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

We investigated whether BRCA1 mRNA 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 Annexin V 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 BRCA1 mRNA (57.2 versus 18.2 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.

Dietary glycaemic index, glycaemic load and endometrial and ovarian cancer risk: a systematic review and meta-analysis.

Long-term consumption of a high glycaemic index (GI) or glycaemic load (GL) diet may lead to chronic hyperinsulinaemia, which is a potential risk factor for cancer. To date, many studies have examined the association between GI, GL and cancer risk, although results have been inconsistent, therefore our objective was to conduct a systematic review of the literature. Medline and Embase were systematically searched using terms for GI, GL and cancer to identify studies published before December 2007. Random effects meta-analyses were performed for endometrial cancer, combining maximally adjusted results that compared risk for those in the highest versus the lowest category of intake. Separate analysis examined risk by body mass index categories. Five studies examining GI and/or GL intake and endometrial cancer risk were identified. Pooled effect estimates for endometrial cancer showed an increased risk for high GL consumers (RR 1.20; 95% CI: 1.06-1.37), further elevated in obese women (RR 1.54; 95% CI: 1.18-2.03). No significant associations were observed for GI. Only two studies examined ovarian cancer and therefore no meta-analysis was performed, but results indicate positive associations for GL also. A high GL, but not a high GI, diet is positively associated with the risk of endometrial cancer, particularly among obese women. © 2008 Cancer Research UK All rights reserved.

BRCA1 and implications for response to chemotherapy in ovarian cancer

Objectives: Treatment of epithelial ovarian cancer (EOC) remains a challenge, despite advances in surgery and chemotherapy. Hereditary ovarian cancer is primarily due to germline mutations in the BRCA1 tumour suppressor gene. In addition, sporadic EOC tumours display signi?cant of loss of BRCA1 function due to epigenetic inactivation of the BRCA1 gene. This article reviews the preclinical and clinical evidence to support a role for BRCA1 as a potential predictive biomarker of response to both platinum and taxane based chemotherapy in EOC.

Methods: We conducted a Medline and Pubmed search for reports between 1990 and 2008 using the search terms: BRCA1 and hereditary ovarian cancer, BRCA1 and sporadic ovarian cancer, ovarian cancer and chemotherapy, ovarian cancer and taxanes, ovarian cancer and platinums, ovarian cancer and clinical response, BRCA1 and DNA damage, BRCA1 and DNA repair, BRCA1 and mitotic checkpoint. If reports identi?ed by these criteria referred to other papers not in the initial search, then these were also reviewed if relevant to BRCA1 and ovarian cancer.

Results: The BRCA1 pathway plays a signi?cant role in the development of both hereditary and sporadic EOC. Evidence suggests that BRCA1 is a potential biomarker of response to platinum chemotherapy in EOC with BRCA1 de?ciency predicting for enhanced response. In contrast, initial evidence suggests that loss of BRCA1 function results in reduced response to antimicrotubule-based chemotherapy. The ability of BRCA1 to differentially modulate response to these agents involves loss of BRCA1 mediated DNA repair and mitotic checkpoint control, respectively.

Conclusions: Standard ?rst line treatment of EOC consists of a combination of platinum and taxane chemotherapy, however clinically useful biomarkers for predicting response to these agents have yet to be established. BRCA1 may prove useful as a biomarker in EOC for assigning chemotherapy treatments based on the presence or absence of BRCA1 function.