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PubMed | Sloan Kettering Cancer Center, Gynecology Service, New York Medical College, Gynecologic Medical Oncology Service. and Computational Biology Program.
Type: Journal Article | Journal: Annals of oncology : official journal of the European Society for Medical Oncology | Year: 2014

BRCA1 expression can be lost by a variety of mechanisms including germline or somatic mutation and promotor hypermethylation. Given the potential importance of BRCA1 loss as a predictive and prognostic biomarker in high-grade serous ovarian cancer, we sought to evaluate the utility of BRCA1 immunohistochemistry (IHC) in screening for BRCA1 loss by germline, somatic, and epigenetic mechanisms.Patients with advanced high-grade serous ovarian cancer who had previously undergone germline BRCA1 testing were identified. Samples from each tumor were stained for BRCA1 and reviewed independently by two pathologists blinded to BRCA status. Tumors with abnormal BRCA1 IHC and wild-type germline testing underwent further evaluation for somatic BRCA1 mutations and promoter hypermethylation. McNemars test was used to determine the association of BRCA1 IHC with germline BRCA1 mutations and BRCA1 loss through any mechanism. Kaplan-Meier methods were used to estimate overall survival (OS), and the log-rank test was used to assess differences between groups.Inter-rater reliability between the two pathologists on BRCA IHC interpretation was very good (kappa coefficient 0.865, P = 0.16; McNemars test). BRCA1 IHC was abnormal in 36% (48/135) of cases. When compared with germline BRCA1 status, BRCA1 IHC had a high negative predictive value (95.4%) but a low positive predictive value (PPV, 52.1%). When accounting for promoter hypermethylation and somatic mutations as alternative methods of BRCA1 loss, the PPV rose to 87.5%. Five-year OS rate was 49.6% [95% confidence interval (CI) 26.3% to 69.3%] for patients with germline BRCA1 mutations, 50.4% (95% CI 27.5% to 69.5%) for germline wild-type BRCA1 and abnormal IHC, and 52.1% (95% CI 38.4% to 64.2%) for germline wild-type BRCA1 and normal IHC (P = 0.92).BRCA1 IHC interpretation was a highly reproducible and accurate modality for detecting germline, somatic, or epigenetic mechanisms of BRCA1 loss. These results support further development of BRCA1 IHC as a potential biomarker for BRCA1 loss in high-grade serous ovarian cancer.


Sandadi S.,Sloan Kettering Cancer Center | Tanner E.J.,Sloan Kettering Cancer Center | Khoury-Collado F.,Sloan Kettering Cancer Center | Kostolias A.,Sloan Kettering Cancer Center | And 7 more authors.
International Journal of Gynecological Cancer | Year: 2013

Objective: The objective of this study was to compare morbidity and outcome following radical surgery with or without adjuvant radiation therapy (RT) in the treatment of stages IB1-IB2 cervical carcinoma. Methods: We retrospectively identified 222 patients with stages IB1-IB2 cervical carcinoma treated initially with radical hysterectomy or radical trachelectomy with or without adjuvant RT from February 2000 to November 2009. All grade 3 or higher complicationsVthose requiring interventional radiology, endoscopic evaluation, or operative interventionVwere documented. Results: One hundred fifty-eight patients (71%) underwent radical hysterectomy; 64 (29%) underwent radical trachelectomy. One hundred fifty-three patients (69%) underwent surgery alone; 69 (31%) received adjuvant radiation with or without chemosensitization. There was a statistically significant difference in the rate of total grades 1 to 5 late complications between the surgery-alone and surgery ± RT groups (12% vs 32%, respectively; P G 0.001); however, the rate of grade 3 or higher complications was similar (5% vs 4%, respectively; P = 0.999). The progression-free and overall survival rates of the entire cohort were both 95%. The 5-year progression-free survival rates for the surgery-alone and surgery ± RT groups were 93% and 90% (P = 0.172). The overall survival rates were 96% and 91%, respectively (P = 0.332). Conclusions: The majority of women with stages IB1-IB2 cervical cancer undergoing radical surgery do not require adjuvant RT, have excellent oncologic outcome, and have low severe complication rates. Nearly one third of our patients required postoperative radiation, with no statistically significant increase in severe complication rate and with similar oncologic outcomes compared with the surgery-only cohort. These data support the continued practice of radical surgery with individualized postoperative radiation for these patients. © 2013 by IGCS and ESGO.


Gallagher D.J.,Gynecologic Medical Oncology Service | Konner J.A.,Gynecologic Medical Oncology Service | Bell-McGuinn K.M.,Gynecologic Medical Oncology Service | Bhatia J.,Clinical Genetics Service | And 7 more authors.
Annals of Oncology | Year: 2011

Background: 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. Patients and methods: 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. Results: Of the 110 patients, 36 had deleterious BRCA mutations [BRCA (+)] and 74 were BRCA wild type [BRCA(2)]. Thirty-one of 36 (86%) BRCA (+) and 60 of 74 (81%) BRCA (2) 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). Conclusions: 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. © The Author 2010. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved.


Suidan R.S.,Sloan Kettering Cancer Center | Ramirez P.T.,Anderson Cancer Center | Sarasohn D.M.,MSKCC | Teitcher J.B.,MSKCC | And 14 more authors.
Gynecologic oncology | Year: 2014

To assess the ability of preoperative computed tomography (CT) scan of the abdomen/pelvis and serum CA-125 to predict suboptimal (>1cm residual disease) primary cytoreduction in advanced ovarian, fallopian tube, and peritoneal cancer. This was a prospective, non-randomized, multicenter trial of patients who underwent primary cytoreduction for stage III-IV ovarian, fallopian tube, and peritoneal cancer. A CT scan of the abdomen/pelvis and serum CA-125 were obtained within 35 and 14 days before surgery, respectively. Four clinical and 20 radiologic criteria were assessed. From 7/2001 to 12/2012, 669 patients were enrolled; 350 met eligibility criteria. The optimal debulking rate was 75%. On multivariate analysis, three clinical and six radiologic criteria were significantly associated with suboptimal debulking: age ≥ 60 years (p=0.01); CA-125 ≥ 500 U/mL (p<0.001); ASA 3-4 (p<0.001); suprarenal retroperitoneal lymph nodes >1cm (p<0.001); diffuse small bowel adhesions/thickening (p<0.001); and lesions >1cm in the small bowel mesentery (p=0.03), root of the superior mesenteric artery (p=0.003), perisplenic area (p<0.001), and lesser sac (p<0.001). A 'predictive value score' was assigned for each criterion, and the suboptimal debulking rates of patients who had a total score of 0, 1-2, 3-4, 5-6, 7-8, and ≥ 9 were 5%, 10%, 17%, 34%, 52%, and 74%, respectively. A prognostic model combining these nine factors had a predictive accuracy of 0.758. We identified nine criteria associated with suboptimal cytoreduction, and developed a predictive model in which the suboptimal rate was directly proportional to a predictive value score. These results may be helpful in pretreatment patient assessment. Copyright © 2014 Elsevier Inc. All rights reserved.


Teo M.Y.,Cork Mercy University Hospitals | Power D.G.,Cork Mercy University Hospitals | Tew W.P.,Gynecologic Medical Oncology Service | Lichtman S.M.,Sloan Kettering Cancer Center
Oncologist | Year: 2012

The aging of the population has focused on the need to evaluate older patients with cancer. Approximately 50% of patients with ovarian cancer will be older than age 65 years. increasing age has been associated with decreased survival. it is uncertain whether this relates to biologic factors, treatment factors, or both. There is concern that undertreatment may be associated with decreased survival. Older patients with ovarian cancer have been underrepresented in clinical trials. Therefore, the evidence base on which make decisions is lacking. Clinicians need to be aware of the currently available data to aid in treatment decisions. Doublet therapy is the most common standard treatment in epithelial ovarian cancer. it usually consists of a taxane and a platinum compound. A series of cooperative group studies in both the United States and Europe established intravenous paclitaxel and carboplatin as the most common standard in optimally debulked patients. The recent introduction of intraperitoneal therapy has complicated decision making in terms of which older patients would benefit from this more toxic therapy. In relapsed patients, the issue of platinum sensitivity is critical in deciding whether to reutilize platinum compounds. It is unclear whether single agents or combinations are superior, particularly in older patients. Geriatric assessment is an important component of decision making. Prospective studies are needed to develop strategies to determine the optimal treatment for older patients with ovarian cancer. © AlphaMed Press.

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