Abstract
Objective: Despite several nationwide cohort studies of germline BRCA1/2 mutations and several small cohort studies of somatic BRCA1/2 mutations in Chinese epithelial ovarian cancer (EOC) patients, little is known about the impact of these findings on survival outcomes in this population. In this study of 172 retrospectively recruited Chinese EOC patients, germline and somatic BRCA1/2 mutations and their value for predicting survival outcomes were evaluated.Methods: Unselected patients who visited the study center from January 1, 2011, to January 1, 2015, were recruited and asked to provide peripheral blood samples for this study if they were pathologically confirmed to have primary EOC. All patients received staging surgeries or debulking surgeries involving systemic platinum-based chemotherapy, and the patients were then followed up to December 1, 2017. DNA was extracted from formalin-fixed, paraffin-embedded (FFPE) sections and peripheral blood and sequenced for somatic and germline testing, respectively. The demographic and clinicopathological characteristics of the patients were collected to analyze the distribution of BRCA mutations in subgroups. Survival outcomes were compared among various BRCA mutation statuses using univariate and multivariate models.Results: In 58 (33.7%) patients, 63 variants were identified, including variants of unknown significance (VUS) in 18 patients (10.5%) and pathogenic or likely pathogenic variants in a partially overlapping set of 41 patients (23.8%). Germline BRCA mutations, somatic BRCA mutations, BRCA1 mutations in general, and BRCA2 mutations in general were found in 35 (20.3%), 7 (4.1%), 28 (16.3%), and 13 (7.6%) patients, respectively. Five recurrent mutations were identified. Personal and family cancer histories as well as hereditary breast and ovarian cancer (HBOC) criteria were associated with deleterious BRCA mutations both overall and in the germline specifically, whereas only age at diagnosis of EOC was associated with somatic BRCA mutations. In univariate and Cox regression analyses, patients with BRCA1/2 mutations in general had significant improvements in progression-free survival (PFS) and overall survival (OS).Conclusions: In Chinese EOC patients, the distributions and risk factors associated with germline and somatic BRCA1/2 mutations were similar to those previously reported in international studies. Deleterious BRCA mutations in general were associated with improved survival outcomes in this cohort.
Highlights
Ovarian cancer is the third most common gynecological malignancy and the leading cause of mortality in female cancers [1], representing 1.3% of all new cancer cases in the United States in 2018 [2]
Once the pathological examination confirmed epithelial ovarian cancer (EOC), the patients were asked to provide samples of peripheral blood for germline testing if they met the following inclusion criteria: [1] age 18 years or older; [2] pathologically confirmed EOC; [3] receipt of comprehensive staging surgery or debulking surgery and systemic platinum-based chemotherapy; [4] sufficient formalin-fixed, paraffin-embedded (FFPE) sections for somatic testing, which could be performed between any two systematic chemotherapy treatments; these tissues could be collected by core biopsy or by laparoscopy for patients prepared for neoadjuvant chemotherapy or by laparotomic sampling for patients of primary staging or cytoreductive surgeries; [5] willingness to provide signed consent in advance of the trial; and [6] provision of peripheral blood for germline testing
We found that germline and somatic BRCA1/2 mutations had prevalence rates of 20.3 and 4.1%, respectively
Summary
Ovarian cancer is the third most common gynecological malignancy and the leading cause of mortality in female cancers [1], representing 1.3% of all new cancer cases in the United States in 2018 [2]. Most cases of inherited susceptibility to EOC are primarily related to germline mutations of BRCA1 and BRCA2, which account for about 80% of hereditary ovarian cancers [17,18,19]. Information on BRCA1/2 germline mutations has predictive value for the platinum sensitivity of tumors and the survival outcomes of patients [26,27,28]. In recent reports, homologous recombination deficiency has gained in importance, in addition to the BRCA mutations, on the targeted treatment [23, 29], chemotherapy [30, 31], and prognosis [32, 33] in EOC patients
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