Germline mutations in the tumor suppressor genes BRCA1 and BRCA2 – and particularly those in BRCA2 – are associated with higher 5-year overall survival rates among patients with confirmed invasive epithelial ovarian cancer, according to a pooled analysis of data from 26 observational studies involving nearly 3,900 women.
The 5-year overall-survival rate was 36% for 2,666 non-BRCA carriers, 44% for 909 BRCA1 carriers, and 52% for 304 BRCA2 carriers, Kelly L. Bolton, Ph.D., of the National Cancer Institute, Bethesda, Md., and her colleagues reported on behalf of EMBRACE, KConFab Investigators, and the Cancer Genome Atlas Research Network.
The findings are reported in the Jan. 25 issue of JAMA.
After adjustment for study and year of diagnosis, BRCA1 carriers were significantly more like to survive than were noncarriers (hazard ratio, 0.78), and their advantage improved slightly after additional adjustment for stage, grade, histology, and age at diagnosis (HR, 0.73), the investigators said (JAMA 2012;307:382-90).
BRCA2 carriers had an even greater advantage when compared with noncarriers (HR, 0.61), particularly after adjustment for other prognostic factors (HR, 0.49). The differences between BRCA1 and BRCA2 carriers were statistically significant.
Although prior smaller studies have also demonstrated survival advantages among invasive epithelial ovarian cancer patients with BRCA2, with some also showing an advantage for those with BRCA1, the current study is the largest to date to assess survival in patients with invasive epithelial ovarian cancer based on BRCA1/2 carrier status.
The studies used in the analysis were reported as 10 from the United States, 6 from Europe, 2 from Israel, 1 each from Hong Kong, Canada, and Australia, and 5 from the United Kingdom. Participants were enrolled between 1987 and 2010 and were actively followed for a mean of 38 months.
Several significant differences were seen in regard to clinical features of BRCA1 and BRCA2 carriers compared with noncarriers. For example, tumors in carriers were more likely to be of serous histology and less likely to be of mucinous histology, and carriers were more likely to have stage III/IV tumors and poorly differentiated or undifferentiated tumors, compared with noncarriers. BRCA2 carriers were more likely than were BRCA1 carriers to have stage III/IV tumors. Also, BRCA1 carriers were younger at diagnosis than noncarriers, and BRCA2 carriers were slightly older.
The investigators also found that the survival advantage of BRCA1/2 carriers, compared with noncarriers, was attenuated in women who had a family history of ovarian cancer, breast cancer, or both.
"The improved survival or BRCA1/2 carriers relative to noncarriers, and the survival advantage of BRCA2 carriers relative to BRCA1 carriers, could be related to intrinsic biological differences, their response to therapeutic agents, or both," the investigators said, noting that in addition to differences in stage, grade, and histology, BRCA1/2 carriers could have differences in other aspects of tumor biology that were not measured in this study.
Although the study is limited by factors associated with the study design such as a heterogeneous population, the sample size and the magnitude of the differences observed between carriers and noncarriers are a testament to the robustness of the findings, they said.
The results have potentially important implications for the clinical management of patients with epithelial ovarian cancer, including immediate use by health care professionals for patient counseling regarding expected survival, they said, adding:
"BRCA1 and BRCA2 carriers with EOC respond better than noncarriers to platinum-based chemotherapies and have improved survival despite the fact that the disease is generally diagnosed at a later stage and higher grade. If patients could be stratified based on their BRCA status, their treatment could be tailored to reflect this, with noncarriers targeted for more aggressive treatment."
Epithelial ovarian cancer clinical trials should be stratified by BRCA status, they said, explaining that this would not only allow more appropriately targeted therapy, but also would allow avoidance of potential bias introduced by unequal numbers of carriers in treatment groups or between study cohorts.
"Furthermore, given 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 EOC may now be warranted," they said.
Numerous funding sources and author disclosures were reported. The complete list is available with the full text of the article at jama.com.