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

Nikhil T Sebastian; Amy Webb; Kenneth W Merrell; Eugene J Koay; Adam R Wolfe; Lizhi Zhang; Tyler J Wilhite; Dalia Elganainy; Ryan Robb; Wei Chen; Jordan Cloyd; Mary Dillhoff; Allan Tsung; Laith Abushahin; Anne Noonan; Terence M Williams

doi:10.3390/cancers13205168

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

Cancers (Basel). 2021 Oct 15;13(20):5168. doi: 10.3390/cancers13205168.

Authors

Nikhil T Sebastian¹, Amy Webb², Kenneth W Merrell³, Eugene J Koay⁴, Adam R Wolfe⁵, Lizhi Zhang⁶, Tyler J Wilhite⁷, Dalia Elganainy⁴, Ryan Robb⁸, Wei Chen⁹, Jordan Cloyd¹⁰, Mary Dillhoff¹⁰, Allan Tsung¹⁰, Laith Abushahin¹¹, Anne Noonan¹¹, Terence M Williams¹²

Affiliations

¹ Department of Radiation Oncology, Emory University Winship Cancer Institute, 1365 Clifton Rd, Atlanta, GA 30322, USA.
² Department of Biomedical Informatics, The Ohio State University College of Medicine, 320 Lincoln Tower, 1800 Cannon Drive, Columbus, OH 43210, USA.
³ Department of Radiation Oncology, Mayo Clinic, 200 First St SW, Rochester, MN 55090, USA.
⁴ Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, 1400 Pressler St, Houston, TX 77030, USA.
⁵ Department of Radiation Oncology, The Winthrop P. Rockefeller Cancer Institute, The University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.
⁶ Division of Anatomic Pathology, Mayo Clinic, 200 First St SW, Rochester, MN 55905, USA.
⁷ Department of Radiation Oncology, UPMC Hillman Cancer Center-Shadyside, 55230 Centre Ave, Pittsburgh, PA 15232, USA.
⁸ Department of Pathology, University of North Carolina, Chapel Hill, NC 27599, USA.
⁹ Department of Pathology, The Ohio State University, 450 W. 10th Ave, Columbus, OH 43210, USA.
¹⁰ Division of Surgical Oncology, Department of Surgery, The Ohio State University Comprehensive Cancer Center-Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, 460 W. 10th Ave, Columbus, OH 43210, USA.
¹¹ Division of Medical Oncology, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center-Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, 460 W. 10th Ave, Columbus, OH 43210, USA.
¹² Department of Radiation Oncology, City of Hope National Medical Center, 1500 E. Duarte Rd, Duarte, CA 91010, USA.

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 institutions 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 NanoString, we identified miRNAs differentially expressed between normal and malignant pancreatic tissue. ElasticNet regression identified two miRNAs most predictive of LRR in the training cohort, 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.

Keywords: adjuvant radiation; local recurrence; locoregional recurrence; microRNA; neoadjuvant radiation; pancreatic cancer.

Abstract

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