Germline BRCA2 mutation is associated with greater progression-free survival in korean women with advanced high-grade serous ovarian cancer

Purpose: In this study, the effect of a germline BRCA1/2 mutation on survival outcomes in Korean patients with advanced high-grade serous ovarian cancer was investigated. Methods: This multicenter retrospective study involved six Korean institutions that included 63 patients with International Federation of Gynecology and Obstetrics stages IIIC or IV high-grade serous ovarian cancer, diagnosed surgically between January 2010 and December 2015, and who had undergone a BRCA mutation test during their follow-up period. Median progression-free survival and 5-year overall survival were measured and compared according to BRCA1/2 mutation status using the Kaplan–Meier method. Results: Of 63 patients, 28 (44.4%) patients with germline BRCA1/2 mutations were identified. Nineteen (30.2%) patients were identified with a germline BRCA1 mutation, and nine (14.3%) patients with a germline BRCA2 mutation. The median progression-free survival of patients with wild-type BRCA, or a BRCA1 or BRCA2 mutation was 15, 17 and 37 months, respectively. Wildtype BRCA and germline BRCA2 mutation groups showed a significant difference in progression-free survival (p = 0.009); however, a significant difference was not found between wild-type BRCA and germline BRCA1 mutation groups (p = 0.262). Five-year overall survival rates of patients with wild-type BRCA, or a BRCA1 or BRCA2 mutation were 65.9%, 67.5% and 87.5%, respectively; significant differences was not found between the three groups. Conclusion: In Patients with advanced high grade serous ovarian cancer, germline BRCA2 mutation group showed a significantly longer median progression-free survival compared to wild-type BRCA group. Five-year overall survival rates were not significantly different among the three groups.

BRCA mutation; Korea; Multicenter study; Ovarian neoplasm; Survival analysis.

[1] Boyd J.: “Specific Keynote: Hereditary Ovarian Cancer: What We Know”. Gynecol. Oncol., 2003, 88, S8-S10.

[2] Zhang S., Royer R., Li S., McLaughlin J.R., Rosen B., Risch H.A., et al.: “Frequencies of BRCA1 and BRCA2 mutations among 1,342 unselected patients with invasive ovarian cancer”. Gynecol. Oncol., 2011, 121, 353-357.

[3] Lim M.C., Kang S., Seo S., Kong S., Lee B., Lee S., et al.: “BRCA1 and BRCA2 germline mutations in Korean ovarian cancer patients”. J. Cancer Res. Clin. Oncol., 2009, 135, 1593-1599.

[4] Weiderpass E., Tyczynski J. E.: “Epidemiology of Patients with Ovarian Cancer with and Without a BRCA12 Mutation”. Molecu-lar Diagnosis & Therapy, 2015, 19, 351-364.

[5] Kuchenbaecker K.B., Hopper J.L., Barnes D.R., Phillips K.A., Mooij T.M., Roos-Blom M.J. et al.: ”Risks of Breast, Ovarian, and Contralateral Breast Cancer for BRCA1 and BRCA2 Mutation Carriers”. JAMA., 2017, 317, 2402-2416.

[6] Alsop K., Fereday S., Meldrum C., deFazio A., Emmanuel C., George J., et al.: “BRCA Mutation Frequency and Patterns of Treatment Response in BRCA Mutation–Positive Women With Ovarian Cancer: A Report From the Australian Ovarian Cancer Study Group”. J. Clin. Oncol., 2012, 30, 2654-2663.

[7] Hirsh-Yechezkel G., Chetrit A., Lubin F., Friedman E., Peretz T., Gershoni R., et al.: “Population attributes affecting the prevalence of BRCA mutation carriers in epithelial ovarian cancer cases in israel”. Gynecol. Oncol., 2003, 89, 494-498.

[8] Tan D.S.P., Rothermundt C., Thomas K., Bancroft E., Eeles R., Shanley S., et al.: “BRCAness” Syndrome in Ovarian Cancer: A Case-Control Study Describing the Clinical Features and Outcome of Patients With Epithelial Ovarian Cancer Associated With-BRCA1andBRCA2Mutations”. J. Clin. Oncol., 2008, 26, 5530-5536.

[9] Meinhold-Heerlein I., Hauptmann S.: “The heterogeneity of ovarian cancer”. Arch. Gynecol. Obstet., 2014, 289, 237-239.

[10] Eisenhauer E.A., Therasse P., Bogaerts J., Schwartz L.H., Sargent D., Ford R., et al.: “New response evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1)”. Eur. J. Cancer, 2009, 45, 228-247.

[11] Wahl R.L., Jacene H., Kasamon Y. and Lodge M.A.: “From RECIST to PERCIST: Evolving Considerations for PET Response Criteria in Solid Tumors”. J. Nucl. Med., 2009, 50, 122S-150S.

[12] Wild C.P.: “International Agency for Research on Cancer”. Ency-clopedia of Toxicology, 2014, 1067-1069.

[13] Jung K.W., Won Y.J., Oh C.M., Kong H.J., Lee D.H., Lee K.H.: ”Ministry of Health and Welfare, Korea: Annual report of cancer registry programme in the Republic of Korea”. Cancer Res. Treat., 2017, 49, 292.

[14] Jelovac D. and Armstrong D.K.: “Recent progress in the diagnosis and treatment of ovarian cancer”. Ca. Cancer J. Clin., 2011, 61, 183- 203.

[15] Brose M.S.: “Cancer Risk Estimates for BRCA1 Mutation Carriers Identified in a Risk Evaluation Program”. Cancerspectrum Knowledge Environment, 2002, 94, 1365-1372.

[16] Moorman P.G., Havrilesky L.J., Gierisch J.M., Coeytaux R.R., Lowery W.J., Peragallo Urrutia R., et al.: “Oral Contraceptives and Risk of Ovarian Cancer and Breast Cancer Among High-Risk Women: A Systematic Review and Meta-Analysis”. J. Clin. Oncol., 2013, 31, 4188-4198.

[17] Domchek S.M., Friebel T.M., Singer C.F., Evans D.G., Lynch H.T., Isaacs C. et al.: ”Association of risk-reducing surgery in BRCA1 or BRCA2 mutation carriers with cancer risk and mortality”. JAMA, 2010, 304, 967.

[18] Liu J.F., Matulonis U.A.: “What Is the Place of PARP Inhibitors in Ovarian Cancer Treatment?” Curr. Oncol. Rep., 2016, 18,

[19] Ledermann J., Harter P., Gourley C., Friedlander M., Vergote I., Rustin G., et al.: “Olaparib maintenance therapy in patients with platinum-sensitive relapsed serous ovarian cancer: a preplanned retrospective analysis of outcomes by BRCA status in a randomised phase 2 trial”. the Lancet Oncology, 2014, 15, 852-861.

Oza A.M., Cibula D., Benzaquen A.O., Poole C., Mathijssen R.H.J., Sonke G.S., et al.: “Olaparib combined with chemotherapy for recurrent platinum-sensitive ovarian cancer: a randomised phase 2 trial”. the Lancet Oncology, 2015, 16, 87-97.

Ledermann J., Harter P., Gourley C., Friedlander M., Vergote I., Rustin G., et al.: “Olaparib Maintenance Therapy in Platinum-Sensitive Relapsed Ovarian Cancer”. N. Engl. J. Med., 2012, 366, 1382-1392.

[22] Zhong Q., Peng H., Zhao X., Zhang L., Hwang W.: “Effects of BRCA1- and BRCA2-Related Mutations on Ovarian and Breast Cancer Survival: A Meta-analysis”. Clin. Cancer Res., 2015, 21, 211- 220.

[23] Bolton K.L., Chenevix-Trench G., Goh C., Sadetzki S., Ramus S.J., Karlan B.Y. et al.: ”Association between BRCA1 and BRCA2 mutations and survival in women with invasive epithelial ovarian cancer”. JAMA, 2012, 307, 382.

[24] Kotsopoulos J., Rosen B., Fan I., Moody J., McLaughlin J.R., Risch H., et al.: “Ten-year survival after epithelial ovarian cancer is not associated with BRCA mutation status”. Gynecol. Oncol., 2016, 140, 42- 47.

[25] McLaughlin J.R., Rosen B., Moody J., Pal T., Fan I., Shaw P.A., et al.: “Long-Term Ovarian Cancer Survival Associated With Mutation in BRCA1 or BRCA2”. JNCI: Journal of the National Cancer Institute, 2013, 105, 141-148.

[26] Candido-dos-Reis F.J., Song H., Goode E.L., Cunningham J.M., Fridley B.L., Larson M.C. et al.: ”Germline mutation in BRCA1 or BRCA2 and ten-year survival for women diagnosed with epithelial ovarian cancer”. Clin. Cancer Res., 2015, 21, 652-657.

[27] Liu G., Yang D., Sun Y., Shmulevich I., Xue F., Sood A.K., et al.: “Differing clinical impact ofBRCA1andBRCA2mutations in serous ovarian cancer”. Pharmacogenomics, 2012, 13, 1523-1535.

[28] Yang D., Khan S., Sun Y., Hess K., Shmulevich I., Sood A.K., et al.: “Association of BRCA1 and BRCA2 Mutations With Survival, Chemotherapy Sensitivity, and Gene Mutator Phenotype in Patients With Ovarian Cancer”. Jama, 2011, 306, 1557.

[29] Fuh K.C., Shin J.Y., Kapp D.S., Brooks R.A., Ueda S., Urban R.R., et al.: “Survival differences of Asian and Caucasian epithelial ovarian cancer patients in the United States”. Gynecol. Oncol., 2015, 136, 491-497.

[30] du Bois A., Floquet A., Kim J., Rau J., del Campo J.M., Friedlander M., et al.: “Incorporation of Pazopanib in Maintenance Therapy of Ovarian Cancer”. J. Clin. Oncol., 2014, 32, 3374-3382.

[31] Aida H., Takakuwa K., Nagata H., Tsuneki I., Takano M., Tsuji S. et al.: ”Clinical features of ovarian cancer in Japanese women with germline mutations of BRCA1”. Clin. Cancer. Res., 1998, 4, 235-240.

[32] The Cancer Genome Atlas Research Network: “Integrated genomic analyses of ovarian carcinoma”. Nature, 2011, 474, 609-615.