Abstract
ObjectiveThe role of BRCA dysfunction on the prognosis of patients with epithelial ovarian cancer (EOCs) remains controversial. This systematic review tried to assess the role of BRCA dysfunction, including BRCA1/2 germline, somatic mutations, low BRCA1 protein/mRNA expression or BRCA1 promoter methylation, as prognostic factor in EOCs.MethodsStudies were selected for analysis if they provided an independent assessment of BRCA status and prognosis in EOC. To make it possible to aggregate survival results of the published studies, their methodology was assessed using a modified quality scale.ResultsOf 35 evaluable studies, 23 identified BRCA dysfucntion status as a favourable prognostic factor. No significant differences were detected in the global score of quality assessment. The aggregated hazard ratio (HR) of overall survival (OS) of 34 evaluable studies suggested that BRCA dysfunction status had a favourable impact on OS (HR = 0.69, 95% CI 0.61–0.79), and when these studies were categorised into BRCA1/2 mutation and low protein/mRNA expression of BRCA1 subgroups, all of them demonstrated positive results (HR = 0.67, 95% CI: 0.57–0.78; HR = 0.62, 95% CI: 0.51–0.75; and HR = 0.51, 95% CI: 0.33–0.78, respectively), except for the subgroup of BRCA1 promoter methylation (HR = 1.59, 95% CI: 0.72–3.50). The meta-analysis of progression-free survival (PFS), which included 18 evaluable studies, demonstrated that BRCA dysfunction status was associated with a longer PFS in EOC (HR = 0.69, 95% CI: 0.63–0.76).ConclusionsPatients with BRCA dysfunction status tend to have a better outcome, but further prospective clinical studies comparing the different BRCA statuses in EOC is urgently needed to specifically define the most effective treatment for the separate patient groups.
Highlights
Epithelial ovarian carcinoma (EOC) is the fifth leading cause of cancer death in women [1], and the five-year relative survival rates for the late stage of EOC were less than 10% between 2004 and 2008 [2]
To reach a final decision on which articles were to be included in the meta-analysis, we examined all 39 papers in detail, which resulted in the further exclusion of 4 papers because survival information was not available for three papers [29,35,46] and one study’s [42] subjects overlapped with a subsequent study that the authors published six years later [26] (Figure 1)
In the subgroup analyses according to different BRCA statuses, BRCA1/ 2 mutations (1,686 cases and 4,941 controls) and low BRCA1 expression by IHC (500 cases and 362 controls) or RT-polymerase chain reaction (PCR) (72 cases and 49 controls) were statistically significantly better prognostic factors for survival (HR = 0.69, 95% confidence interval (CI): 0.59–0.80; hazard ratio (HR) = 0.62, 95% CI: 0.51–0.75; and HR = 0.51, 95% CI: 0.33– 0.78 in the random-effects model, respectively; and HR = 0.72, 95% CI: 0.67–0.78; HR = 0.62, 95% CI: 0.51–0.75; and HR = 0.51, 95% CI: 0.33–0.78 in the fixed-effects model, respectively)
Summary
Epithelial ovarian carcinoma (EOC) is the fifth leading cause of cancer death in women [1], and the five-year relative survival rates for the late stage of EOC were less than 10% between 2004 and 2008 [2]. The mechanism underlying the association between BRCA1/2 germline mutations and survival is not fully understood, in vitro experiments have shown that BRCA1/2 deficient cells display a deficiency in repairing double-strand DNA breaks by homologous recombination [9,10,11]. This biological mechanism may be responsible for increased chemo-sensitivity, which results in a longer progressionfree survival (PFS) and overall survival (OS) [12]. In sporadic EOCs, low BRCA1 expression detected by immunohistochemistry (IHC) or RT-PCR or BRCA1 promoter methylation had been reported as a clinically useful tool to provide important information on prognosis [15]
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