Sex hormone, insulin, and insulin-like growth factor signaling in recurrence of high stage endometrial cancer: Results from the NRG Oncology/Gynecologic Oncology Group 210 trial.

Abstract

5509 Background: Sex hormone and insulin/insulin-like growth factor (IGF) axis signaling pathways play an important role in endometrial cancer development but their role in endometrial cancer recurrence is unknown. In this study GOG-8015 we evaluated these pathways in a prospective cohort of patients diagnosed with the most common type of endometrial cancer, endometrioid adenocarcinoma. Methods: Stage II-IV endometrioid endometrial adenocarcinoma patients (N = 816) enrolled in the GOG-210 study with pre-treatment specimens were tested for tumor mRNA and protein expression levels of IGF1, IGF2, IGF binding proteins ( IGFBP) -1and -3, the insulin (IR) and IGF-I receptors (IGF1R), and phosphorylated (activated) IR/IGF1R as well as estrogen (ER) and progesterone receptors (PR) using quantitative PCR and immunohistochemistry (IHC). Serum concentrations of insulin, IGF-I, IGFBP-3, estradiol, estrone and sex hormone binding globulin were measured using ELISAs. Hazard ratios (HR) and 95% confidence intervals (CI) for risk of recurrence were obtained from multivariable Cox proportional hazard’s models with adjustment for age, stage and grade. Results: Recurrence occurred in 280 (34%) cases during a mean of 5.4 years of follow-up. ER-positivity (HR 0.67, 95% CI 0.47-0.95), IR-positivity (HR 0.53, 95% CI 0.29-0.98) and serum IGF-I levels (highest versus lowest quartile, HR 0.66, 95% CI 0.47-0.92) were inversely associated with recurrence risk. Conversely, circulating estradiol (highest versus lowest tertile, HR 1.55, 95% CI 1.02-2.36) and insulin (per 10 uU/ml, HR 1.52, 95% CI 1.12-2.06) and phosphorylated IGF1R/pIR expression (HR 1.40, 95% CI 1.02-1.92) were associated with increased risk of recurrence. Conclusions: We identified novel sex hormone and insulin/IGF axis tissue and circulating biomarkers of recurrence in a prospective study of high stage endometrioid endometrial cancer. Circulating insulin and estradiol, and tissue phosphorylated (activated) IGR1R/IR were independently associated with recurrence. These findings support prioritizing studies to establish their clinical utility as prognostic biomarkers and to investigate new strategies that target these pathways for prevention and treatment of endometrial cancer recurrence.