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BRCA1 and BRCA2 Mutations in Ovarian Cancer

BRCA1 and BRCA2 Mutations in Ovarian Cancer To the Editor: Dr Yang and colleagues found significantly better progression-free survival rates in women with ovarian cancer and BRCA2 mutations compared with BRCA1 mutations or wild-type BRCA.1 In addition, they reported that BRCA2 mutations were associated with a 100% primary chemotherapy sensitivity rate compared with 82% for BRCA wild-type and 80% for BRCA1- mutated cases, suggesting an improved primary chemotherapy response in women with a BRCA2 mutation. We would like to suggest 2 alternative explanations for the observed differences in outcomes. The authors' definition of primary response to adjuvant chemotherapy included completely debulked cases (no macroscopically visible residual tumor at the end of frontline surgery), optimally debulked cases (<1 cm of residual tumor), and suboptimally debulked cases (>1 cm of residual tumor). These 3 groups have significantly different prognoses for survival and platinum sensitivity.2 Therefore, the difference in outcomes between BRCA2 -mutated cases and BRCA1 -mutated cases and BRCA wild-type cases may be due to a difference in the proportion of completely, optimally, and suboptimally debulked cases, reflecting different surgical resectability. In addition, completely and optimally debulked cases have no residual tumor large enough to objectively assess primary response to chemotherapy and therefore should not be combined with suboptimally debulked cases, which might bias any effect in the primary response to adjuvant chemotherapy. Second, stage distribution may also be an explanation for the observed differences. BRCA2 -mutated cases were classified as stage IV disease in 4% of cases compared with 17% of cases in the BRCA1 -mutated group (Table 1 in the article). Women with stage IV disease have by definition distant metastases, which usually cannot be resected during frontline surgery. Thus, the proportion of women fulfilling the authors' criteria of primary response to adjuvant chemotherapy will likely be higher in BRCA2 -mutated cases based on stage distribution alone. BRCA1 -mutated cases as a group may have worse survival, irrespective of chemotherapy sensitivity, given their higher rate of stage IV disease. Finally, it would be interesting to know whether the differences in chemotherapy response observed between BRCA1 - and BRCA2 -mutated cases persist when looking at chemotherapy response to recurrent disease. If BRCA2 -deficient tumor cells are less likely to repair cisplatin-induced DNA cross-links and thus are more sensitive to platinum-based chemotherapy, the observed difference in chemotherapy response rates between cases with BRCA2 and BRCA1 or wild-type BRCA may no longer be present because early recurrent disease can be expected to consist mostly of platinum-resistant clones. Back to top Article Information Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported. References 1. Yang D, Khan S, Sun Y, et al. Association of BRCA1 and BRCA2 mutations with survival, chemotherapy sensitivity, and gene mutator phenotype in patients with ovarian cancer. JAMA. 2011;306(14):1557-156521990299PubMedGoogle ScholarCrossref 2. du Bois A, Reuss A, Pujade-Lauraine E, Harter P, Ray-Coquard I, Pfisterer J. Role of surgical outcome as prognostic factor in advanced epithelial ovarian cancer: a combined exploratory analysis of 3 prospectively randomized phase 3 multicenter trials: by the Arbeitsgemeinschaft Gynaekologische Onkologie Studiengruppe Ovarialkarzinom (AGO-OVAR) and the Groupe d’Investigateurs Nationaux Pour les Etudes des Cancers de l’Ovaire (GINECO). Cancer. 2009;115(6):1234-124419189349PubMedGoogle ScholarCrossref http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png JAMA American Medical Association

BRCA1 and BRCA2 Mutations in Ovarian Cancer

JAMA , Volume 307 (4) – Jan 25, 2012

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Publisher
American Medical Association
Copyright
Copyright © 2012 American Medical Association. All Rights Reserved.
ISSN
0098-7484
eISSN
1538-3598
DOI
10.1001/jama.2012.8
Publisher site
See Article on Publisher Site

Abstract

To the Editor: Dr Yang and colleagues found significantly better progression-free survival rates in women with ovarian cancer and BRCA2 mutations compared with BRCA1 mutations or wild-type BRCA.1 In addition, they reported that BRCA2 mutations were associated with a 100% primary chemotherapy sensitivity rate compared with 82% for BRCA wild-type and 80% for BRCA1- mutated cases, suggesting an improved primary chemotherapy response in women with a BRCA2 mutation. We would like to suggest 2 alternative explanations for the observed differences in outcomes. The authors' definition of primary response to adjuvant chemotherapy included completely debulked cases (no macroscopically visible residual tumor at the end of frontline surgery), optimally debulked cases (<1 cm of residual tumor), and suboptimally debulked cases (>1 cm of residual tumor). These 3 groups have significantly different prognoses for survival and platinum sensitivity.2 Therefore, the difference in outcomes between BRCA2 -mutated cases and BRCA1 -mutated cases and BRCA wild-type cases may be due to a difference in the proportion of completely, optimally, and suboptimally debulked cases, reflecting different surgical resectability. In addition, completely and optimally debulked cases have no residual tumor large enough to objectively assess primary response to chemotherapy and therefore should not be combined with suboptimally debulked cases, which might bias any effect in the primary response to adjuvant chemotherapy. Second, stage distribution may also be an explanation for the observed differences. BRCA2 -mutated cases were classified as stage IV disease in 4% of cases compared with 17% of cases in the BRCA1 -mutated group (Table 1 in the article). Women with stage IV disease have by definition distant metastases, which usually cannot be resected during frontline surgery. Thus, the proportion of women fulfilling the authors' criteria of primary response to adjuvant chemotherapy will likely be higher in BRCA2 -mutated cases based on stage distribution alone. BRCA1 -mutated cases as a group may have worse survival, irrespective of chemotherapy sensitivity, given their higher rate of stage IV disease. Finally, it would be interesting to know whether the differences in chemotherapy response observed between BRCA1 - and BRCA2 -mutated cases persist when looking at chemotherapy response to recurrent disease. If BRCA2 -deficient tumor cells are less likely to repair cisplatin-induced DNA cross-links and thus are more sensitive to platinum-based chemotherapy, the observed difference in chemotherapy response rates between cases with BRCA2 and BRCA1 or wild-type BRCA may no longer be present because early recurrent disease can be expected to consist mostly of platinum-resistant clones. Back to top Article Information Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported. References 1. Yang D, Khan S, Sun Y, et al. Association of BRCA1 and BRCA2 mutations with survival, chemotherapy sensitivity, and gene mutator phenotype in patients with ovarian cancer. JAMA. 2011;306(14):1557-156521990299PubMedGoogle ScholarCrossref 2. du Bois A, Reuss A, Pujade-Lauraine E, Harter P, Ray-Coquard I, Pfisterer J. Role of surgical outcome as prognostic factor in advanced epithelial ovarian cancer: a combined exploratory analysis of 3 prospectively randomized phase 3 multicenter trials: by the Arbeitsgemeinschaft Gynaekologische Onkologie Studiengruppe Ovarialkarzinom (AGO-OVAR) and the Groupe d’Investigateurs Nationaux Pour les Etudes des Cancers de l’Ovaire (GINECO). Cancer. 2009;115(6):1234-124419189349PubMedGoogle ScholarCrossref

Journal

JAMAAmerican Medical Association

Published: Jan 25, 2012

References