Survival Improved in Ovarian Cancer With BRCA Mutation

Roxanne Nelson

January 24, 2012

January 24, 2012 — Mutations in BRCA1 and BRCA2 genes are currently the strongest known genetic risk factors for developing both breast and epithelial ovarian cancer, but in the case of ovarian cancer, they are also associated with improved survival.

According to a study published in the January 25 issue of the JAMA: The Journal of the American Medical Association, having a germline mutation in BRCA1 or BRCA2 is associated with improved 5-year overall survival from ovarian cancer, with BRCA2 carriers having the best prognosis.

The 5-year overall survival was 36% (95% confidence interval [CI], 34% to 38%) for noncarriers of the mutation, compared with 44% (95% CI, 40% to 48%) for BRCA1 carriers and 52% (95% CI, 46% to 58%) for BRCA2 carriers.

The authors note that these differences in survival remained even after adjustment for confounders such as stage, grade, histology, and age at diagnosis (hazard ratio [HR] for BRCA1, 0.73; P < .001; HR for BRCA2, 0.49; P < .001).

However, the implications of these results could still be limited in the clinical setting, explained study author Paul Pharoah, BM, BCh, PhD, reader in cancer epidemiology at the University of Cambridge, United Kingdom. "Knowing BRCA1/2 status would allow the clinician to say something about likely prognosis but, until we know more about the interaction with specific treatments, one would not have sufficient evidence to treat the different cancers differently," he told Medscape Medical News.

"However, we believe that in the context of randomized controlled trials, it will be important to include BRCA testing in the protocol so that we can learn whether BRCA carriers respond differently than noncarriers, so that, in due course, it will be possible to provide targeted therapies," he said.

Dr. Pharoah pointed out that PARP inhibitors target the molecular pathways affected by BRCA mutations. "One can envision the testing of patients and the use of such targeted therapy in the near future," he added.

Implications for Research

In an accompanying editorial, David M. Hyman, MD, from the Memorial Sloan-Kettering Cancer Center, and David R. Spriggs, MD, from the Weill Cornell Medical College, both in New York City, agree that these data have implications for future research.

They note that phase 3 studies that do not "stratify by BRCA mutation status or account for this factor in a preplanned statistical analysis risk possible confounding," because about 15% of unselected patients with serous ovarian cancer carry these mutations.

Other studies have also found differences in chemotherapy response and progression-free survival between sporadic BRCA1- and BRCA2-associated ovarian cancers, the editorialists continue. "Germline BRCA testing needs to be consistently incorporated into both the routine management and future phase 3 trials of ovarian cancer."

Of perhaps equal importance, these results "provide impetus for rethinking the current approach to the development of targeted agents in molecularly defined subsets of ovarian cancer," they add.

Tumor Differences, Better Survival

In their study, Dr. Pharoah and colleagues investigated 1213 ovarian cancer patients with pathogenic germline mutations in BRCA1 (n = 909) or BRCA2 (n = 304) and 2666 noncarriers drawn from 26 observational studies on the survival of women with ovarian cancer.

The women were followed-up at variable intervals from 1987 to 2010; during the 5 years after diagnosis, 1766 deaths occurred.

There were a number of significant differences between the clinical features of BRCA1 and BRCA2 carriers and those of noncarriers. Tumors in women with the BRCA1/2 mutations were more likely to be of serous histology and less likely to be mucinous than those in noncarriers. BRCA1 and BRCA2 carriers were also more likely to have stage III/IV tumors and poorly differentiated or undifferentiated tumors.

When the data were adjusted for only study site and year of diagnosis, BRCA1 carriers had better survival than noncarriers (HR, 0.78; P < .001). When adjusted for other factors, such as stage and age at diagnosis, survival improved slightly (HR, 0.73; P < .001).

Patients with BRCA2 mutations had a greater survival advantage than noncarriers (HR, 0.61; P < .001); this improved after adjustment for other factors (HR, 0.49; P < .001).

In a subset of 1129 patients who had residual disease after primary surgery, the authors found that optimal debulking had taken place in 85% of noncarriers, 87% of BRCA1 carriers, and 91% of BRCA2 carriers. After adjustment for year of diagnosis and study site, they found no significant difference in the likelihood of optimal debulking between noncarriers and BRCA1 (P = .74) or BRCA2 (P = .46) carriers. After adjustment for residual disease, the HR estimates did not substantially change for relative survival.

Routine testing of women with high-grade serous epithelial ovarian cancer might be warranted, write the authors, given the prognostic information provided by BRCA1 and BRCA2 status and the potential for personalized treatment in mutation carriers.

"Our results also show that more research is needed into the cellular differences between tumors in BRCA carriers and noncarriers so that we might begin to understand why the latter do less well and perhaps help identify targeted therapies for them," said Dr. Pharoah.

The study was funded from multiple sources, as noted in the paper. Dr. Pharoah, Dr. Hyman, and Dr. Spriggs have disclosed no relevant financial relationships. Several of the study coauthors report financial relationships, as noted in the paper.

JAMA. 2012;307:382-390, 408-410. Abstract, Editorial

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