Improved Survival in Women With Invasive Epithelial Ovarian Cancer and Germline BRCA Gene Mutations

BRCA1 Protein.

Researchers are reporting better survival rates in women with invasive epithelial ovarian cancer (EOC) and germline mutations in the tumor suppressor genes BRCA1 and BRCA2 than in patients who are noncarriers.

Kelly L. Bolton, PhD, with the National Cancer Institute in Bethesda, Maryland, and associates analyzed pooled data from 26 observational studies on the survival of women with confirmed invasive EOC.

While about 6% to 15% of women with invasive EOC carry deleterious germline mutations in BRCA1 or BRCA2, there are an absence of definitive data on the relative prognosis of BRCA1/2 carriers, the authors pointed out in their article.

The present analysis included data from 3879 EOC cases: 909 BRCA1 and 304 BRCA2 mutation carriers and 2666 noncarriers. The primary endpoint was overall survival up to 5 years following EOC diagnosis.

The analysis found a 5-year overall survival of 36% (95% CI, 34%-38%) for noncarriers, 44% (95% CI, 40%-48%) for BRCA1 carriers, and 52% (95% CI, 46%-58%) for BRCA2 carriers.

When the investigators conducted a Cox proportional hazards model that adjusted solely for study site and year of diagnosis, BRCA1 and BRCA2 carriers had a more favorable survival than noncarriers (hazard ratio [HR] = 0.78; 95% CI, 0.68-0.89; P <.001), which improved only marginally after they additionally controlled for stage, grade, histology, and age at diagnosis (HR = 0.73; 95% CI, 0.64-0.84; P <.001).

The data also showed that BRCA2 carriers had a larger survival advantage than noncarriers. Bolton and colleagues said that the improved survival of BRCA1/2 carriers relative to noncarriers, along with the survival advantage of BRCA2 carriers over BRCA1 carriers, “could be related to intrinsic biological differences, their response to therapeutic agents, or both.” Besides differences in stage, grade, and histology, BRCA1/2 carriers may have differences in other aspects of tumor biology that were not examined in this study.

The investigators pointed out that their analysis was based on a heterogeneous population, which represents both a strength and limitation. For example, the studies used in the analysis had different ethnic populations, mutation screening methodologies, and case ascertainment, which enabled the investigators “…to generate a large enough sample size to adequately address the issue of heterogeneity of the survival effect between BRCA1 and BRCA2 carriers.” At the same time, “differences in study design and population may limit the specificity of the conclusions drawn.”

Bolton et al noted that their findings can be used by healthcare professionals to counsel BRCA1/2 carriers about their expected survival. Also, stratification by BRCA status allows oncologists to better tailor treatment. BRCA1/2 carriers with EOC are known to have better responses than noncarriers to platinum-based chemotherapy and better survival, even though the disease is usually diagnosed at a later stage and a higher grade, they added.

Finally, in view of the important prognostic information provided by BRCA1/2 status, coupled with the potential for personalized treatment in women carrying these mutations, the authors called for routine testing in women who present with high-grade serous EOC.

Bolton KL, Chenevix-Trench G, Goh C, et al. Association between BRCA1 and BRCA2 mutations and survival in women with invasive epithelial ovarian cancer. JAMA 2012;307(4):382-389.