Molecular characterization in the prediction of disease extent in endometrial carcinoma.

OBJECTIVE: Patients with endometrial carcinoma are usually triaged to staging lymphadenectomy selectively based on estimated risk of lymphatic spread. The risk is generally assessed by the presence of uterine risk factors, but their preoperative and intraoperative identification remain a challenge. The objective of this study was to assess the capability of molecular classification, described by The Cancer Genome Atlas (TCGA), to predict the stage of endometrial carcinoma. STUDY DESIGN: Sequencing of polymerase-ε (POLE) and immunohistochemistry of mismatch repair (MMR) proteins and p53 were performed to stratify endometrial carcinomas into subgroups of POLE exonuclease domain mutation (EDM), MMR deficiency, abnormal p53 (p53 abn) and 'no specific molecular profile' (NSMP). NSMP was the reference subgroup for comparisons. Associations of molecular subgroups and uterine risk factors with stage were examined in univariable and multivariable analyses. RESULTS: Six hundred and four patients were included in the study. None of the POLE EDM tumours extended beyond the uterine cervix. In an unadjusted analysis, p53 abn was associated with increased risk for stage IIIC-IV disease [odds ratio (OR) 4.6, 95% confidence interval (CI) 2.3-9.2; p < 0.0005]. When controlling for uterine risk factors (histotype and grade, depth of myometrial invasion, tumour size, lymphovascular space invasion), p53 was not an independent predictor of advanced disease. In contrast, POLE EDM independently predicted local disease (OR 0.12, 95% CI 0.015-0.99; p = 0.049 for stage II-IV cancer). Of the molecular subgroups, p53 abn was most strongly associated with the presence of high-risk uterine factors (ORs between 2.2 and 19; p ≤ 0.010). CONCLUSION: Of the TCGA-based molecular subgroups, POLE EDM independently predicted early-stage endometrial carcinoma. Although p53 abn was not an independent predictor of advanced disease, its association with uterine risk factors could allow utilization of molecular data in deciding the type of staging surgery if knowledge of uterine factors is deficient.

Clinical factors as prognostic variables among molecular subgroups of endometrial cancer.

BACKGROUND: Clinical factors may influence endometrial cancer survival outcomes. We examined the prognostic significance of age, body mass index (BMI), and type 2 diabetes among molecular subgroups of endometrial cancer. METHODS: This was a single institution retrospective study of patients who underwent surgery for endometrial carcinoma between January 2007 and December 2012. Tumors were classified into four molecular subgroups by immunohistochemistry of mismatch repair (MMR) proteins and p53, and sequencing of polymerase-ϵ (POLE). Overall, cancer-related, and non-cancer-related mortality were estimated using univariable and multivariable survival analyses. RESULTS: Age >65 years was associated with increased mortality rates in the whole cohort (n = 515) and in the "no specific molecular profile" (NSMP) (n = 218) and MMR deficient (MMR-D) (n = 191) subgroups during a median follow-up time of 81 months (range 1‒136). However, hazard ratios for cancer-related mortality were non-significant for NSMP and MMR-D. Diabetes was associated with increased overall and non-cancer-related mortality in the whole cohort and MMR-D subgroup. Overweight/obesity had no effect on outcomes in the whole cohort, but was associated with decreased overall and cancer-related mortality in the NSMP subgroup, and increased overall and non-cancer-related mortality in the MMR-D subgroup. Overweight/obesity effect on cancer-related mortality in the NSMP subgroup remained unchanged after controlling for confounders. High-risk uterine factors were more common, and estrogen and progesterone receptor expression less common in NSMP subtype cancers of normal-weight patients compared with overweight/obese patients. No clinical factors were associated with outcomes in p53 aberrant (n = 69) and POLE mutant (n = 37) subgroups. No cancer-related deaths occurred in the POLE mutant subgroup. CONCLUSIONS: The prognostic effects of age, BMI, and type 2 diabetes do not appear to be uniform for the molecular subgroups of endometrial cancer. Our data support further evaluation of BMI combined with genomics-based risk-assessment.

American Society of Anesthesiologists physical status score as a predictor of long-term outcome in women with endometrial cancer.

OBJECTIVE: To study the association of the American Society of Anesthesiologists (ASA) physical status score with long-term outcome in endometrial cancer. METHODS: Overall, disease-specific and non-cancer-related survival were estimated using simple and multivariable Cox regression analyses and the Kaplan-Meier method. RESULTS: A total of 1166 patients were included in the study. Median follow-up time was 76 (range 1-136) months. All-cause and non-cancer-related mortality were increased in patients whose ASA physical status score was III (HRs 2.5 and 8.0, respectively) or IV (HRs 5.7 and 25, respectively), and cancer-related mortality was increased in patients whose score was IV (HR 2.7). Kaplan-Meier analyses demonstrated a worse overall, disease-specific and non-cancer-related survival for patients whose score was ≥III (p<0.0001 for all). Disease-specific survival was also separately analyzed for patients with stage I and stage II-IV cancer. Compared with patients whose score was ≤II, the survival was worse for patients whose score was ≥III in both subgroups of stages (p=0.003 and p=0.017 for stage I and stages II-IV, respectively). ASA physical status score remained an independent predictor of all-cause mortality (HR 2.2 for scores ≥III), cancer-related mortality (HRs 1.7 and 2.2 for scores ≥III and IV, respectively) and non-cancer related mortality (HR 3.1 for scores ≥III) after adjustment for prognostically relevant clinicopathologic and blood-based covariates. ASA physical status score also remained an independent predictor of cancer-related mortality after exclusion of patients who were at risk for nodal involvement based on features of the primary tumor but who did not undergo lymphadenectomy, and patients with advanced disease who received suboptimal chemotherapy (HRs 1.6 and 2.5 for scores ≥III and IV, respectively). CONCLUSIONS: ASA physical status score independently predicts overall survival, disease-specific survival, and non-cancer-related survival in endometrial cancer.