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BRCA mutations common in triple-negative ca.

The incidence of BRCA mutations in women with triple-negative breast cancer appears to be greater than previously thought, which may have important screening and treatment implications.

In all, 20% of unselected patients with triple-negative breast cancer had BRCA mutations in a small study of 77 patients. Surprisingly, the mutations were associated with significantly better recurrence-free survival and a trend toward better survival, Dr. Ana M. Gonzalez-Angulo said during a press conference in advance of the meeting, which was sponsored by the American Society of Clinical Oncology.

The study obtained DNA from tumor and normal tissue samples that had been taken from each of 77 patients with triple-negative breast cancer. The samples had been stored in a tissue bank.

In all, 20% of patients had BRCA mutations (BRCA1 mutations, 12 patients; BRCA2 mutations, 3 patients). All but one (a BRCA1 mutation) were germline mutations.

Seven mutation carriers had not been referred for genetic analysis. Nine of 14 germline mutation carriers had no first-degree family history of breast or ovarian cancer.

A rate of "almost 20% mutations in an unselected population is quite high," said Dr. Gonzalez-Angulo of the department of breast medical oncology at the University of Texas M.D. Anderson Cancer Center in Houston. "So I think that we probably have to start lowering our [threshold] for at least sending these patients for genetic counseling," she said.

Dr. Jennifer C. Obel, moderator of the press briefing, agreed. "We may need to consider offering genetic testing to more of these patients in order to better screen them for more BRCA-associated malignancies, and to extend testing for their family members, who may also be at risk," said Dr. Obel, a medical oncologist at NorthShore University HealthSystem and a clinical faculty member at the University of Chicago.

If the findings are replicated, they may have treatment implications for triple-negative breast cancer patients.

BRCA is a DNA-repair enzyme. "So tumors that have BRCA mutations are basically very, very sensitive to agents that damage DNA," said Dr. Gonzalez-Angulo. Although there are conventional chemotherapy drugs to consider, newer investigational agents - such as PARP (ADP ribose polymerase) inhibitors - are particularly promising. Several of these agents are under investigation in clinical trials, with promising early results reported so far in breast and ovarian cancers.

BRCA1 or 2 mutations can cause errors in DNA repair that lead to breast cancer. Basically PARP-inhibiting drugs block PARP from compensating for the loss of BRCA function and from repairing DNA damage. With no functioning repair mechanism in place, the cell dies in a process called synthetic lethality.

"It may become important to identify women with these mutations because the mutation provides a rational target for treatment with PARP inhibitors - a class of drugs currently under development," said Dr. Obel.

Over a median follow-up of 43 months, there were 33 recurrences and 35 deaths in the study population.

The estimated 5-year recurrence-free survival rates were 51.7% for patients with wild-type BRCA 1/2 vs. 82.6% for patients with a BRCA mutation. This difference was significant.

The estimated 5-year overall survival rates were 52.8% for patients with the wild-type gene, compared with 73.3% for patients with BRCA mutations. This difference was not significant, however.

Three of the study authors reported significant financial relationships with Myriad Genetics Inc., a company that has a monopoly on molecular diagnostic testing for BRCA1 and 2


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Title Annotation:WOMEN'S HEALTH; breast cancer
Author:Wachter, Kerri
Publication:Internal Medicine News
Geographic Code:1USA
Date:Oct 15, 2010
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