Prognostic impact of BRCA1 pathogenic and BRCA1/BRCA2 unclassified variant mutations in patients with ovarian carcinoma

Abstract

BACKGROUNDThe clinical relevance of BRCA1/2 alterations in ovarian carcinoma patients is debatable. Our aim was to determine factors influencing the risk of recurrence and death in ovarian carcinoma patients with BRCA pathogenic and unclassified variant mutations.METHODSA consecutive series of 205 women with primary ovarian carcinoma were screened for mutations in BRCA1 and BRCA2 genes using a conformational sensitive gel electrophoresis and direct sequencing. Data regarding medical and familial history were collected using questionnaires. Clinical and pathologic data were extracted from medical records.RESULTSUnclassified variant mutations in BRCA1 or BRCA2 genes were found in 16 (8%) patients, and BRCA1 pathogenic mutations were found in 18 (9%) patients. No pathogenic mutation was found in BRCA2 gene. Multivariate analysis showed that BRCA1 pathogenic mutation was an independent predictor of reduced risk of relapse and death (Hazard ratios [HR] 0.52 [confidence interval {CI} 0.28–0.98] and 0.38 [CI 0.10–0.96], respectively). Unclassified variant mutation did not affect recurrence and survival (HR 0.84 [CI 0.43–1.66] and 0.94 [CI 0.48–1.82], respectively). Other factors associated with reduced risk of relapse and death were complete pathologic remission at second‐look laparotomy and family history of breast and ovarian carcinoma, respectively. Recurrence and death outcomes among unclassified variant mutation carriers did not differ significantly from those in sporadic cases.CONCLUSIONSPatients with BRCA1 pathogenic mutation seem to have reduced risk of recurrence and death. These results should be interpreted with caution as they may be influenced by more intensive treatment, better response to cisplatin, and younger age of mutation carriers. Clinical relevance of BRCA1/2 unclassified variant mutations warrants further studies. Cancer 2005. © 2005 American Cancer Society.

Small Interfering RNA Screens Reveal Enhanced Cisplatin Cytotoxicity in Tumor Cells Having both BRCA Network and TP53 Disruptions

“…Our results also suggest that cells with defects in the BRCA pathway may be more responsive to treatment with cisplatin than BRCA1/ 2-proficient cells. Indeed, clinical results support that patients with defects in BRCA1 or BRCA2 have better responses to platinum-based therapies than patients with BRCA1/2 intact (10,39,45). The ability to perform genome-scale siRNA screens in cells of different genetic backgrounds in the presence of different combinations of approved chemotherapeutic drugs may provide a rational way to guide clinical trials.…”

Comparison of effectiveness of treatment of patients with sporadic and germline BRCA1-related ovarian cancer

“…No differences in response to chemotherapy was also observed in a large Norwegian follow-up study [8,11,15].…”

“…The literature lacks reports on patients of East Central Europe origin, different in genetic regard as mentioned before. The only report on the outcome of the treatment in Polish BRCA1-OC patients was presented in 2005 by Majdak et al; however, it included only 18 cases [8]. Results presented in the report should be analysed, taking into account limitations of the study material.…”

“…Additionally, literature reports do not distinguish the advanced-stage (FIGO III/IV) patient group. Moreover, except for one paper on 18 BRCA1 mutation carriers, there are no reports on Polish women [8]. It seems that genetic differences might induce a different clinical course of OC in the Central-European population.…”

Clinical characteristics and outcomes of BRCA-associated ovarian cancer (OC): Genotype and survival.

“…Although some studies have observed no significant difference (5,6), several studies have now demonstrated that BRCA1 or BRCA2 germline mutation confers an improved prognosis in terms of overall survival compared to sporadic disease (7)(8)(9)(10)(11)(12)(13)(14)(15). As both BRCA1 and BRCA2 are known to play roles in the repair of DNA by homologous recombination, one possibility is that the improved survival observed in BRCA-deficient EOC is secondary to increased sensitivity to platinum-based therapy, since homologous recombination is critical to the repair of DNA-damage caused by the cross-linking effects of platinum.…”