarian cancer who took part in the Cancer Genome Atlas project, researchers found that the 29 women with the BRCA2 mutation had a 61 percent chance of surviving five years, compared to 44 percent of women with BRCA1 mutation and 25 percent of women without either mutation.

The three-year progression-free survival rate, or the time during which the tumor did not grow, was 44 percent for BRCA2 women, 22 percent for BRCA1 women and 16 percent for women with neither mutation.

Women with BRCA2 also responded better to platinum-based chemotherapy, the standard treatment for ovarian cancer.

All women with the BRCA2 mutation saw their tumor shrink in response to chemo, compared to 80 percent for women with BRCA1 and 82 percent of women with the typical form of the gene.

After treatment ended, women with BRCA2 went an average of 18 months without the tumor re-growing, compared to 12.5 months for women with BRCA1 and 11.7 months for women without either mutation, the investigators found.

To determine why women with BRCA2 respond better to chemotherapy, researchers conducted whole-exome sequencing using blood and tumor tissue samples. The exome is the portion of the genome that contains genes that code for proteins.

The BRCA gene is involved with repairing DNA errors. The BRCA mutations are believed to make women more susceptible to certain cancers because their ability to fix DNA damage is impaired, Yang said.

Platinum-based chemotherapy also causes a large amount of DNA damage.

The exome sequencing revealed that women with BRCA2 had more DNA mutations that had occurred throughout their lifetimes (as opposed to being inherited at birth) than women with BRCA1.

In women with BRCA2, the ability to repair DNA damage is impaired not just in healthy cells, but in the cancerous tissues as well.

In women with BRCA2, because the tumor cells are not able to repair themselves against the assault of the platinum, that means the tumor itself is less likely to thrive as the cells die off, Yang said.

"We have shown that only the BRCA2 is associated with better chemotherapy response, better progression-free survival and better overall survival, " Yang said. "BRCA1 is not correlated with those observations. This study suggests there may be different functions in the BRCA1 and BRCA2 gene and provides evidence for what we observed in the clinical association studies."

The overarching messages for physicians and researchers is that BRCA1 and BRCA2 are different mutations that can affect survival and how well medications work, he said. New drugs to treat ovarian cancer in the pipeline should avoid lumping the mutations together and instead study each individually, Yang said.

Dr. Victor Grann, a professor of medicine, epidemiology and health policy at Columbia University who wrote an accompanying editorial, noted that although BRCA1 and BRCA2 puts women at heightened risk of breast cancer, many women with the mutations will never go on to develop either cancer, or will die of other causes (such as old age) before developing cancer.

And though the study suggests that platinum-based chemo may be more effective in women with BRCA2, chemotherapy can still be effective in other women, Grann said. Of the 316 women in the study, 225 saw at least some benefit from chemotherapy.

New medications that are currently showing promise in clinical trials may also prove to be more effective in women with BRCA1 or BRCA2.

"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," Grann wrote in the editorial.

There are already other things known about differences between tumors in BRCA1 versus BRCA2 patients. Most breast cancer tumors in women with BRCA2 mutation are estrogen-receptor positive, meaning they respond better to drugs that interfere with the activity of estrogen or estrogen levels such as tamoxifen or aromatase inhibitors, while most BRCA1 cancers are estrogen-receptor negative, Grann said.

More information

The U.S. National Cancer Institute has more on ovarian cancer.

SOURCES: Da Yang, Ph.D., postdoctoral fellow, University of Texas M.D. Anderson Cancer Center, Houston; Victor Grann, M.D., M.P.H., professor, medicine, epidemiology and health policy, Mailman School of Public Health, Columbia University, New York City; Oct. 12, 2011, Journal of the American Medical Association


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