Development of a MicroRNA Signature Predictive of Recurrence and Survival in Pancreatic Ductal Adenocarcinoma

• Type of Material: Article
• Authors: Amy Girard, Emory University; Nikhil Sebastian, Emory University; Amy Webb, Ohio State University; Kenneth W Merrell, Mayo Clinic; Eugene J Koay, Univ Texas MD Anderson Canc Ctr; Adam R Wolfe, University of Arkansas Medical Sciences; Lizhi Zhang, Mayo Clinic; Tyler J Wilhite, UPMC Hillman Canc Ctr Shadyside; Dalia Elganainy, The University of Texas MD Anderson Cancer Center; Ryan Robb, University of North Carolina; Wei Chen, Ohio State University; Jordan Cloyd, Ohio State University; Mary Dillhoff, Ohio State University; Allan Tsung, Ohio State University; Laith Abushahin, The Ohio State University Comprehensive Cancer Center; Anne Noonan, The Ohio State University Comprehensive Cancer Center; Terence M Williams, City of Hope National Medical Center
• Language: English
• Date: 2021-10-01
• Publisher: MDPI
• Publication Version: Final Published Version
• Copyright Statement: © 2021 by the authors.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.3390/cancers13205168
• Title of Journal or Parent Work: CANCERS
• Volume: 13
• Issue: 20
• Grant/Funding Information: This work was supported by the following grants: Radiation Oncology Institute Grant (ROI) 2019-913 (T.W./A.W.) and NIH grant R01 CA198128 (TW). Research was also supported through the OSU Gastrointestinal Cancer Research Development fund. Research reported in this article was also supported by The Ohio State University Comprehensive Cancer Center (OSU-CCC) and National Institute of Health (P30 CA016058). Radiation Oncology Institute Grant (ROI) 2019-913 (T.M.W./A.W.).
• Keywords: RADIATION; microRNA; PHASE-III TRIAL; GEMCITABINE RESISTANCE; locoregional recurrence; neoadjuvant radiation; ADJUVANT CHEMORADIATION; PROSPECTIVE VALIDATION; Life Sciences & Biomedicine; EXPRESSION; Oncology; CHEMORADIOTHERAPY; CANCER; CHEMOTHERAPY; adjuvant radiation; local recurrence; Science & Technology; pancreatic cancer; PLUS RADIOTHERAPY
• Research Categories: Health Sciences, Oncology

Abstract

Background: Optimal patient selection for radiotherapy in pancreatic ductal adenocarcinoma (PDAC) is unestablished. Molecular profiling may select patients at high risk for locoregional recurrence (LRR) who would benefit from radiation. Methods: We included resectable pancreatic cancer (R-PDAC) patients, divided into training and validation cohorts, treated among three insti-tutions with surgery and adjuvant chemotherapy, and borderline resectable or locally advanced pancreatic cancer (BR/LA-PDAC) patients treated with chemotherapy with or without radiation at the primary study institution. We isolated RNA from R-PDAC surgical specimens. Using NanoS-tring, we identified miRNAs differentially expressed between normal and malignant pancreatic tissue. ElasticNet regression identified two miRNAs most predictive of LRR in the training co-hort, miR-181b/d and miR-575, which were used to generate a risk score (RS). We evaluated the association of the median-dichotomized RS with recurrence and overall survival (OS). Results: We identified 183 R-PDAC and 77 BR/LA-PDAC patients with median follow up of 37 months treated between 2001 and 2014. On multivariable analysis of the R-PDAC training cohort (n = 90), RS was associated with worse LRR (HR = 1.34; 95%CI 1.27–11.38; p = 0.017) and OS (HR = 2.89; 95%CI 1.10–4.76; p = 0.027). In the R-PDAC validation cohort, RS was associated with worse LRR (HR = 2.39; 95%CI 1.03–5.54; p = 0.042), but not OS (p = 0.087). For BR/LA-PDAC, RS was associated with worse LRR (HR = 2.71; 95%CI 1.14–6.48; p = 0.025), DR (HR = 1.93; 95%CI 1.10–3.38; p = 0.022), and OS (HR = 1.97; 95%CI 1.17–3.34; p = 0.011). Additionally, after stratifying by RS and receipt of radiation in BR/LA-PDAC patients, high RS patients who did not receive radiation had worse LRR (p = 0.018), DR (p = 0.006), and OS (p < 0.001) compared to patients with either low RS or patients who received radiation, irrespective of RS. Conclusions: RS predicted worse LRR and OS in R-PDAC and worse LRR, DR, and OS in BR/LA-PDAC. This may select patients who would benefit from radiation and should be validated prospectively.