BRCA1 and BRCA2 mutations are bad news to their carriers; the genes, which were the first cancer susceptibility genes to be identified, strongly raise the risk of developing breast and ovarian cancers – in some cases, up to fivefold.

But a meta-analysis published this week showed that once an ovarian cancer patient is diagnosed, having a BRCA gene mutation amounts to good news: Patients with either BRCA1 or BRCA2 mutations had higher five-year survival rates than women without either mutation.

Perhaps most impressively, BRCA mutation carriers had better odds despite the fact that their cancers tended to have worse characteristics at diagnosis. When the team adjusted their analysis to account for the fact that BRCA mutation carriers had worse tumors at the time of their diagnosis, their survival benefit compared to patients without BRCA mutations increased even further.

For some time, the notion has been building that "BRCA1 and BRCA2 testing should be almost routine in women with ovarian cancer," senior author Paul Pharoah told BioWorld Today. "Our notion strengthens this idea."

Earlier, smaller studies had shown that ovarian cancer patients with BRCA mutations have a survival advantage, but those studies lumped together BRCA1 and BRCA2 mutations. In their meta-analysis of 26 studies, which appeared in the Jan. 25, 2012, issue of the Journal of the American Medical Association, a consortium of researchers, including the University of Cambridge's Pharoah, who is the study's corresponding author, confirmed the survival advantage, and showed that it exists for both patients with BRCA1 and BRCA2 mutations.

The survival advantage for patients with BRCA2 mutations was higher than for those with BRCA1 mutations. The difference was not large enough to be statistically significant. But it was large enough to prompt the authors of an editorial that accompanied the paper to note that it may mean that BRCA1 and BRCA2 mutations affect survival via subtly different mechanisms. And if that is the case, the findings may have implications for the development of targeted agents aimed at BRCA mutations.

BRCA mutations make their carriers more susceptible to developing cancer because they interfere with cells' ability to repair double-stranded DNA breaks. Though Pharoah and his team did not address the reasons behind the survival advantage they saw in their paper, the reason BRCA mutations increase the odds of survival may be that they make patients more susceptible to the effects of platinum-based chemotherapies, which bind to DNA and cause such double-stranded breaks. Platinum-based drugs are part of the standard treatment for ovarian cancer.

One class of drugs that targets BRCAs inability to repair itself is Poly(ADP-ribose) polymerase, or PARP inhibitors, a class that includes AstraZeneca plc's olaparib, Abbott's veliparib (ABT-888) and BSI-201 (iniparib), which Sanofi SA acquired in a 2009 buyout of BiPar Sciences Inc.

David Hyman and David Spriggs wrote in their JAMA editorial that "upcoming trials of PARP inhibitors in ovarian cancer that specifically enrich for BRCA1 and BRCA2 carriers may be at particular risk for confounding if differences in these two biologically distinct groups are not considered."

In the current paper in JAMA, Pharoah and his colleagues looked at about 900 ovarian cancer patients with deleterious BRCA1 mutations, about 300 ovarian cancer patients with BRCA2 mutations and more than 2,600 controls. They found that the overall survival rate was 36 percent for women without BRCA mutations, 44 percent for women with BRCA1 mutations and 52 percent for women with BRCA2 mutations.

Those results contrast with the published effects of BRCA mutations on breast cancer patient survival, which have been mixed, with some studies showing a survival advantage, while others found no difference or lower survival rate in breast cancer patients with BRCA mutations than in those without. Study size might have something to do with the conflicting results.

So might another factor that correlates with BRCA mutations but is not caused by them. BRCA mutations tend to cause breast cancer at an early age. Such breast cancers, in turn, tend to be estrogen-receptor negative, and ER-negative breast tumors have a worse prognosis. Unless those correlations are taken into account, studies may ascribe worse outcomes to BRCA mutations that are actually due to ER-negative tumors.