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Journal of Clinical Oncology, Vol 26, No 1 (January 1), 2008: pp. 9-10 © 2008 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.14.0244
Is It Time to Stratify for BRCA Mutation Status in Therapeutic Trials in Ovarian Cancer?Clinical Genetics Service, Department of Medicine; and Gynecology Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY Since the first report by Rubin et al,1 in 1996 suggesting that BRCA1-associated ovarian cancer had an improved prognosis compared with sporadic ovarian cancer, there have been close to a dozen studies that have looked at potential differences in outcomes between BRCA-associated and sporadic ovarian cancer. Although the majority of these studies have suggested that BRCA-associated ovarian cancers are associated with improved outcome, these reports have been limited by a number of issues including inadequate adjustment for known factors influencing prognosis (such as stage, age of diagnosis, histology, and extent of surgical debulking), retrospective designs, short follow-up, and nonuniform therapy in cases and controls. Arguably, the two most robust studies to date are the series from Boyd et al reported in 20002 and the series from Ben David et al reported in the Journal of Clinical Oncology in 2002.3 In the Boyd series, paraffin tissue from a retrospective cohort of 189 consecutive Jewish ovarian cancer patients ascertained during a 12-year period from 1986 through 1998 were genotyped for the three Ashkenazi founder mutations. Outcomes in individuals with BRCA-associated ovarian cancer were compared with individuals who were BRCA wild type. In this series, BRCA mutation status in advanced stage (III and IV) disease was associated with both improved disease-free and overall survival compared with sporadic ovarian cancer. The difference in overall survival remained significant after adjusting for age at diagnosis as well as optimal versus suboptimal debulking. Limitations of this study included the nonsignificant, but potentially relevant, differences in the proportion of patients in each of the study groups receiving primary chemotherapy with cisplatin and paclitaxel as well as differences in the proportion of patients with serous versus nonserous cancers. In 2002, Ben David et al3 examined this issue as part of the National Israeli Study of Ovarian Cancer. In this study, all ovarian cancer patients of Jewish heritage diagnosed in Israel from March 1994 through July 1999 were approached shortly after diagnosis and offered participation in a population-based case-control study designed to elucidate epidemiologic risk factors for the development of ovarian cancer. Beginning in January 1996, study participants were also asked to provide DNA for analysis of the three Ashkenazi founder mutations. This study ultimately enrolled 84.8% of all Israeli ovarian patients diagnosed during this time period with more than 70% of participants agreeing to genotyping.4 In this cohort, Ben David et al were able to demonstrate that the presence of a BRCA mutation was associated with an increase in both median and 3-year survival. However, median follow-up in participants was only 2.5 years. Given this short follow-up, it was possible that these results reflected early sensitivity of BRCA-associated ovarian cancer to primary therapy rather than an improved long-term natural history. To address this possibility, in the current issue of the Journal, Chetrit et al5 report long-term follow-up on the cohort initially reported on by Ben David et al. In this series, now with a median follow-up of 6.2 years, the authors provide unequivocal evidence that BRCA-associated ovarian cancer is associated with improved survival compared with sporadic ovarian cancer (median survival, 55.7 v 37.9 months; P = .002). This difference persisted when the cohort was limited to patients with advanced-stage disease and adjusted for age of diagnosis and tumor morphology. Although treatment information was not collected as part of this study, it is likely that only a portion of the differential survival can be attributed to different primary chemotherapy regimens, because the majority of patients in this series were ascertained after 1995 when platinum and paclitaxel became standard primary chemotherapy in Israel. The major limitation of this report is the lack of information regarding the extent of surgical cytoreduction. Although this information would likely be relevant in helping to elucidate biologic differences between BRCA-associated and sporadic ovarian cancer, it is not clear that its absence detracts from the study's primary conclusion, given that primary surgical cytoreductive intent was almost certainly the same in both patients with BRCA-associated and sporadic ovarian cancer. Given that BRCA-associated ovarian cancer appears to be associated with an unequivocal improvement in survival, how do we use this information to (a) favorably influence treatment of inherited ovarian cancer and (b) interpret results of past and ongoing therapeutic trials? Although some of the difference in prognosis associated with BRCA-associated ovarian cancer is likely a result of nonmodifiable risk factors such as age at diagnosis, performance status, and ability to optimally cytoreduce disease, almost certainly some of the advantage is conferred by differing responses to chemotherapy. Data in support of this hypothesis first appeared in the late 1990s, when BRCA-deficient cells were found to be particularly sensitive to platinum agents.6,7 Unfortunately, there have been limited opportunities to use this information because nearly all patients with epithelial ovarian cancer receive platinum-based chemotherapy until they become resistant. Recently, a novel approach was suggested to exploit defects in BRCA-null tumor cells' ability to repair double stranded DNA breaks by inhibiting the Poly (ADP-Ribose) polymerase enzyme (PARP) 1 enzyme8,9 Promising phase I data in support of this approach were reported at the 2007 Annual Meeting of the American Society of Clinical Oncology.10 Although the ultimate utility of this particular class of agents in treatment of BRCA-associated cancers awaits the results of ongoing and future prospective trials, approaches such as these suggest the possibility of targeted therapies for the 8% to 13% of ovarian cancers that develop as a result of germline mutations in either BRCA1 or BRCA2.11-13 Additionally, because 9% to 15% of sporadic ovarian cancers have silencing of the BRCA1 gene,14,15 these therapeutic approaches may also be of value in a substantial fraction of sporadic ovarian cancer cases. Perhaps an equally provocative question, how we should use the data from Chetrit et al to interpret results of prior and ongoing therapeutic trials in ovarian cancer? Certainly, these data suggest that findings of nonrandomized trials in which historical controls were used may be influenced by differing proportions of BRCA mutation carriers in the cohorts studied. This may also be an issue in randomized trials, given the magnitude of survival advantage suggested by Chetrit et al. If BRCA mutation carriers are not equally assigned to both treatment and control groups, a bias in favor of the group with a higher proportion of BRCA mutation carries will likely result. Given this issue, a strong argument can be made that, for women enrolled on therapeutic ovarian cancer trials, we need to know their BRCA mutation status so that participants can be stratified appropriately. The data from Chetrit et al clearly suggest that BRCA mutation status is one of the most important prognostic factors in epithelial ovarian cancer other than stage and extent of surgical debulking. Given its favorable impact on survival, women with BRCA-associated ovarian cancer likely should be offered risk-reduction for second primary cancers associated with these mutations. Perhaps, more importantly, exciting preclinical work has put us on the threshold of using BRCA mutation status to more appropriately target therapies for women with both BRCA-associated and sporadic ovarian cancer. To reach this goal, future therapeutic trials in ovarian cancer will need to obtain BRCA mutation status in a prospective manner and link it with clinical outcome so we can better identify and evaluate therapeutic opportunities in both inherited and sporadic ovarian cancer. AUTHOR'S DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest. REFERENCES
1. Rubin SC, Benjamin I, Behbakht K, et al: Clinical and pathological features of ovarian cancer in women with germ-line mutations of BRCA1. N Engl J Med 335:1413-1416, 1996 2. Boyd J, Sonoda Y, Federici MG, et al: Clinicopathologic features of BRCA-linked and sporadic ovarian cancer. JAMA 283:2260-2265, 2000 3. Ben David Y, Chetrit A, Hirsh-Yechezkel G, et al: Effect of BRCA mutations on the length of survival in epithelial ovarian tumors. J Clin Oncol 20:463-466, 2002 4. Modan B, Hartge P, Hirsh-Yechezkel G, et al: Parity, oral contraceptives, and the risk of ovarian cancer among carriers and noncarriers of a BRCA1 or BRCA2 mutation. N Engl J Med 345:235-240, 2001 5. Chetrit A, Hirsh-Yechezkel G, Ben-David Y, et al: Effect of BRCA1/2 mutations on long-term survival of invasive ovarian cancer. J Clin Oncol 26:20-25, 2008 6. Husain A, He G, Venkatraman ES, et al: BRCA1 up-regulation is associated with repair-mediated resistance to cis-diamminedichloroplatinum (II). Cancer Res 58:1120-1123, 1998 7. Yuan SS, Lee SY, Chen G, et al: BRCA2 is required for ionizing radiation-induced assembly of Rad51 complex in vivo. Cancer Res 59:3547-3551, 1999 8. Bryant HE, Schultz N, Thomas HD, et al: Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase. Nature 434:913-917, 2005[CrossRef][Medline] 9. Farmer H, McCabe N, Lord CJ, et al: Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature 434:917-921, 2005[CrossRef][Medline] 10. Yap TA, Boss DS, Fong PC, et al: First in human phase I pharmacokinetic and pharmacodynamic study of KU-0059436, a small molecule inhibitor of poly ADP-ribose polymerase (PARP) in cancer patients, including BRCA1/2 mutation carriers. J Clin Oncol Vol 25:145s, 2007 (suppl; abstr 3529) 11. Risch HA, McLaughlin JR, Cole DE, et al: Prevalence and penetrance of germline BRCA1 and BRCA2 mutations in a population series of 649 women with ovarian cancer. Am J Hum Genet 68:700-710, 2001[CrossRef][Medline] 12. Rubin SC, Blackwood MA, Bandera C, et al: BRCA1, BRCA2 and hereditary nonpolyposis colorectal cancer gene mutations in an unselected ovarian cancer population: Relationship to family history and implications for genetic testing. Am J Obstet Gynecol 178:670-677, 1998[CrossRef][Medline] 13. Pal T, Permuth-Wey J, Betts JA, et al: BRCA1 and BRCA2 mutations account for a large proportion of ovarian carcinoma cases. Cancer. 104:2807-2816, 2005[CrossRef][Medline] 14. Baldwin RL, Nemeth E, Tran H, et al: BRCA1 promoter region hypermethylation in ovarian carcinoma: A population-based study. Cancer Res 60:5329-5333, 2000 15. Geisler JP, Hatterman-Zogg MA, Rathe JA, et al: Frequency of BRCA1 dysfunction in ovarian cancer. J Natl Cancer Inst 94:61-67, 2002 Related Article
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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