Article

Survival in epithelial ovarian cancer: A multivariate analysis incorporating BRCA mutation status and platinum sensitivity

Department of Medicine, Memorial Sloan-Kettering Cancer Center, NY, USA.
Annals of Oncology (Impact Factor: 7.04). 11/2010; 22(5):1127-32. DOI: 10.1093/annonc/mdq577
Source: PubMed

ABSTRACT

Patients with BRCA-associated ovarian cancer (OC) have a survival advantage over those with sporadic OC. To further explore this, we examined the impact of prognostic factors on disease-free survival (DFS) and overall survival (OS) in patients with known BRCA mutation status.
We reviewed stage III-IV OC patients treated at our institution between 1 December 1996 and 30 September 2006 and also tested on protocol for BRCA mutations. Impact on DFS and OS was determined by Kaplan-Meier analysis and a Cox proportional hazards model.
Of the 110 patients, 36 had deleterious BRCA mutations [BRCA (+)] and 74 were BRCA wild type [BRCA(-)]. Thirty-one of 36 (86%) BRCA (+) and 60 of 74 (81%) BRCA (-) patients were platinum sensitive (P = 0.60). Median OS was longer for BRCA (+) patients (not reached versus 67.8 months; P = 0.02), but DFS was similar (26.9 versus 24.0, P = 0.3). On multivariate analysis, OS correlated with primary platinum sensitivity [HR = 0.15; 95% CI (confidence interval) 0.06-0.34] and BRCA (+) mutation status (HR = 0.33; 95% CI 0.12-0.86).
BRCA mutation status predicted OS independent of primary platinum sensitivity, suggesting that underlying tumor biology contributes to disease outcome and may be worthy of consideration in future clinical trial design.

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    • "The serum CA125, both at the beginning of treatment and after treatment completion, is a widely confirmed prognostic factor in patients with OC1314151617181920. For patients with BRCA1-OC, the reported average serum CA125 before treatment ranges from 445 U/ml to 824 U/ml[11,21,22]. However, there are no data on serum CA125 levels at the end of treatment. In the present study, the average serum CA125 in patients with BRCA1-OC was 113 U/ml and 71 U/ml before and after treatment, respectively. "
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    ABSTRACT: Treatment outcomes appear to be better for ovarian cancer (OC) patients carrying the BRCA1/2 germline mutation than for patients with sporadic OC. However, most published data are for North American, British and Jewish populations. There have been very few studies on treatment outcomes in Central and Eastern European patients with OC. The aim of this study was to analyse prognostic factors in Polish patients with BRCA1-dependent OC (BRCA1-OC). The records of patients with OC treated with surgery and chemotherapy at the Centre of Oncology in Kraków, Poland, between 2004 and 2009 were reviewed. Based on family history, a group of 249 consecutive patients fulfilling the criteria for risk of hereditary OC were selected and tested for the germline BRCA1 mutation. Response to combination therapy (surgery and chemotherapy) in the BRCA1-OC group was assessed based on clinical examination, imaging and serum CA125. Germline BRCA1 mutations were detected in 69 of the 249 patients, but three of these patients failed to complete the study. Finally, 66 patients with BRCA1-OC were included in the study group. The median age of the study patients was 49.5 years. All had undergone primary or interval cytoreductive surgery and chemotherapy. Progression occurred in 48 (72.7 %) of the 66 patients and median time to progression was 20 months. The 5-year overall survival rate in was 43.9 % and median survival time was 32.3 months. On multivariate analysis, the endometrial subtype of OC and serum CA125 < 12.5 U/ml at the end of treatment were independent, positive prognostic factors for 5-year overall survival. Prognostic factors for favourable treatment outcomes in Polish patients with BRCA1-OC do not appear to differ from those in patients with sporadic OC. The incidence of the endometrial subtype of OC was relatively high (34.9 %) among women in the study. This was unexpected and has not been reported previously. This subtype of OC was an independent prognostic factor for favourable treatment outcomes.
    Full-text · Article · Dec 2016 · Hereditary Cancer in Clinical Practice
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    • "Platinum-salts interfere with DNA cross-links creating double-strand breaks in the DNA helix, which cannot be repaired in BRCA due to HR deficiency. Studies demonstrated an improved long term-survival in women with OC treated with platinum-salts if compared to sporadic OC [75]. Intraperitoneal cisplatin chemotherapy has been shown to lead to favorable long term outcome in advanced OC women with BRCA mutation [76]. "
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    ABSTRACT: Ovarian cancer (OC) mostly arises sporadically, but a fraction of cases are associated with mutations in BRCA1 and BRCA2 genes. The presence of a BRCA mutation in OC patients has been suggested as a prognostic and predictive factor. In addition, the identification of asymptomatic carriers of such mutations offers an unprecedented opportunity for OC prevention. This review is aimed at exploring the current knowledge on epidemiological and molecular aspects of BRCA-associated OC predisposition, on pathology and clinical behavior of OC occurring in BRCA mutation carriers, and on the available options for managing asymptomatic carriers.
    Full-text · Article · Jul 2014 · BioMed Research International
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    • "The BRCA-like behavior has been described based on clinical and molecular features that parallel gBRCAm-associated cancers’ characteristics. The major clinical BRCA-like behavior identified is susceptibility to platinums and other DNA-damaging agents (54–56). Some of the molecular events described in BRCA-like behavior include epigenetic silencing of BRCA1 through promoter methylation (57–59) and overexpression of EMSY, suppressing BRCA2 transcription (60). "
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    ABSTRACT: Poly(ADP-ribose) polymerase inhibitors (PARPi) have shown clinical activity in patients with germline BRCA1/2 mutation (gBRCAm)-associated breast and ovarian cancers. Accumulating evidence suggests that PARPi may have a wider application in the treatment of cancers defective in DNA damage repair pathways, such as prostate, lung, endometrial, and pancreatic cancers. Several PARPi are currently in phase I/II clinical investigation, as single-agents and/or combination therapy in these solid tumors. Understanding more about the molecular abnormalities involved in BRCA-like phenotype in solid tumors beyond breast and ovarian cancers, exploring novel therapeutic trial strategies and drug combinations, and defining potential predictive biomarkers are critical to expanding the scope of PARPi therapy. This will improve clinical outcome in advanced solid tumors. Here, we briefly review the preclinical data and clinical development of PARPi, and discuss its future development in solid tumors beyond gBRCAm-associated breast and ovarian cancers.
    Full-text · Article · Feb 2014 · Frontiers in Oncology
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