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In the Know --- 2016 In The Know Gyn Onc Literature of Significance Ed’s List December 2016- January 2016 Prepared by Ed Pavlik (Ed’s List) --- University of Kentucky Medical Center December 2016 Confirmation of ProMisE: A simple, genomics-based clinical classifier for endometrial cancer . Al Talhouk, MK McConechy, S Leung, W Yang, A Lum, J Senz, N Boyd, J Pike, M Anglesio, JS Kwon, AN Karnezis, DG Huntsman, CB Gilks, JN McAlpine. Cancer Early view: DOI: 10.1002/cncr.30496 http://onlinelibrary.wiley.com/doi/10.1002/cncr.30496/full BACKGROUND Classification of endometrial carcinomas (ECs) by morphologic features is irreproducible and imperfectly reflects tumor biology. The authors developed the Proactive Molecular Risk Classifier for Endometrial Cancer (ProMisE), a molecular classification system based on The Cancer Genome Atlas genomic subgroups, and sought to confirm both feasibility and prognostic ability in a new, large cohort of ECs. METHODS Immunohistochemistry (IHC) for the presence or absence of mismatch repair (MMR) proteins (to identify MMR deficiency [MMR-D]), sequencing for polymerase-ɛ (POLE) exonuclease domain mutations (POLE EDMs), and IHC for tumor protein 53 (p53) (wild type vs null/missense mutations; p53 wt and p53 abn, respectively) were performed on 319 new EC samples. Subgroups were characterized and assessed relative to outcomes. The prognostic ability of ProMisE was compared with that of current risk-stratification systems (European Society of Medical Oncology [ESMO]). RESULTS ProMisE decision-tree classification achieved categorization of all cases and identified 4 prognostic subgroups with distinct overall, disease-specific, and progression-free survival (P < .001). Tumors with POLE EDMs had the most favorable prognosis, and those with p53 abn the worst prognosis, and separation of the 2 middle survival curves (p53 wt and MMR-D) was observed. There were no significant differences in survival between the ESMO low-risk and intermediate-risk groups. ProMisE improved the ability to discriminate outcomes compared with ESMO risk stratification. There was substantial overlap (89%) between the p53 abn and high-risk ESMO subgroups; but, otherwise, there were no predictable associations between molecular and ESMO risk groups. CONCLUSIONS Molecular classification of ECs can be achieved using clinically applicable methods and provides independent prognostic information beyond established clinicopathologic risk factors available at diagnosis. Consistent, biologically relevant categorization enables stratification for clinical trials and/or targeted therapy, identification of women who are at increased risk of having Lynch syndrome, and may guide clinical management. ---------------------------------------------------------------------------------------------------------------------------------- Vulvar and vaginal melanoma: A unique subclass of mucosal melanoma based on a comprehensive molecular analysis of 51 cases compared with 2253 cases of nongynecologic melanoma. JY Hou MD, C Baptiste, RB Hombalegowda, AI Tergas, R Feldman, NL Jones, S Chatterjee-Paer, A Bus- Kwolfski, JD Wright, WM Burke Cancer Early view DOI: 10.1002/cncr.30473 http://onlinelibrary.wiley.com.ezproxy.uky.edu/doi/10.1002/cncr.30473/full BACKGROUND Optimal treatments for vulvar and vaginal melanomas (VVMs) have not been identified. Herein, the authors compare molecular profiles between VVM and nongynecologic melanoma (NGM) subtypes with the objective of identifying novel, targetable biomarkers. METHODS In total, 2304 samples of malignant melanoma that were submitted to Caris Life Sciences between 2009 and 2015 were reviewed. In situ hybridization and immunohistochemistry were used to assess copy numbers and protein expression of selected genes. Sequenced variants were analyzed using a proprietary cancer panel. RESULTS In total, 51 VVMs (14 vaginal and 37 vulvar melanomas) were compared with 2253 malignant NGMs, including 2127 cutaneous, 105 mucosal, and 21 acral melanomas. In VVMs, B-Raf proto-oncogene serine/threonine kinase (BRAF) was the most frequently mutated gene (26%) compared with 8.3% of mucosal NGMs (P = .008). In BRAF-mutated tumors, fewer VVMs (50%), compared with NGMs (82.1%), had a variant within the valine codon 600 (V600) domain. The KIT mutation rate was highest in VVMs (22%) compared with 3% in cutaneous (P < .001) and 8.8% in mucosal (P = .05) melanoma subtypes. NRAS mutations were rare in VVMs compared with cutaneous (25.9%; P = .009) and acral (40.6%; P = .002) melanoma subtypes. PD-L1 (56%) and PD-1 (75%) were frequently expressed in VVM, whereas PI3KCA pathway mutations and estrogen receptor/progesterone receptor expression were rare. Compared with VVMs that had In The Know 2016 page 1 KIT mutations, wild-type KIT VVMs were more likely to express molecular markers suggestive of platinum resistance (ERCC1), alkylating sensitivity (MGMT), and anthracycline sensitivity (TOP2A). CONCLUSIONS The unique molecular features of VVM render this disease a distinct subtype of melanoma. Gene-based molecular therapy and immunotherapies may be promising and should be evaluated in clinical trials. -------------------------------------------------------------------------------------------------------------------------------------------------------- Does hormonal therapy for fertility preservation affect the survival of young women with early- stage endometrial cancer? ZR Greenwald, LN Huang, MD Wissing, EL Franco, WH Gotlieb Cancer Early view DOI: 10.1002/cncr.30529 http://onlinelibrary.wiley.com.ezproxy.uky.edu/doi/10.1002/cncr.30529/full BACKGROUND The incidence of endometrial cancer among young women is increasing. Some patients with low-grade endometrial cancer receive hormone therapy (HT) before surgery to preserve fertility. It is unclear whether this adversely affects survival. METHODS Patients with localized, low-grade endometrial cancer who were aged <45 years were selected from the Surveillance, Epidemiology, and End Results database between 1993 and 2012. Propensity score matching was used to select comparable groups receiving HT or primary surgery. Cancer-specific and overall survival were measured using Kaplan-Meier methods. Hazard ratios and 95% confidence intervals (95% CIs) were estimated using Cox models adjusted for age, period of diagnosis, marital status, race, tumor grade, morphology, and previous radiotherapy. RESULTS A total of 6339 women were included in the current study cohort, 161 of whom initially received HT and 6178 of whom received primary surgery. After 15 years of follow-up, all-cause mortality did not differ between the groups (HT group: 14.1% [95% CI, 6.7%-28.4%] and propensity score-matched primary surgery group: 9.3% [95% CI, 4.1%-20.5%]). Cancer-specific mortality appeared higher in patients treated with HT compared with those treated with primary surgery (9.2% [95% CI, 3.4%-24.0%] vs 2.1% [95% CI, 1.5%-2.8%]). However, this difference was driven by 3 late deaths in the HT group. Sensitivity analyses using a broader definition of cancer-specific mortality provided no statistical evidence of a survival difference between the treatment groups. The hazard ratio for the overall risk of death was 1.45 (95% CI, 0.44- 4.74). CONCLUSIONS Based on this population-based cohort, young patients with low-grade endometrial cancer appear to have excellent survival, regardless of the primary therapy chosen (HT vs primary surgery). The current selection of patients for HT to preserve fertility, which is managed carefully by experienced clinicians, does not appear to significantly worsen clinical outcomes. ------------------------------------------------------------------------------------------------------------------------------------------------------- What is the role of retroperitoneal exploration in optimally debulked stage IIIC epithelial ovarian cancer? An NRG Oncology/Gynecologic Oncology Group ancillary data study. BJ Rungruang, A Miller, TC Krivak, NS Horowitz, N Rodriguez, CA.Hamilton, FJ Backes, LF Carson, M Friedlander, DG Mutch, MJ Goodheart, K S Tewari, RM Wenham, MA.Bookman, GL Maxwell, SD Richard. Cancer Early view DOI: 10.1002/cncr.30414 http://onlinelibrary.wiley.com.ezproxy.uky.edu/doi/10.1002/cncr.30414/full BACKGROUND The purpose of this study was to determine the effect of retroperitoneal (RP) exploration on progression- free survival (PFS) and overall survival (OS) in epithelial ovarian cancer (EOC) patients with stage IIIC disease who underwent optimal debulking surgery. METHODS Data were collected from records of the Gynecologic Oncology Group 182 (GOG-182) study of stage IIIC EOC patients cytoreduced to no gross residual disease (R0) or minimal gross residual (<1 cm) disease (MGRD) at primary surgery. Patients with stage IIIC disease by intraperitoneal (IP) tumor were included and divided into 3 groups: 1) > 2 cm IP tumor without lymph node involvement (IP/RP−), 2) > 2 cm IP tumor with lymph node involvement (IP/RP+), and 3) > 2 cm IP tumor with no RP exploration (IP/RP?). The effects of disease distribution and RP exploration on PFS and OS were assessed using Kaplan–Meier and proportional hazards methods. RESULTS There were 1871 stage IIIC patients in GOG-182 who underwent optimal primary debulking surgery. Of these, 689 (36.8%) underwent RP exploration with removal of lymph nodes from at least 1 para-aortic site, and 1182 (63.2%) did not. There were 269 patients in the IP/RP− group, 420 patients in the IP/RP + group, and 1182 patients in the IP/RP? group. Improved PFS (18.5 vs 16.0 months; P < .0001)
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