BRCA1 mRNA Expression Levels Predict for Overall Survival in Ovarian Cancer after Chemotherapy

Abstract

Purpose:We investigated whether BRCA1mRNA expression levels may represent a biomarker of survival in sporadic epithelial ovarian cancer following chemotherapy treatment. Experimental Design: The effect of loss of BRCA1 expression on chemotherapy response in ovarian cancer was measured in vitro using dose inhibition assays and AnnexinV flow cytometry. Univariate and multivariate analyses were done to evaluate the relationship between BRCA1 mRNA expression levels and survival after chemotherapy treatment in 70 fresh frozen ovarian tumors. Results: We show that inhibition of endogenous BRCA1 expression in ovarian cancer cell lines results in increased sensitivity to platinum therapy and decreased sensitivity to antimicrotubule agents. In addition, we show that patients with low/intermediate levels of BRCA1 mRNA have a significantly improved overall survival following treatment with platinum-based chemotherapy in comparison with patients with high levels of BRCA1mRNA (57.2 versus18.2 months; P = 0.0017; hazard ratio, 2.9). Furthermore, overall median survival for higher-BRCA1-expressing patients was found to increase following taxane-containing chemotherapy (23.0 versus 18.2 months; P = 0.12; hazard ratio, 0.53). Conclusions: We provide evidence to support a role for BRCA1 mRNA expression as a predictive marker of survival in sporadic epithelial ovarian cancer.The BRCA1 tumor suppressor gene is associated with susceptibility to both hereditary breast and ovarian cancer (1,2). Approximately 5% to 15% of ovarian cancers are inherited and BRCA1 germ-line mutations account for 90% of these cases conferring a cumulative lifetime risk of 54% compared with 1.8% within the general population (3, 4). Although somatic mutations of BRCA1 are uncommon in sporadic ovarian tumors (5), down-regulation of BRCA1 has been reported in >72% of high-grade sporadic ovarian cancers, suggesting that BRCA1 may also play a major role in the development of sporadic epithelial ovarian cancer (6, 7). Epigenetic inactivation of BRCA1 is at least partially due to hypermethylation of the BRCA1 promoter, which has been observed in up to 15% of cases (8,9).Several preclinical breast cancer studies have indicated that BRCA1 is an important determinant of response to both DNAdamaging and taxane-based chemotherapy. Evidence that BRCA1 deficiency, whether through inherited mutation or epigenetic down-regulation, confers marked sensitivity to DNAdamaging agents is derived from numerous in vitro studies (10 -15). Furthermore, several retrospective breast cancer clinical studies are in agreement with these preclinical findings. It has been shown that BRCA1 mutation carriers gain a significant survival advantage from DNA damage -based chemotherapy compared with non -mutation carriers (16,17). In addition, reduced BRCA1 protein expression in sporadic epithelial ovarian cancer was found to correlate with improved survival (18). Finally, a retrospective analysis of BRCA1 mRNA levels in a cohort of sporadic lung tumors showed that low-BRCA1-expressing ...

The DNA repair proteins BRCA1 and ERCC1 as predictive markers in sporadic ovarian cancer

“…Although Harkin's group has shown that reduced BRCA1 expression confers increased resistance to taxanes in vitro, there was a non-significant trend in their retrospective patient analysis to suggest that patients with high tumor levels of BRCA1 may gain a survival advantage with taxane-based chemotherapy. 2 In this patient cohort, Cox proportional modeling revealed a significant correlation of low ERCC1 expression with a better OS, implying that ERCC1 may also be a relevant predictive marker in OC. Our study supports preclinical data demonstrating that inhibition of the ERCC1 protein by antisense RNA expression in A2780 and the highly resistant OC cell line OVCAR10, enhanced platinum sensitivity in vitro.…”

“…9 A recent study of 70 patients treated with platinum-based therapy concluded that low to intermediate levels of BRCA1 mRNA were associated with improved survival compared to those with high levels. 2 However, in this study, there were heterogeneous BRCA1 levels in the high BRCA1 group and a significant number of patients were treated with an outdated chemotherapy regimen, platinum and cyclophosphamide, which may not be reflective of patients receiving current chemotherapy. Although BRCA1 deficiency is generally associated with improved prognosis after platinum-based treatment, not all reports have validated this finding, 12,13 indicating that further studies are needed.…”

“…10,11 Recent clinical data suggests that tumor expression of BRCA1 has predictive value in patients without a BRCA1 mutation. 2,9 A large correlative study on BRCA1 protein expression in 230 ovarian tumors with survival data on 152 patients, revealed that patients with minimal BRCA1 expression had a longer overall survival (OS). 9 A recent study of 70 patients treated with platinum-based therapy concluded that low to intermediate levels of BRCA1 mRNA were associated with improved survival compared to those with high levels.…”

High mesothelin correlates with chemoresistance and poor survival in epithelial ovarian carcinoma

“…However, the treatment can still be viewed largely as a 'shot in the dark' and the tools available to help predict who will respond optimally to which treatment are still relatively crude. Some molecules, such as BRCA1 (Quinn et al, 2007), soluble Fas levels (Chaudhry et al, 2008), Death Receptor 4 and TNF receptor 2 (TNFR2) (Dong et al, 2008), EF24 (Selvendiran et al, 2007), and trophinin (Baba et al, 2007), have been shown to correlate with cisplatin resistance in human ovarian cancer. The molecular markers involved in the activity of chemotherapeutic agents can shed light on the successes and failures of treatment in ovarian cancer patients and can also provide a basis for individualised therapy.…”

Carboplatin and taxol resistance develops more rapidly in functional BRCA1 compared to dysfunctional BRCA1 ovarian cancer cells

“…It has been shown that hypermethylation of the BRCA1 promoter region causes increased sensitivity to platinum drugs (Teodoridis et al 2005). Also in two ovarian cancer cell lines decreasing BRCA1 mRNA using inhibition assays correlated to increased sensitivity to platinums (Quinn et al 2007). They also show that patients with low/intermediate levels of BRCA1 mRNA have a significantly improved overall survival following platinum-based chemotherapy compared to patients with high levels of BRCA1 mRNA.…”