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Breast, Ovarian Cancer Risk Refined in Prospective Study of BRCA Mutation Carriers

NEW YORK (GenomeWeb) – A large, international research team has taken a prospective look at the actual breast and ovarian cancer rates in individuals with known pathogenic mutations in the BRCA1 or BRCA2 genes.

"We have been able to provide the most precise estimates of age-specific risks to date," corresponding author Antonis Antoniou, a cancer genetic epidemiology researcher at the University of Cambridge, said in a statement. "These should provide more confidence in the counseling and clinical management of women with faults in the BRCA1 and BRCA2 genes."

In a study published today in the Journal of the American Medical Association, Antoniou and his colleagues tracked ovarian, breast, and contralateral breast cancer development over time in thousands of individuals with pathogenic BRCA1 or BRCA2 mutations.

Based on hundreds of cancer diagnoses made over several years of follow up, they estimated cumulative breast cancer risk is roughly 72 percent by age 80 in pathogenic BRCA1 mutation carriers, for example, while ovarian cancer risk is around 44 percent in the women with BRCA1 mutations.

Beyond the risk associated with the BRCA1/2 gene mutations, the team noted that there are additional clues for predicting breast and ovarian cancer in BRCA-mutation carriers' family histories and in the nature of the mutation identified.

"The results show clearly and for the first time in a prospective study, that the cancer risks for women with faults in BRCA1 and BRCA2 depend both on the precise mutation and the woman's family cancer history," co-senior author Douglas Easton, a University of Cambridge researcher leading one of the national studies tapped for the analysis, said in a statement.

Starting from 9,856 individuals with BRCA1 or BRCA2 mutations who were enrolled in the UK, Netherlands, France, and elsewhere between 1997 and 2011, the team identified sub-groups of individuals eligible for prospective breast and ovarian cancer analyses. Participants were followed until late 2013, unless they turned 80 before that.

In 2,276 of the women with BRCA1 germline mutations and 1,610 BRCA2 mutation carriers, the researchers saw 426 new breast cancer diagnoses. From those data, they estimated that breast cancer risk was 72 percent in BRCA1 mutation carriers and 69 percent overall in individuals with pathogenic BRCA2 mutations.

Breast cancer cases rose in BRCA1 mutation carriers between 30 and 40 years old, though the upturn in breast cancer occurred roughly a decade later in individuals with the BRCA2 mutations. The team noted that breast cancer risk appeared to be ratcheted up with each close relative diagnosed with the disease in a BRCA-mutation carrier's family.

From the 2,905 women with BRCA1 mutations and 2,161 women with BRCA2 mutations who were eligible for that analysis, meanwhile, the researchers identified 109 new ovarian cancer cases. They put the cumulative risk of ovarian cancer prior to 80 years old at 44 percent in women with BRCA1 mutations and 17 percent in the BRCA2 mutation group.

Finally, when they focused on the risk of contralateral breast cancer — marked by seemingly distinct cancers in each breast — the investigators found more than 2,200 BRCA-mutation carriers who could be considered in that analysis. Based on the 245 contralateral breast cancers diagnosed in this group, they put BRCA1 carriers' long-term risk of the disease at 40 percent, compared to 26 percent in women with BRCA2 mutations.

Antoniou, Easton, and co-authors wrote that "optimal clinical management of women with BRCA1 and BRCA2 mutations depends on accurate age-specific cancer risk estimates."

"These finding provide information on cancer risk for BRCA1 and BRCA2 mutation carriers using prospective data and demonstrate the potential importance of family history and mutation location in risk assessment," they concluded.