Exosomal miRNA Predicts Response to Preoperative Chemoradiotherapy in Locally Advanced Rectal Cancer

BACKGROUND: We recently reported blood-based transcriptomic biomarkers for the identification of response to preoperative chemoradiotherapy followed by surgery in patients with locally advanced rectal cancer. OBJECTIVE: We sought to develop a liquid biopsy assay of exosomal miRNAs for identifying the response to preoperative chemoradiotherapy. DESIGN: This was a retrospective study. SETTINGS: This was a worldwide multicenter study with 2 international hospitals. PATIENTS: We analyzed serum specimens from 81 patients in two independent international multicenter clinical cohorts (training n = 54; validation n = 27). MAIN OUTCOME MEASURES: Diagnostic performance and risk estimation for predicting pathological complete response. RESULTS: A 5-miRNA panel was developed and integrated with CEA level into a final risk-assessment model. We identified patients with response to preoperative chemoradiotherapy (AUC = 0.86, 95% CI = 0.74-0.94). We validated the panel's performance in an independent validation cohort (AUC = 0.87, 95% CI = 0.68-0.97). The risk model was more accurate for the identification of response to PCRT than the panel (AUC = 0.90, 95% CI = 0.82-0.96, sensitivity = 0.82, specificity = 0.90). The risk model was applied to detect patients with pathologic complete response and it was superior to currently used pathological features (AUC = 0.92, 95% CI = 0.84-0.97, sensitivity = 0.78, specificity = 1.00). A comparative test for correlated ROC curves showed no significance ( p = 0.17). In multivariable analysis in the training and validation cohort, the miRNA panel was strongly associated with response (training: adjusted OR = 3.69, 95% CI = 3.16-59.32, p < 0.01; validation: adjusted OR = 32.93; 95% CI = 3.94-275.53; p < 0.01), respectively. LIMITATIONS: Retrospective clinical data. CONCLUSIONS: Our signature panel for predicting response to preoperative chemoradiotherapy has the potential for clinical translation as a liquid biopsy assay. (See Video Abstract ).