Sir Peter MacCallum Department of Oncology - Research Publications

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Author: Bowtell, David × Author: Fereday, Julie × Author: Mitchell, Gillian × End date: 2016 × Start date: 2013 ×

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    Germline Mutation in BRCA1 or BRCA2 and Ten-Year Survival for Women Diagnosed with Epithelial Ovarian Cancer
    Candido-dos-Reis, FJ ; Song, H ; Goode, EL ; Cunningham, JM ; Fridley, BL ; Larson, MC ; Alsop, K ; Dicks, E ; Harrington, P ; Ramus, SJ ; de Fazio, A ; Mitchell, G ; Fereday, S ; Bolton, KL ; Gourley, C ; Michie, C ; Karlan, B ; Lester, J ; Walsh, C ; Cass, I ; Olsson, H ; Gore, M ; Benitez, JJ ; Garcia, MJ ; Andrulis, I ; Mulligan, AM ; Glendon, G ; Blanco, I ; Lazaro, C ; Whittemore, AS ; McGuire, V ; Sieh, W ; Montagna, M ; Alducci, E ; Sadetzki, S ; Chetrit, A ; Kwong, A ; Kjaer, SK ; Jensen, A ; Hogdall, E ; Neuhausen, S ; Nussbaum, R ; Daly, M ; Greene, MH ; Mai, PL ; Loud, JT ; Moysich, K ; Toland, AE ; Lambrechts, D ; Ellis, S ; Frost, D ; Brenton, JD ; Tischkowitz, M ; Easton, DF ; Antoniou, A ; Chenevix-Trench, G ; Gayther, SA ; Bowtell, D ; Pharoah, PDP (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 EXPERIMENTAL DESIGN: We used unpublished survival time data for 2,242 patients from two case-control studies and extended survival time data for 4,314 patients from previously reported studies.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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    High Levels of Genomic Aberrations in Serous Ovarian Cancers Are Associated with Better Survival
    Baumbusch, LOB ; Helland, AH ; Wang, YW ; Liestol, KL ; Schaner, MES ; Holm, RH ; Etemadmoghadam, D ; Alsop, KA ; Brown, PB ; Mitchell, G ; Fereday, SF ; DeFazio, AD ; Bowtell, DD ; Kristensen, GBK ; Lingjaerde, OCL ; Borresen-Dale, AB ; Bishop, AJR (Public Library of Science (PLoS), 2013)
    Genomic instability and copy number alterations in cancer are generally associated with poor prognosis; however, recent studies have suggested that extreme levels of genomic aberrations may be beneficial for the survival outcome for patients with specific tumour types. We investigated the extent of genomic instability in predominantly high-grade serous ovarian cancers (SOC) using two independent datasets, generated in Norway (n = 74) and Australia (n = 70), respectively. Genomic instability was quantified by the Total Aberration Index (TAI), a measure of the abundance and genomic size of copy number changes in a tumour. In the Norwegian cohort, patients with TAI above the median revealed significantly prolonged overall survival (p<0.001) and progression-free survival (p<0.05). In the Australian cohort, patients with above median TAI showed prolonged overall survival (p<0.05) and moderately, but not significantly, prolonged progression-free survival. Results were confirmed by univariate and multivariate Cox regression analyses with TAI as a continuous variable. Our results provide further evidence supporting an association between high level of genomic instability and prolonged survival of high-grade SOC patients, possibly as disturbed genome integrity may lead to increased sensitivity to chemotherapeutic agents.