Original Article
carriers and BRCA-negative patients. The relative contributions of improved chemotherapy sensitivity versus underlying differences in tumor biology are unclear. A case-control study by Tan and colleagues revealed higher rates of platinum sensitivity across first-line, second-line, and third-line therapy for patients with BRCA1/BRCA2 mutation-positive ovarian cancer compared with matched controls.18 However, their report included only 22 BRCA mutation carriers (17 BRCA1 mutation carriers and 5 BRCA2 mutation carriers) and did not attempt to compare BRCA1-associated and BRCA2-associated outcomes. More recently, our group examined predictors of survival in a subset of the patients included in the current report.15 In that previous work, both the presence of a BRCA mutation and platinum sensitivity were independent predictors of survival, suggesting that both tumor biology and chemotherapy sensitivity may contribute to prolonged survival. However, that earlier study also was not powered to examine at differences between carriers of BRCA1 mutations and BRCA2 mutations. Ultimately, the mechanisms through which BRCA1 and BRCA2 mutations may result in different tumor biology are poorly understood and require further research. Until recently, all ovarian cancers have been managed similarly regardless of germline BRCA mutation status. Although it has been suggested for more than a decade that BRCA1/BRCA2-associated ovarian cancers have a more favorable prognosis compared with BRCAnegative tumors, there have been no targeted therapies available to exploit the underlying biologic differences between these tumors. Since the development of PARP inhibitors, which may be specifically active in BRCA-deficient tumors, the molecular subclassification of ovarian cancers has become increasingly important.24 BRCA-deficient tumors have alterations in homologous recombination, the DNA repair pathway responsible for highfidelity resolution of double-stranded DNA breaks and cross-links.25 PARP inhibitors block base excision repair, a lower fidelity salvage DNA repair pathway necessary to maintain genomic stability in tumors deficient in homologous recombination, and are an extremely promising class of agents for treating BRCA-deficient ovarian cancer.26 However, the mechanism of BRCA inactivation, and the associated loss of homologous recombination function, may be important. Hennessy et al reported on a cohort of 44 ovarian cancer specimens that were tested for BRCA1/ BRCA2 mutations.27 Thirty-three (75%) of the mutations were germline, and the remaining 11 (25%) were somatic. In that analysis, patients who had loss of BRCA function through either mechanism had improved progression-free
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survival compared with patients who had intact BRCA function. However, those authors did not report the outcomes of germline and somatically mutated tumors separately. Finally, their analysis did not examine specimens for epigenetic BRCA inactivation. Recent data generated by The Cancer Genome Atlas Ovarian Project demonstrate that, although approximately 50% of high-grade serous ovarian tumors have alterations in the homologous recombination pathway by BRCA1/BRCA2 germline mutation, somatic mutation, epigenetic silencing, or other putative homologous recombination defects, patients who have tumors with epigenetically silenced BRCA1 have significantly worse outcomes than patients who had tumors with germline and somatic BRCA1/BRCA2 mutations.19 Like our current findings, these results strongly suggest that the methods and types of BRCA inactivation may have different prognostic implications. Although our analysis indicates that presence of a BRCA2 mutation is an important predictor of survival compared with both being BRCA-negative or having a BRCA1 mutation, it seems appropriate to consider this report hypothesis generating rather then definitive given the relatively small number of patients and events (only 3 deaths in the BRCA2-associated cohort). These conclusions certainly will need to be validated in prospective data sets. However, our findings indicate that, in the emerging era of targeted therapies for molecularly characterized subtypes of ovarian cancer, the grouping of BRCA1 and BRCA2 mutations, which cause two related but distinct cancer susceptibility syndromes, may not be appropriate, and strong consideration should be given to stratifying future studies in ovarian cancer according to BRCA1 and BRCA2 mutation status.
FUNDING SOURCES This work was supported by Project Hope for Ovarian Cancer Research and Education, the Kaleidoscope of Hope Foundation, the Genet Fund, and by NIH Grant # P01-CA52477-17.
CONFLICT OF INTEREST DISCLOSURES N.D.K. has received consulting fees and has been an expert witness for Pfizer.
REFERENCES 1. Jemal A, Siegel R, Ward E, Hao Y, Xu J, Thun MJ. Cancer statistics, 2009. CA Cancer J Clin. 2009;59:225-249. 2. Pal T, Permuth-Wey J, Betts JA, et al. BRCA1 and BRCA2 mutations account for a large proportion of ovarian carcinoma cases. Cancer. 2005;104:2807-2816. 3. Risch HA, McLaughlin JR, Cole DE, et al. Prevalence and penetrance of germline BRCA1 and BRCA2 mutations in a
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August 1, 2012