Impacto pronóstico de las mutaciones de BRCA1 y BRCA2 en el cáncer de ovario hereditario

Abstract

Introduction: Genetic mutations are estimated to cause 10-15% of epithelial ovarian cancers. As many as 80% of cases of epithelial ovarian cancer are associated with mutations in the genes BRCA1 and BRCA2. The remaining 20% are caused by mutations in mismatch repair (MMR) genes, other genes involved in homologous recombination and TP53. The clinical characteristics of ovarian cancer are related to the underlying genetic mutation. Prognosis of ovarian cancers associated to BRCA 1 or BRCA2 mutations is supposed to be more favorable, although data are not homogeneous. Objectives: Assessing overall survival (OS), progression-free survival (PFS) and platinum-free interval (PFI) in ovarian cancer patients with pathogenic mutations in BRCA1/2, as compared to patients with sporadic cancer. Materials and Methods: A retrospective cohort study was performed. The sample was composed of all ovarian cancer patients with mutations in BRCA1/BRCA2 examined in the Genetic Counseling Units of Murcia, Spain, between January 2008 and January 2016. The evolution of this cohort was compared with that of patients with ovarian cancer not meeting the indications for a genetic test. Based on genetic test results, patients were classified as "carriers of BRCA mutations", "carriers of MMR mutations", and "patients with uninformative test results". Then, we investigated the potential relationship between these mutations and prognosis. Results: Carriers of germline mutations in BRCA1/2 had a more favorable prognosis in terms of OS and PFS, as compared to patients with sporadic cancer. Multivariate analysis revealed that mutations in BRCA1/2 and platinum sensitivity were the only factors with significant effects on both OS and PFS. The alterations in homologous recombination mechanisms exhibited by BRCA1/BRCA2-mutated cells may explain BRCA1/2-mutation carriers' higher sensitivity to platinum-based chemotherapy, which results in higher survival rates. The prognosis of patients who met criteria of hereditary ovarian cancer syndrome with uninformative test results was similar to that of BRCA-mutation carriers in terms of OS and PFS. In addition, PFI was significantly higher in these patients, as compared to that of patients with sporadic cancer. This suggests that these patients might carry somatic or germline mutations in genes other than BRCA1/2 involved in the homologous recombination pathway. Conclusions: Survival was significantly higher in ovarian cancer patients with BRCA1/2 mutations, compared to patients with sporadic ovarian cancer. Diagnosis of ovarian cancer based on genetic criteria may have prognostic value and could guide the choice of the best treatment for each patient.