Prognostic and Practical Implications of Germline BRCA Status
Prognostic and Practical Implications of Germline BRCA Status
Abstract & Commentary
By Robert L. Coleman, MD, Professor, University of Texas; M.D. Anderson Cancer Center, Houston, is Associate Editor for OB/GYN Clinical Alert.
Dr. Coleman reports no financial relationships relevant to this field of study.
Synopsis: Women with ovarian cancer who carry germline mutations in BRCA1 or BRCA2 have a better prognosis (overall survival) than those women with ovarian cancer who do not. BRCA2 mutation confers a stronger effect compared to BRCA1. These findings affect treatment decisions and clinical investigation.
Source: Bolton KL, et al. Association between BRCA1 and BRCA2 mutations and survival in women with invasive epithelial ovarian cancer. JAMA 2012;307:382-390.
Women who carry a deleterious germline mutation in BRCA1 or BRCA2 have a substantially higher lifetime risk of developing ovarian cancer. Previous reports have suggested that if ovarian cancer develops in these women, their prognosis is better, particularly if they carry a mutation in BRCA2. However, the association has been inconsistent and limited by small series, variable treatments, and identification techniques. To better elucidate the association of BRCA status and outcome, the authors conducted a pooled analysis of 26 observational studies that included data from 1213 ovarian cancer cases with pathogenic germline mutations in BRCA1 (n = 909) or BRCA2 (n = 304) and from 2666 non-carriers. Untested patients with ovarian cancer from families with a documented germline mutation were assumed to carry the same mutation. Patients were recruited and followed between 1987 and 2010. The 5-year overall survival was 36% for non-carriers, 44% for BRCA1 carriers, and 52% for BRCA2 carriers. After adjusting for study and year of diagnosis, BRCA1 and BRCA2 mutation carriers showed a more favorable survival than non-carriers (for BRCA1: hazard ratio [HR], 0.78; 95% confidence interval [CI], 0.68-0.89; P < 0.001; and for BRCA2: HR, 0.61; 95% CI, 0.50-0.76; P < 0.001). These survival differences remained after additional adjustment for stage, grade, histology, and age at diagnosis. Of interest, this effect was attenuated when the analysis was based on women recruited solely by strong family history (without formal testing). Overall, ovarian cancer patients harboring a germline mutation in BRCA1 or BRCA2 have a significantly improved 5-year overall survival. BRCA2 carriers have the best prognosis.
Commentary
The current report provides the most definitive information to date on the prognostic significance of germline BRCA1 and BRCA2 mutations on epithelial ovarian cancer mortality. The data are important because prognostic associations about ovarian cancers that develop in BRCA1 or BRCA2 germline carriers have been inconsistent in previous reports, particularly in BRCA1 carriers. BRCA1 carriers have a higher overall risk, develop cancer at a younger age, and may benefit, to a lesser degree, from prophylactic surgery compared to BRCA2 carriers.1 The study's diverse population, large sample size, and statistical rigor are its strengths and provide the most convincing data to date that BRCA-associated ovarian cancer (both BRCA1 and BRCA2) has sufficiently different biology compared to wild-type ovarian cancer. This becomes important in making treatment recommendations because the BRCA genes perform many important functions in normal cells, including a major role in high-fidelity DNA damage repair through homologous recombination. Their altered or truncated function in cancer cells leads to augmented cell kill, particularly with agents (chemotherapy and radiation) that cause DNA double-strand injury. Indeed, recent studies have suggested improved ovarian cancer outcomes also may result from aberrations in other genes governing the homologous recombination pathway like EMSY, PTEN, and the Fanconi genes.2
A second important implication from this study is that, like age, performance status and debulking result; BRCA status should be included as an important stratification variable when assessing the outcomes of treatment trials. The strength of this effect is not considered in a treatment population (10-15% of participants), it could significantly vary the interpretation of clinical trials involving cytotoxic agents. Since BRCA testing is not universally performed in women with the disease, preinvestigational assessment of homologous recombination deficiency is warranted. Finally, knowledge of BRCA mutation status in this population will help to identify patients likely to benefit from agents targeting DNA repair mechanism "workarounds," such as the poly(ADP)-ribose polymerase inhibitors.3,4
References
- Kauff ND, et al. Risk-reducing salpingo-oophorectomy for the prevention of BRCA1- and BRCA2-associated breast and gynecologic cancer: A multicenter, prospective study. J Clin Oncol 2008;26:1331-1337.
- Cancer Genome Atlas Research Network. Integrated genomic analyses of ovarian carcinoma. Nature 2011;474:609-615.
- Audeh MW, et al. Phase II trial of the oral PARP inhibitor olaparib (AZD2281) in BRCA-deficient advanced ovarian cancer. J Clin Oncol 2009;27:15s.
- Fong PC, et al. AZD2281 (KU-0059436), a PARP (poly ADP-ribose polymerase) inhibitor with single agent anticancer activity in patients with BRCA deficient ovarian cancer: Results from a phase I study. J Clin Oncol 2008;26.
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