Yuma Wada1,2,3, Mitsuo Shimada2, Yuji Morine2, Tetsuya Ikemoto2, Yu Saito2, Zhongxu Zhu4, Xin Wang4, Ane Etxart5, Yangsoon Park6, Luis Bujanda7, In Ja Park8, Ajay Goel1,3,9. 1. Department of Molecular Diagnostics and Experimental Therapeutics, Beckman Research Institute of City of Hope, Monrovia, CA. 2. Department of Surgery, Tokushima University, Tokushima, Japan. 3. Center for Gastrointestinal Research, Baylor Scott & White Research Institute and Charles A. Sammons Cancer Center, Baylor University Medical Center, Dallas, TX. 4. Department of Biomedical Sciences, City University of Hong Kong, Hong Kong, China. 5. Department of Surgery, Donostia Hospital University, Instituto Biodonostia, San Sebastián, Spain. 6. Department of Pathology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea. 7. Gastroenterology Department, Instituto Biodonostia, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Universidad del País Vasco (UPV/EHU), San Sebastián, Spain. 8. Division of Colon and Rectal Surgery, Department of Surgery, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea. 9. City of Hope Comprehensive Cancer Center, Duarte, CA.
Abstract
Patients with locally advanced rectal cancer (LARC) are recommended to receive preoperative chemoradiotherapy (PCRT) followed by surgery. Response to PCRT varies widely: 60%-70% of patients with LARC do not derive therapeutic benefit from PCRT, whereas 15%-20% of patients achieve pathologic complete response (pCR). We sought to develop a liquid biopsy assay for identifying response to PCRT in patients with LARC. MATERIALS AND METHODS: We analyzed two genome-wide microRNA (miRNA) expression profiling data sets from tumor tissue samples for in silico discovery (GSE68204) and validation (GSE29298). We prioritized biomarkers in pretreatment plasma specimens from clinical training (n = 41; 15 responders and 26 nonresponders) and validation (n = 65; 29 responders and 36 nonresponders) cohorts of patients with LARC. We developed an integrated miRNA panel and established a risk assessment model, which was combined with the miRNA panel and carcinoembryonic antigen levels. RESULTS: Our comprehensive discovery effort identified an 8-miRNA panel that robustly predicted response to PCRT, with an excellent accuracy in the discovery (area under the curve [AUC] = 0.95) and validation (AUC = 0.92) cohorts. We successfully established a circulating miRNA panel with remarkable diagnostic accuracy in the clinical training (AUC = 0.82) and validation (AUC = 0.81) cohorts. Moreover, the predictive accuracy of the panel was significantly superior to conventional clinical factors in both cohorts (P < .01) and the risk assessment model was superior (AUC = 0.83). Finally, we applied our model to detect patients with pathologic complete response and showed that it was dramatically superior to currently used pathologic features (AUC = 0.92). CONCLUSION: Our novel risk assessment signature for predicting response to PCRT has a potential for clinical translation as a liquid biopsy assay in patients with LARC.
Patients with locally advanced rectal cancer (LARC) are recommended to receive preoperative chemoradiotherapy (PCRT) followed by surgery. Response to PCRT varies widely: 60%-70% of patients with LARC do not derive therapeutic benefit from PCRT, whereas 15%-20% of patients achieve pathologic complete response (pCR). We sought to develop a liquid biopsy assay for identifying response to PCRT in patients with LARC. MATERIALS AND METHODS: We analyzed two genome-wide microRNA (miRNA) expression profiling data sets from tumor tissue samples for in silico discovery (GSE68204) and validation (GSE29298). We prioritized biomarkers in pretreatment plasma specimens from clinical training (n = 41; 15 responders and 26 nonresponders) and validation (n = 65; 29 responders and 36 nonresponders) cohorts of patients with LARC. We developed an integrated miRNA panel and established a risk assessment model, which was combined with the miRNA panel and carcinoembryonic antigen levels. RESULTS: Our comprehensive discovery effort identified an 8-miRNA panel that robustly predicted response to PCRT, with an excellent accuracy in the discovery (area under the curve [AUC] = 0.95) and validation (AUC = 0.92) cohorts. We successfully established a circulating miRNA panel with remarkable diagnostic accuracy in the clinical training (AUC = 0.82) and validation (AUC = 0.81) cohorts. Moreover, the predictive accuracy of the panel was significantly superior to conventional clinical factors in both cohorts (P < .01) and the risk assessment model was superior (AUC = 0.83). Finally, we applied our model to detect patients with pathologic complete response and showed that it was dramatically superior to currently used pathologic features (AUC = 0.92). CONCLUSION: Our novel risk assessment signature for predicting response to PCRT has a potential for clinical translation as a liquid biopsy assay in patients with LARC.
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