Improving Risk Assessment for Metastatic Disease in Endometrioid Endometrial Cancer Patients Using Molecular and Clinical Features: An NRG Oncology/Gynecologic Oncology Group Study

SIMPLE SUMMARY: Judging the chance (risk) of cancer spread and bad outcome in endometrial cancer continues to be a challenge. Molecular and clinical factors offer the hope of improving the accuracy of judging the danger of cancer spread (metastasis) and a bad outcome (prognosis) to help guide patient care. The aim of this research was to develop a risk score for cancer spread and bad outcome for the most common type of endometrial cancer, endometrioid endometrial cancer, using molecular features and clinical factors in endometrial cancers removed during surgery. The molecular score, referred to as MS7, was more accurate at judging the chance of nodal and distant metastasis than clinical factors like grade 3 disease and myometrial invasion. MS7 score was also better than aggressive molecular subtypes or endometrial cancer-associated genes identified by other research groups. The combination of MS7 score and myometrial invasion was the best at accurately judging the chance of nodal and distant metastasis in the most common type of endometrial cancer. The MS7 score was also shown to accurately indicate bad outcome including cancer progression and death. This research hopes to help guide patient care stopping overtreatment in lower-risk and undertreatment in higher-risk endometrial cancer patients. ABSTRACT: Objectives: A risk assessment model for metastasis in endometrioid endometrial cancer (EEC) was developed using molecular and clinical features, and prognostic association was examined. Methods: Patients had stage I, IIIC, or IV EEC with tumor-derived RNA-sequencing or microarray-based data. Metastasis-associated transcripts and platform-centric diagnostic algorithms were selected and evaluated using regression modeling and receiver operating characteristic curves. Results: Seven metastasis-associated transcripts were selected from analysis in the training cohorts using 10-fold cross validation and incorporated into an MS7 classifier using platform-specific coefficients. The predictive accuracy of the MS7 classifier in Training-1 was superior to that of other clinical and molecular features, with an area under the curve (95% confidence interval) of 0.89 (0.80–0.98) for MS7 compared with 0.69 (0.59–0.80) and 0.71 (0.58–0.83) for the top evaluated clinical and molecular features, respectively. The performance of MS7 was independently validated in 245 patients using RNA sequencing and in 81 patients using microarray-based data. MS7 + MI (myometrial invasion) was preferrable to individual features and exhibited 100% sensitivity and negative predictive value. The MS7 classifier was associated with lower progression-free and overall survival (p ≤ 0.003). Conclusion: A risk assessment classifier for metastasis and prognosis in EEC patients with primary tumor derived MS7 + MI is available for further development and optimization as a companion clinical support tool.