OBJECTIVE: Rapamycin analogs have reproducible but modest efficacy in endometrial cancer (EC). Identification of molecular biomarkers that predict benefit could guide clinical development. METHODS: Fixed primary tissue and whole blood were collected prospectively from patients enrolled on GOG 248. DNA was isolated from macro-dissected tumors and blood; next-generation sequence analysis was performed on a panel of cancer related genes. Associations between clinical outcomes [response rate (RR) 20%; progression-free survival (PFS) median 4.9months] and mutations (PTEN, PIK3CA, PIK3R1, KRAS, CTNNB1, AKT1, TSC1, TSC2, NF1, FBXW7) were explored. RESULTS: Sequencing data was obtained from tumors of 55 of the 73 enrolled pts. Mutation rates were consistent with published reports: mutations in PTEN (45%), PIK3CA (29%), PIK3R1 (24%), K-RAS (16%), CTNNB1 (18%) were common and mutations in AKT1 (4%), TSC1 (2%), TSC2 (2%), NF1 (9%) and FBXW7 (4%) were less common. Increased PFS (HR 0.16; 95% CI 0.01-0.78) and RR (response difference 0.83; 95% CI 0.03-0.99) were noted for AKT1 mutation. An increase in PFS (HR 0.46; 95% CI 0.20-0.97) but not RR (response difference 0.00, 95% CI -0.34-0.34) was identified for CTNNB1 mutation. Both patients with TSC mutations had an objective response. There were no statistically significant associations between mutations in PIK3CA, PTEN, PIK3R1, or KRAS and PFS or RR. CONCLUSIONS: Mutations in AKT1, TSC1 and TSC2 are rare, but may predict clinical benefit from temsirolimus. CTNNB1 mutations were associated with longer PFS on temsirolimus.

INTRODUCTION: Routine preoperative evaluation of the endometrium before Le Fort colpocleisis is often recommended. There are no data, however, to support this practice. In select patients, it may not be a necessary addition to the preoperative evaluation of Le Fort colpocleisis. METHODS: A decision analysis model was created to compare uterine evaluation, by either endometrial (EM) biopsy or transvaginal ultrasound, to no evaluation for a hypothetical cohort of women undergoing Le Fort colpocleisis. We assumed the absence of risk factors for EM cancer. Probabilities and health outcome utilities were obtained from literature review. Medicare charges were used to estimate cost in 2012 US dollars. Cost-utility analysis was performed using US recommendations from a health plan perspective. RESULTS: At willingness-to-pay thresholds of $50,000 and $100,000, no evaluation is superior to both biopsy and ultrasound. At a 64% probability of cancer, biopsy is more cost-effective than no evaluation and ultrasound. CONCLUSIONS: Compared to biopsy and ultrasound, in low-risk women, no EM evaluation before Le Fort colpocleisis demonstrates superior cost-utility.

Objective: Endometrial evaluation is routinely performed in elderly women undergoing Le Fort colpocleisis. There is little evidence to support this practice. We sought to investigate the cost-utility of routine evaluation of the uterine cavity prior to performing a Le Fort colpocleisis. Study Design: A decision analysis model was created to compare uterine evaluation, by either endometrial biopsy or transvaginal ultrasound, to no evaluation for a cohort of women > 80 years old undergoing Le Fort colpocleisis. Baseline assumptions for our model were made to reflect women who did not carry significant risk for the development of endometrial cancer, such as history of postmenopausal bleeding, abnormal uterine pathology, obesity, diabetes, and tamoxifen use. Decision paths included no screening, ultrasound evaluation, and biopsy. The horizon was five years until the endpoint of survival, death, or the development of cancer. Those pathways in which cancer was diagnosed were carried out to the endpoint of either five-year survival or death. Treatment arms for endometrial cancer were based on management methods used at our institution. Probabilities and utilities for health outcomes were estimated through literature review or, when unavailable, by expert opinion. Costs were obtained from US Medicare charges for the appropriate CPT and DRG codes and are reported in 2012 US Dollars. Cost-utility analysis was performed using US recommendations from a societal perspective. Sensitivity analysis using Monte Carlo simulation was performed to test the validity of our model. Results: Analysis of our decision tree demonstrates that a strategy of no evaluation is superior to that of either biopsy or ultrasound. Univariate sensitivity analysis demonstrates that at a 0.55 probability of cancer, biopsy surpasses both no evaluation and ultrasound as the dominant strategy. Using Monte Carlo simulation, at willingness-to-pay thresholds of $50,000 and $100,000, no evaluation was superior to both biopsy and ultrasound from the patient, health-plan, and societal perspectives. Biopsy appears to be a more effective strategy than ultrasound when uterine evaluation is needed. Conclusions: Our model shows that a practice of not evaluating the endometrial cavity prior to performing Le Fort colpocleisis is superior to either biopsy or ultrasound. These results are likely being driven by the low incidence of endometrial cancer in this population. It may not be necessary to perform uterine evaluation prior to Le Fort colpocleisis in a low-risk population. If uterine evaluation is needed, biopsy appears to be the preferred strategy over ultrasound. More studies are needed to determine utility values for health states experienced by women with pelvic organ prolapse and with endometrial cancer. This will enhance our ability to develop more accurate cost-utility models for treating these women.