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Article

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

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Department of Radiation Oncology, Emory University Winship Cancer Institute, 1365 Clifton Rd, Atlanta, GA 30322, USA
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Department of Biomedical Informatics, The Ohio State University College of Medicine, 320 Lincoln Tower, 1800 Cannon Drive, Columbus, OH 43210, USA
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Department of Radiation Oncology, Mayo Clinic, 200 First St SW, Rochester, MN 55090, USA
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Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, 1400 Pressler St, Houston, TX 77030, USA
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Department of Radiation Oncology, The Winthrop P. Rockefeller Cancer Institute, The University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA
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Division of Anatomic Pathology, Mayo Clinic, 200 First St SW, Rochester, MN 55905, USA
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Department of Radiation Oncology, UPMC Hillman Cancer Center-Shadyside, 55230 Centre Ave, Pittsburgh, PA 15232, USA
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Department of Pathology, University of North Carolina, Chapel Hill, NC 27599, USA
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Department of Pathology, The Ohio State University, 450 W. 10th Ave, Columbus, OH 43210, USA
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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
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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
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Department of Radiation Oncology, City of Hope National Medical Center, 1500 E. Duarte Rd, Duarte, CA 91010, USA
*
Author to whom correspondence should be addressed.
Academic Editor: Julien Taieb
Cancers 2021, 13(20), 5168; https://doi.org/10.3390/cancers13205168
Received: 19 August 2021 / Revised: 30 September 2021 / Accepted: 6 October 2021 / Published: 15 October 2021
(This article belongs to the Section Cancer Biomarkers)
Optimal patient selection for radiotherapy in pancreatic cancer is unestablished and may be improved with molecular profiling. To this end, we developed and validated a microRNA signature that predicted for worse locoregional recurrence and overall survival in patients with resectable pancreatic cancer. In a separate cohort of patients with borderline resectable and locally advanced pancreatic cancer, this risk signature was also predictive of worse locoregional recurrence, distant recurrence, and overall survival. Additionally, borderline resectable or locally advanced patients who had high risk score and did not receive radiation had worse outcomes compared to patients who either had low risk score or received radiation, irrespective of risk score. This risk signature may be useful in assessing patient prognosis and tailor therapy in patients with resectable, borderline resectable, or locally advanced pancreatic cancer, but requires further study.
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. View Full-Text
Keywords: pancreatic cancer; microRNA; locoregional recurrence; local recurrence; adjuvant radiation; neoadjuvant radiation pancreatic cancer; microRNA; locoregional recurrence; local recurrence; adjuvant radiation; neoadjuvant radiation
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MDPI and ACS Style

Sebastian, N.T.; Webb, A.; Merrell, K.W.; Koay, E.J.; Wolfe, A.R.; Zhang, L.; Wilhite, T.J.; Elganainy, D.; Robb, R.; Chen, W.; Cloyd, J.; Dillhoff, M.; Tsung, A.; Abushahin, L.; Noonan, A.; Williams, T.M. Development of a MicroRNA Signature Predictive of Recurrence and Survival in Pancreatic Ductal Adenocarcinoma. Cancers 2021, 13, 5168. https://doi.org/10.3390/cancers13205168

AMA Style

Sebastian NT, Webb A, Merrell KW, Koay EJ, Wolfe AR, Zhang L, Wilhite TJ, Elganainy D, Robb R, Chen W, Cloyd J, Dillhoff M, Tsung A, Abushahin L, Noonan A, Williams TM. Development of a MicroRNA Signature Predictive of Recurrence and Survival in Pancreatic Ductal Adenocarcinoma. Cancers. 2021; 13(20):5168. https://doi.org/10.3390/cancers13205168

Chicago/Turabian Style

Sebastian, Nikhil T., 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, and Terence M. Williams. 2021. "Development of a MicroRNA Signature Predictive of Recurrence and Survival in Pancreatic Ductal Adenocarcinoma" Cancers 13, no. 20: 5168. https://doi.org/10.3390/cancers13205168

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