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


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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    • "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.
    BioMed Research International 07/2014; 2014:787143. DOI:10.1155/2014/787143 · 1.58 Impact Factor
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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.
    Frontiers in Oncology 02/2014; 4:42. DOI:10.3389/fonc.2014.00042
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    • "Stage, preoperative albumin, family history suggestive of HBOC syndrome, and ASA status were not used in the prior nomogram but were found to be significant contributors to predicted disease-specific mortality in this analysis of all-stage ovarian cancer patients. Taking into account the publication by Gallagher et al., which demonstrated that BRCAassociated ovarian cancer has an overall survival advantage over sporadic ovarian cancer independent of platinum sensitivity [11], this is the first ovarian cancer nomogram to incorporate the significance of family history into the prognostic model. "
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    ABSTRACT: To develop a nomogram based on established prognostic factors to predict the probability of 5-year disease-specific mortality after primary surgery for patients with all stages of epithelial ovarian cancer (EOC) and compare the predictive accuracy with the currently used International Federation of Gynecology and Obstetrics (FIGO) staging system. Using a prospectively kept database, we identified all patients with EOC who had their primary surgery at our institution between January 1996 and December 2004. Disease-specific mortality was estimated using the Kaplan-Meier method. Twenty-eight clinical and pathologic factors were analyzed. Significant factors on univariate analysis were included in the Cox proportional hazards regression model, which identified factors utilized in the nomogram. The concordance index (CI) was used as an accuracy measure, with bootstrapping to correct for optimistic bias. Calibration plots were constructed. A total of 478 patients with EOC were included. The most predictive nomogram was constructed using seven variables: age, FIGO stage, residual disease status, preoperative albumin level, histology, family history suggestive of hereditary breast/ovarian cancer (HBOC) syndrome, and American Society of Anesthesiologists (ASA) status. This nomogram was internally validated using bootstrapping and shown to have excellent calibration with a bootstrap-corrected CI of 0.714. The CI for FIGO staging alone was significantly less at 0.62 (P=0.002). We have developed an all-stage nomogram to predict 5-year disease-specific mortality after primary surgery for epithelial ovarian cancer. This tool is more accurate than FIGO staging and should be useful for patient counseling, clinical trial eligibility, postoperative management, and follow-up.
    Gynecologic Oncology 12/2011; 125(1):25-30. DOI:10.1016/j.ygyno.2011.12.423 · 3.77 Impact Factor
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