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Study Suggests Survival Advantage for Ovarian Cancer Patients with BRCA Mutations

NEW YORK (GenomeWeb News) – The five-year survival rate for individuals with invasive epithelial ovarian cancer is generally higher for women with mutations in BRCA1 or BRCA2 than it is for those without, according to a new study in the Journal of the American Medical Association.

A large international group led by investigators at the University of Cambridge looked at five-year survival data, tumor characteristics, and more for thousands of epithelial ovarian cancer patients with or without BRCA1/2 mutations who were enrolled in dozens of previous studies.

Results of their analyses indicated that the five-year survival rate was highest for epithelial ovarian cancer patients with BRCA2 mutations, followed by those with BRCA1 mutations. On the other hand, women with no known mutations in the BRCA1/2 genes had worse five-year survival outcomes, overall, even when researchers took into account other variables such as age at diagnosis, tumor grade, and so on.

"[G]iven the important prognostic information provided by BRCA1 and BRCA2 status and the potential for personalized treatment in carriers, the routine testing of women presenting with high-grade serous [epithelial ovarian cancer] may now be warranted," University of Cambridge researcher Paul Pharaoh, the study's corresponding author, and colleagues wrote.

Mutations in both BRCA1 and BRCA2 are associated with increased risk of breast and ovarian cancer. And previous research suggests that women who have known BRCA1 mutations also tend to be diagnosed with more advanced, high-grade epithelial ovarian tumors, the study authors explained.

But a handful of recent studies have hinted that mutations in BRCA1 and/or BRCA2 genes are also associated with better survival for ovarian cancer patients. Among them: a study published in JAMA last year by American and Chinese researchers who found that BRCA2 mutations corresponded with better ovarian cancer survival and drug response.

Even so, other studies have been less conclusive and the relative importance of BRCA1 and BRCA2 mutations in survival, if any, is not known.

In an effort to understand whether BRCA1 had any discernible impact on ovarian cancer outcomes, and to look in more detail at the suspected BRCA2 effects, Pharaoh and his collaborators drew on data for 3,879 women diagnosed with invasive epithelial ovarian cancer between 1981 and 2010 who were followed for a median of 38 months after diagnosis.

The epithelial ovarian cancer patients, enrolled through 26 studies done in the US, Canada, Europe, the UK, Israel, Hong Kong, and Australia, included 909 women with pathogenic BRCA1 mutations, 304 with BRCA2 mutations, and 2,666 with no known mutations in either gene. Women with BRCA1/2 variants of unknown significance were not included in the study, researchers noted.

"The goal of our study was to collate the data from multiple [epithelial ovarian cancer] case series with data on BRCA1 and BRCA2 mutation status to provide definitive evidence of the relative effect of germline BRCA1 and BRCA2 mutations on prognosis," they wrote.

Indeed, results of the analysis did point to better outcomes in patients with pathogenic BRCA1/2 mutations.

In epithelial ovarian cancer patients lacking mutations in either BRCA1 or BRCA2 the five-year survival rate was 36 percent, compared to a five-year survival rate of 44 percent in patients with BRCA1 mutations and 52 percent in those with BRCA2 mutations.

After researchers took into account factors known to influence ovarian cancer outcomes, such as age at ovarian cancer diagnosis, year of diagnosis, and so on, they saw some shifts in the extent of survival differences related to the presence or absence of BRCA1/2 mutation, though the trend toward improved survival for those with mutations in the genes generally remained.

Based on the findings so far, those involved in the study speculated that BRCA1/2 mutation status may be informative not only for classifying, counseling, and treating epithelial ovarian cancer patients, but also for providing insights into disease biology.

"The findings … are the latest evidence that ovarian cancer is a much more genetically and biologically heterogeneous disease than previously appreciated," David Hyman and David Spriggs, both from the Memorial Sloan-Kettering Cancer Center, wrote in an editorial accompanying the JAMA study.

Though the pair cautioned that some of new analyses were limited by a lack of information on tumor, treatment, or other relevant features for a subset of study participants, they also called the work "by far, the largest study of BRCA-associated ovarian cancer outcomes reported to date."

"Further studies in similarly large data sets are needed to better understand the effects of somatic and epigenetic alterations in BRCA gene function as well as complex interactions with other inherited alleles," Hyman and Spriggs concluded.

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