Epithelial ovarian cancer (EOC) is the leading cause of death from gynecological malignancies in the Western world.1-3 The strongest known risk factors are mutations in either the BRCA1 or BRCA2 gene, which account for approximately 10% of EOC cases.3-5
BRCA1 and BRCA2 are tumor suppressor genes involved in the regulation of cellular proliferation, chromosomal stability, and DNA repair by homologous recombination (HR).5 Cells that cannot repair DNA double-strand breaks due to deficiencies in the HR pathway are more susceptible to malignant transformation.5 Homologous recombination–deficient cells also cannot repair DNA damage induced by platinum adducts; therefore, they are particularly platinum-sensitive.6
BRCA mutation carriers represent a unique group of patients who are commonly diagnosed at a younger age, have improved sensitivity to platinum-based chemotherapy, and have an overall improved prognosis.4,6
Variation in the worldwide prevalence of BRCA1 and BRCA2 mutations is well recognized.7-9 In the Ashkenazi Jewish (AJ) population, the BRCA1/2 mutation spectrum is represented mainly by 185delAG and 5382insC in BRCA1 and 6174delT in BRCA2.10 Other populations display a large variety of BRCA mutations, so that ethnicity-specific prevalences of BRCA1/2 mutations are less clearly defined.
We previously described BRCA mutation type variability in a retrospective cohort comprising 190 stage IV BRCA-tested patients with EOC from New York City, Israel, and Italy diagnosed between 1995 and 2009.11 The present paper is an update of that study; the analysis was extended to include 585 BRCA-tested patients with EOC from the same medical centers diagnosed between 1995 and 2014. The study objectives were to describe BRCA mutation type variability in different ethnic populations, and to compare progression-free survival (PFS) and overall survival (OS) among patients with nonhereditary EOC, BRCA mutation carriers, and subtypes of BRCA mutations.
We reviewed medical records of 1200 patients diagnosed with EOC between 1995 and 2014 at New York University (NYU) Cancer Institute, Tel Aviv Sourasky Medical Center (Israel), and Padova Clinical Cancer Centers (Italy). Patients with EOC or histologically confirmed extra-uterine Müllerian carcinoma (ovarian, tubal, and primary peritoneal) who were tested for BRCA mutation status were included in the analysis. Clinical data retrieved included institution, patient age at diagnosis, ethnicity, comorbidities, stage of disease, tumor histology, tumor grade, patient and family cancer history, BRCA mutation status, BRCA mutation type, prior surgical management, first-line chemotherapy, chemotherapy for recurrent disease, date of first relapse, platinum sensitivity, PFS, OS, and status at the most recent follow-up.
The characteristics of BRCA carriers were compared with those of the noncarriers (NCs). Progression-free survival and OS were evaluated by Kaplan-Meyer and multivariate Cox proportional hazards regression models with adjustments for age at diagnosis, platinum sensitivity, stage at diagnosis, and histology to exclude dependency. All statistical analyses were performed using SAS version 9.2 statistical software.
BRCA mutations were assessed in 585 patients (median age, 58 years; range, 33-86 years) of 1200 EOC patient records reviewed. Of the patients assessed for mutations, 132 (22.5%) tested positive, 98 (16.8%) were carriers of the BRCA1 mutation, and 34 (5.8%) were carriers of BRCA2. The clinical characteristics of the BRCA carriers and the NCs are shown in Table 1. The BRCA carrier population tended to be approximately 10 years younger than the NC population, as previously reported.4
More than half of the BRCA carriers (78/132, 59.1%) were of AJ descent. Other BRCA carriers were non-AJ, non-Jewish Caucasian, African American, Hispanic, and unknown.
Among the BRCA1/2 carriers, there were 29 mutation types (Table 2). The widest variation was among non-Jew- ish Caucasians. The most common BRCA1 mutations in AJ carriers were 185delAG (49 patients) and 5382insC (8 patients); the most common BRCA2 mutation was 6174del (16 patients). Thirteen non-AJ patients had 185delAG mutations, and 3 of them had 6174delT mutations.
Assessment of Prognosis
As shown in Figure 1, median OS was significantly longer in BRCA carriers compared with NCs (82.5 vs 50.7 months; P =.0012).
Analysis of OS by mutation type showed a median OS of 74.8 months for 185delAG mutation carriers, 126.6 months for 5382insC carriers, and 56.2 months for all other mutation subtypes (combined). Median OS was statistically significantly longer in 185delAG, 617delT, and 5382insC mutation carriers compared with NCs (P = .02, P = .03, and P = .02, respectively; Figure 2).
Analysis of PFS by mutation type showed a median PFS of 16.7 months for 185delAG, 9.1 months for 6174delT, 16.7 months for 5382insC, and 10.5 months for all other mutation subtypes compared with a median PFS of 9.6 months in NCs (Figure 3).
- Rathkopf D, Scher HI. Androgen re- ceptor antagonists in 1. Saito T, Katabuchi H. Annual Report of the Committee on Gynecologic Oncology, Japan Society of Obstetrics and Gynecology: Patient Annual Report for 2013 and Treatment Annual Report for 2008. J Obstet Gynaecol Res. 2016;42(9):1069-1079. doi: 10.1111/jog.13043.
- Siegel R, Naishadham D, Jemal A. Cancer statistics, 2013. CA Cancer J Clin. 2013;63(1):11-30. doi: 10.3322/ caac.21166.
- Vencken PM, Kriege M, Hoogwerf D, et al. Chemosensitivity and outcome of BRCA1- and BRCA2-associated ovarian cancer patients after first-line chemotherapy compared with sporad- ic ovarian cancer patients. Ann Oncol. 2011;22(6):1346-1352. doi: 10.1093/an- nonc/mdq628.
- Biglia N, Sgandurra P, Bounous VE, et al. Ovarian cancer in BRCA1 and BRCA2 gene mutation carriers: analysis of prognostic factors and survival [pub- lished online May 3, 2016]. Ecancermedicalscience. 2016;10:639. doi: 10.3332/ ecancer.2016.639
- Tutt A, Ashworth A. The relation- ship between the roles of BRCA genes in DNA repair and cancer predisposition. Trends Mol Med. 2002;8(12):571-576.
- Tan DS, Rothermundt C, Thomas K, 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 BRCA1 and BRCA2 mutations. J Clin Oncol. 2008;26(34):55305536. doi: 10.1200/JCO.2008.16.1703.
- Szabo CI, King MC. Population genetics of BRCA1 and BRCA2. Am J Hum Genet. 1997;60(5):1013-1020.
- Olopade OI, Fackenthal JD, Dunston G, Tainsky MA, Collins F, Whitfield-Broome C. Breast Cancer genetics in African Americans. Cancer. 2003;97(1 suppl):236245.
- John EM, Miron A, Gong G, et al. Prevalence of pathogenic BRCA1 mutation carriers in 5 US racial/ethnic roups. JAMA. 2007;298(24):2869-2876.
- Dillenburg CV, Bandeira IC, Tubino TV, et al. Prevalence of 185delAG and 5382insC mutations in BRCA1, and 6174delT in BRCA2 in women of Ashkenazi Jewish origin in southern Brazil. Genet Mol Biol. 2012,35(3):599-602. doi: 10.1590/S1415-47572012000400009.
- Safra T, Lai WC, Borgato L, et al. BRCA mutations and outcome in epithelial ovarian cancer (EOC): experience in ethnically diverse groups. Ann Oncol. 2013;24(8):viii63-viii68. doi: 10.1093/annonc/mdt315.
- Yang D, Khan S, Sun Y, et al. Association of BRCA1 and BRCA2 mutations with survival, chemotherapy sensitivy, and gene mutator phenotype in patients with ovarian cancer. JAMA. 2011;306(14):1557-1565. doi:10.1001/jama.2011.1456.
- Vallee MP, Francy TC, Judkins MK, et al. Classification of missense substitutions in the BRCA genes: a database dedicated to Ex-UVs. Hum Mutat. 2012;33(1):22-28. doi: 10.1002/humu.21629.
- Spurdle AB, Healey S, Devereau A, et al. ENIGMA - Evidence-based Network for the Interpretation of Germline Mutant Alleles: an international initiative to evaluate risk and clinical significance associated with sequence variation in BRCA1 and BRCA2 genes. Hum Mutat. 2012;33(1):2-7. doi: 10.1002/humu.21628.
- Akbari MR, Zhang S, Fan I, et al. Clinical impact of unclassified variants of the BRCA1 and BRCA2 genes. J Med Genet. 2011;48(11):783-786. doi: 10.1136/jmedgenet-2011-100305.