Utilizing the Radiosensitivity Index (RSI) to Predict Pelvic Failure in Endometrial Cancer Treated with Adjuvant Radiotherapy

Abstract

Various adjuvant approaches are utilized in the management of endometrial cancer based on surgical pathology and institutional preference. The radiosensitivity index (RSI) is a previously validated multi-gene expression index that estimates tumor radiosensitivity. In this study, we evaluate RSI as a genomic predictor for pelvic failure (PF) in patients treated with adjuvant radiotherapy. A total of 204 consecutively treated patients with endometrial cancer were identified from our IRB-approved institutional tissue biorepository. All patients underwent hysterectomy with bilateral salpingo-oophorectomy with the majority undergoing lymph node dissection (n=181; 88%) between 01/99 and 04/11 and followed until 01/19. Gene expression was from Affymetrix Hu-RSTA-2a520709 (Affymetrix; Santa Clara, CA). The RSI 10-gene signature was calculated for each sample using the previously published algorithm. Radiophenotype was determined by dichotomization of RSI at the previously identified cutpoint of 0.375; ≥0.375 = radioresistant (RR) and <0.375 = radiosensitive (RS). Time to event analysis was performed with Kaplan-Meier estimates and the log-rank test. Associations between radiophenotype and outcomes were explored with univariable (UVA) and multivariable (MVA) Cox regression. The threshold for statistical significance in all tests was set at p<0.05. Median follow-up was 38.5 months (range: 0.2-216). The median RSI was 0.42 (range: 0.11-0.70). There were no significant differences in RS and RR patients in age (p=0.99), serosa and/or adnexa involvement (p=0.37), vaginal and/or parametrial involvement (p=0.48), cervical stromal invasion (p=0.59), receipt of adjuvant chemotherapy (p=0.12), and node involvement (p=0.78). A total of 83 (41%) patients were treated with adjuvant radiotherapy with vaginal brachytherapy (n=19; 23%), pelvic radiotherapy (n=26; 31%), or both (n=38; 46%). In patients treated with radiation, RR patients were more likely to undergo PF (3 year pelvic control 84% vs 100%; p=0.02) with worse PF free survival (PFFS) (3 year PFFS 65% vs. 89%; p=0.04). However, since RSI is a radiation specific signature it did not predict PF (p=0.86) or PFFS (p=0.57) in patients not treated with radiation. Factors found to predict PF on UVA included grade 3/1-2 (HR 3.8; 95% CI 1.2-14.8, p=0.03), serosa and/or adnexa involvement (5.9; 95% CI 1.6-20.2, p=0.008), lymph node involvement (4.9; 95% CI 1.5-18.8, 0.009), and RR/RS (7.7; 95% CI 1.5-140.9, 0.01). On MVA, factors that continued to predict for PF included RR/RS (10.7; 95% CI 1.9-202.4, p=0.004), lymph node involvement (4.1; 95% CI 1.2-16.3, p=0.03), and serosa and/or adnexa involvement (4.3; 95% CI 1.2-16.4, p=0.03). RSI was found to be a significant predictor of PF in patients treated with adjuvant radiotherapy on MVA. We propose RSI may be a method to predict which patients are most likely to fail in the pelvis and candidates for treatment escalation in the adjuvant setting.