Identification of Novel Biomarkers in Pancreatic Tumor Tissue to Predict Response to Neoadjuvant Chemotherapy.

Sumit Sahni,Anthony J Gill,Viive M Howell,Anubhav Mittal,Stephen Clarke,Christopher Nahm,Mark P Molloy,David Chan,Christoph Krisp,Shreya Mehta,Malinda Itchins,Nick Pavlakis,Sarah Maloney,Jaswinder Samra

doi:10.3389/fonc.2020.00237

Abstract

Background: Neoadjuvant chemotherapy (NAC) has been of recent interest as an alternative to upfront surgery followed by adjuvant chemotherapy in patients with pancreatic ductal adenocarcinoma (PDAC). However, a subset of patients does not respond to NAC and may have been better managed by upfront surgery. Hence, there is an unmet need for accurate biomarkers for predicting NAC response in PDAC. We aimed to identify upregulated proteins in tumor tissue from poor- and good-NAC responders.Methods: Tumor and adjacent pancreas tissue samples were obtained following surgical resection from NAC-treated PDAC patients. SWATH-MS proteomic analysis was performed to identify and quantify proteins in tissue samples. Statistical analysis was performed to identify biomarkers for NAC response. Pathway analysis was performed to characterize affected canonical pathways in good- and poor-NAC responders.Results: A total of 3,156 proteins were identified, with 19 being were significantly upregulated in poor-responders compared to good-responders (log2 ratio > 2, p < 0.05). Those with the greatest ability to predict poor-NAC response were GRP78, CADM1, PGES2, and RUXF. Notably, canonical pathways that were significantly upregulated in good-responders included acute phase signaling and macrophage activation, indicating a heightened immune response in these patients.Conclusion: A novel biomarker signature for poor-NAC response in PDAC was identified.

Highlights

Pancreatic ductal adenocarcinoma (PDAC) has the lowest survival rate of all major cancers (∼6% at 5 years post-diagnosis) and is projected to become the second most common cause of cancer related death by 2030 [1, 2]
Neoadjuvant chemotherapy (NAC) has been of recent interest as an alternative to upfront surgery followed by adjuvant chemotherapy in patients with pancreatic ductal adenocarcinoma (PDAC)
The patients were divided on the basis of their response to neoadjuvant chemotherapy (NAC), which was determined by the residual tumor viability in the specimen

Summary

Introduction

Pancreatic ductal adenocarcinoma (PDAC) has the lowest survival rate of all major cancers (∼6% at 5 years post-diagnosis) and is projected to become the second most common cause of cancer related death by 2030 [1, 2]. Adjuvant chemotherapy in patients with resected PDAC has been shown to extend survival over surgery alone, and more recently, more intensive regimens such as FOLFIRONOX have been shown to be even more effective [4]. There is a need for discovering more readily applicable tissue and/or blood-based secreted biomarkers that can predict a NAC response, which may be detected by more cost-effective tests. Neoadjuvant chemotherapy (NAC) has been of recent interest as an alternative to upfront surgery followed by adjuvant chemotherapy in patients with pancreatic ductal adenocarcinoma (PDAC). A subset of patients does not respond to NAC and may have been better managed by upfront surgery. We aimed to identify upregulated proteins in tumor tissue from poor- and good-NAC responders

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Methods

Results

Discussion

Conclusion