Karen Chiam1,2, George C Mayne2,3, David I Watson2,3, Richard J Woodman4, Tim F Bright2,3, Michael Z Michael3, Christos S Karapetis3, Tanya Irvine2,3, Wayne A Phillips5,6, Richard Hummel2,7, Tingting Wang2,3, Letitia K Pimlott3, Shashikanth Marri3, David StJ Astill8, Andrew R Ruszkiewicz9, Sarah K Thompson10, Damian J Hussey11,12. 1. Cancer Research Division, Cancer Council New South Wales, Sydney, Australia. 2. Discipline of Surgery, College of Medicine and Public Health, Flinders University of South Australia, Adelaide, SA, Australia. 3. Flinders Centre for Innovation in Cancer, College of Medicine and Public Health, Flinders University, Adelaide, SA, Australia. 4. Flinders Centre for Epidemiology and Biostatistics, College of Medicine and Public Health, Flinders University, Adelaide, SA, Australia. 5. Cancer Biology and Surgical Oncology Laboratory, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia. 6. Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, VIC, Australia. 7. Department of Surgery, University Hospital Schleswig-Holstein, Campus Lübeck, Lübeck, Germany. 8. Department of Anatomical Pathology, Flinders Medical Centre, Adelaide, SA, Australia. 9. Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, SA, Australia. 10. Department of Surgery, University of Adelaide, Royal Adelaide Hospital, Adelaide, SA, Australia. 11. Discipline of Surgery, College of Medicine and Public Health, Flinders University of South Australia, Adelaide, SA, Australia. damian.hussey@flinders.edu.au. 12. Flinders Centre for Innovation in Cancer, College of Medicine and Public Health, Flinders University, Adelaide, SA, Australia. damian.hussey@flinders.edu.au.
Abstract
BACKGROUND: Clinical trials report improved overall survival following neoadjuvant chemoradiotherapy in patients undergoing surgery for esophageal adenocarcinoma, with a 10-15% survival improvement. MicroRNAs (miRNAs) are small noncoding RNAs that are known to direct the behavior of cancers, including response to treatment. We investigated the ability of miRNAs to predict outcomes after neoadjuvant chemoradiotherapy. METHODS: Endoscopic biopsies from esophageal adenocarcinomas were obtained before neoadjuvant chemoradiotherapy and esophagectomy. miRNA levels were measured in the biopsies using next generation sequencing and compared with pathological response in the surgical resection, and subsequent survival. miRNA ratios that predicted pathological response were identified by Lasso regression and leave-one-out cross-validation. Association between miRNA ratio candidates and relapse-free survival was assessed using Kaplan-Meier analysis. Cox regression and Harrell's C analyses were performed to assess the predictive performance of the miRNAs. RESULTS: Two miRNA ratios (miR-4521/miR-340-5p and miR-101-3p/miR-451a) that predicted the pathological response to neoadjuvant chemoradiotherapy were found to be associated with relapse-free survival. Pretreatment expression of these two miRNA ratios, pretreatment tumor differentiation, posttreatment AJCC histopathological tumor regression grading, and posttreatment tumor clearance/margins were significant factors associated with survival in Cox regression analysis. Multivariate analysis of the two ratios together with pretherapy factors resulted in a risk prediction accuracy of 85% (Harrell's C), which was comparable with the prediction accuracy of the AJCC treatment response grading (77%). CONCLUSIONS: miRNA-ratio biomarkers identified using next generation sequencing can be used to predict disease free survival following neoadjuvant chemoradiotherapy and esophagectomy in patients with esophageal adenocarcinoma.
BACKGROUND: Clinical trials report improved overall survival following neoadjuvant chemoradiotherapy in patients undergoing surgery for esophageal adenocarcinoma, with a 10-15% survival improvement. MicroRNAs (miRNAs) are small noncoding RNAs that are known to direct the behavior of cancers, including response to treatment. We investigated the ability of miRNAs to predict outcomes after neoadjuvant chemoradiotherapy. METHODS: Endoscopic biopsies from esophageal adenocarcinomas were obtained before neoadjuvant chemoradiotherapy and esophagectomy. miRNA levels were measured in the biopsies using next generation sequencing and compared with pathological response in the surgical resection, and subsequent survival. miRNA ratios that predicted pathological response were identified by Lasso regression and leave-one-out cross-validation. Association between miRNA ratio candidates and relapse-free survival was assessed using Kaplan-Meier analysis. Cox regression and Harrell's C analyses were performed to assess the predictive performance of the miRNAs. RESULTS: Two miRNA ratios (miR-4521/miR-340-5p and miR-101-3p/miR-451a) that predicted the pathological response to neoadjuvant chemoradiotherapy were found to be associated with relapse-free survival. Pretreatment expression of these two miRNA ratios, pretreatment tumor differentiation, posttreatment AJCC histopathological tumor regression grading, and posttreatment tumor clearance/margins were significant factors associated with survival in Cox regression analysis. Multivariate analysis of the two ratios together with pretherapy factors resulted in a risk prediction accuracy of 85% (Harrell's C), which was comparable with the prediction accuracy of the AJCC treatment response grading (77%). CONCLUSIONS: miRNA-ratio biomarkers identified using next generation sequencing can be used to predict disease free survival following neoadjuvant chemoradiotherapy and esophagectomy in patients with esophageal adenocarcinoma.
Authors: Frederike Butz; Ann-Kathrin Eichelmann; George C Mayne; Tingting Wang; Isabell Bastian; Karen Chiam; Shashikanth Marri; Pamela J Sykes; Bas P Wijnhoven; Eelke Toxopeus; Michael Z Michael; Christos S Karapetis; Richard Hummel; David I Watson; Damian J Hussey Journal: Int J Mol Sci Date: 2020-11-24 Impact factor: 5.923
Authors: G C Mayne; C M Woods; N Dharmawardana; T Wang; S Krishnan; J C Hodge; A Foreman; S Boase; A S Carney; E A W Sigston; D I Watson; E H Ooi; D J Hussey Journal: J Transl Med Date: 2020-07-10 Impact factor: 5.531