Biochemistry and Pharmacology - Research Publications
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ItemNo Preview AvailableEnhanced GAB2 Expression Is Associated with Improved Survival in High-Grade Serous Ovarian Cancer and Sensitivity to PI3K Inhibition(AMER ASSOC CANCER RESEARCH, 2015-06)Identification of genomic alterations defining ovarian carcinoma subtypes may aid the stratification of patients to receive targeted therapies. We characterized high-grade serous ovarian carcinoma (HGSC) for the association of amplified and overexpressed genes with clinical outcome using gene expression data from 499 HGSC patients in the Ovarian Tumor Tissue Analysis cohort for 11 copy number amplified genes: ATP13A4, BMP8B, CACNA1C, CCNE1, DYRK1B, GAB2, PAK4, RAD21, TPX2, ZFP36, and URI. The Australian Ovarian Cancer Study and The Cancer Genome Atlas datasets were also used to assess the correlation between gene expression, patient survival, and tumor classification. In a multivariate analysis, high GAB2 expression was associated with improved overall and progression-free survival (P = 0.03 and 0.02), whereas high BMP8B and ATP13A4 were associated with improved progression-free survival (P = 0.004 and P = 0.02). GAB2 overexpression and copy number gain were enriched in the AOCS C4 subgroup. High GAB2 expression correlated with enhanced sensitivity in vitro to the dual PI3K/mTOR inhibitor PF-04691502 and could be used as a genomic marker for identifying patients who will respond to treatments inhibiting PI3K signaling.
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ItemNo Preview AvailableGermline Mutation in BRCA1 or BRCA2 and Ten-Year Survival for Women Diagnosed with Epithelial Ovarian Cancer(AMER ASSOC CANCER RESEARCH, 2015-02-01)PURPOSE: To analyze the effect of germline mutations in BRCA1 and BRCA2 on mortality in patients with ovarian cancer up to 10 years after diagnosis. EXPERIMENTAL DESIGN: We used unpublished survival time data for 2,242 patients from two case-control studies and extended survival time data for 4,314 patients from previously reported studies. All participants had been screened for deleterious germline mutations in BRCA1 and BRCA2. Survival time was analyzed for the combined data using Cox proportional hazard models with BRCA1 and BRCA2 as time-varying covariates. Competing risks were analyzed using Fine and Gray model. RESULTS: The combined 10-year overall survival rate was 30% [95% confidence interval (CI), 28%-31%] for non-carriers, 25% (95% CI, 22%-28%) for BRCA1 carriers, and 35% (95% CI, 30%-41%) for BRCA2 carriers. The HR for BRCA1 was 0.53 at time zero and increased over time becoming greater than one at 4.8 years. For BRCA2, the HR was 0.42 at time zero and increased over time (predicted to become greater than 1 at 10.5 years). The results were similar when restricted to 3,202 patients with high-grade serous tumors and to ovarian cancer-specific mortality. CONCLUSIONS: BRCA1/2 mutations are associated with better short-term survival, but this advantage decreases over time and in BRCA1 carriers is eventually reversed. This may have important implications for therapy of both primary and relapsed disease and for analysis of long-term survival in clinical trials of new agents, particularly those that are effective in BRCA1/2 mutation carriers.
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ItemMolecular characterization of mucinous ovarian tumours supports a stratified treatment approach with HER2 targeting in 19% of carcinomas(WILEY, 2013-01)Mucinous ovarian carcinomas (MCs) typically do not respond to current conventional therapy. We have previously demonstrated amplification of HER2 in 6 of 33 (18.2%) mucinous ovarian carcinomas (MCs) and presented anecdotal evidence of response with HER2-targeted treatment in a small series of women with recurrent HER2-amplified (HER2+) MC. Here, we explore HER2 amplification and KRAS mutation status in an independent cohort of 189 MCs and 199 mucinous borderline ovarian tumours (MBOTs) and their association to clinicopathological features. HER2 status was assessed by immunohistochemistry (IHC), FISH, and CISH, and interpreted per ASCO/CAP guidelines, with intratumoural heterogeneity assessment on full sections, where available. KRAS mutation testing was performed with Sanger sequencing. Stage and grade were associated with recurrence on both univariate and multivariate analysis (p < 0.001). Assessment of HER2 status revealed overexpression/amplification of HER2 in 29/154 (18.8%) MCs and 11/176 (6.2%) MBOTs. There was excellent agreement between IHC, FISH, and CISH assessment of HER2 status (perfect concordance of HER2 0 or 1+ IHC with non-amplified status, and 3+ IHC with amplified status). KRAS mutations were seen in 31/71 (43.6%) MCs and 26/33 (78.8%) MBOTs, and were near mutually exclusive of HER2 amplification. In the 189 MC cases, a total of 54 recurrences and 59 deaths (53 of progressive disease) were observed. Within MCs, either HER2 amplification/overexpression or KRAS mutation was associated with decreased likelihood of disease recurrence (p = 0.019) or death (p = 0.0041) when compared to cases with neither feature. Intratumoural heterogeneity was noted in 26% of HER2-overexpressing cases. These data support the stratification of MCs for the testing of new treatments, with HER2-targeted therapy as a viable option for HER2+ advanced or recurrent disease. Further research is required to delineate the molecular and clinical features of the ∼34% of MC cases with neither HER2 amplification nor KRAS mutations.