Molecular targets for diagnostic and intraoperative imaging of pancreatic ductal adenocarcinoma after neoadjuvant FOLFIRINOX treatment

F A Vuijk,B A Bonsing,L D A N De Muynck,M G Besselink,P J K Kuppen,A L Vahrmeijer,O R Busch,J W Wilmink,A Fariňa-Sarasqueta,R J Swijnenburg,L C Franken,J Verheij,C F M Sier,J S D Mieog,S S Bhairosingh

doi:10.1038/s41598-020-73242-6

Abstract

Neoadjuvant systemic treatment is increasingly being integrated in the standard treatment of pancreatic ductal adenocarcinoma (PDAC) patients to improve oncological outcomes. Current available imaging techniques remain unreliable in assessing response to therapies, as they cannot distinguish between (vital) tumor tissue and therapy induced fibrosis (TIF). Consequently, resections with tumor positive margins and subsequent early post-operative recurrences occur and patients eligible for potential radical resection could be missed. To optimize patient selection and monitor results of neoadjuvant treatment, PDAC-specific diagnostic and intraoperative molecular imaging methods are required. This study aims to evaluate molecular imaging targets for PDAC after neoadjuvant FOLFIRINOX treatment. Expression of integrin αvβ6, carcinoembryonic antigen cell adhesion molecule 5 (CEACAM5), mesothelin, prostate-specific membrane antigen (PSMA), urokinase-type plasminogen activator receptor, fibroblast activating receptor, integrin α5 subunit and epidermal growth factor receptor was evaluated using immunohistochemistry. Immunoreactivity was determined using the semiquantitative H-score. Resection specimens from patients after neoadjuvant FOLFIRINOX treatment containing PDAC (n = 32), tumor associated pancreatitis (TAP) and TIF (n = 15), normal pancreas parenchyma (NPP) (n = 32) and tumor positive (n = 24) and negative (n = 56) lymph nodes were included. Integrin αvβ6, CEACAM5, mesothelin and PSMA stainings showed significantly higher expression in PDAC compared to TAP and NPP. No expression of αvβ6, CEACAM5 and mesothelin was observed in TIF. Integrin αvβ6 and CEACAM5 allow for accurate metastatic lymph node detection. Targeting integrin αvβ6, CEA, mesothelin and PSMA has the potential to distinguish vital PDAC from fibrotic tissue after neoadjuvant FOLFIRINOX treatment. Integrin αvβ6 and CEACAM5 detect primary tumors and tumor positive lymph nodes.

Highlights

Pancreatic ductal adenocarcinoma (PDAC) is a devastating malignancy with a five year survival rate of merely 7–9%1
This study aims to evaluate the immunohistochemical expression of potential molecular imaging targets integrin αvβ[6], carcinoembryonic antigen cell adhesion molecule 5 (CEACAM5), mesothelin, prostate-specific membrane antigen (PSMA), urokinase-type plasminogen activator receptor (uPAR), fibroblast activation protein alpha (FAP), ITGA5 and epidermal growth factor receptor (EGFR) for the identification of vital residual pancreatic ductal adenocarcinoma (PDAC) and metastatic lymph nodes after neoadjuvant FOLFIRINOX treatment[13,14,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37]
No expression of integrin αvβ[6], CEACAM5 and mesothelin was observed in fibrotic tissue, indicating these are potentially suitable targets for vital cancer cell identification after neoadjuvant therapy

Summary

Introduction

Pancreatic ductal adenocarcinoma (PDAC) is a devastating malignancy with a five year survival rate of merely 7–9%1. NIRF imaging is a relatively novel technique that can be used during surgery to discriminate malignant from benign tissue in real time[11], whereas tumor-specific PET-CT may contribute to improved surgical planning, stratification and diagnosis as well as therapy response monitoring after neoadjuvant treatment. Both modalities exploit tumor-specific tracers (either labeled with a fluorescent protein or radioisotope), targeting biomarkers abundantly present on tumor tissue and absent on (or minimally expressed by) benign or inflamed tissue. In addition to CEACAM5 and integrin αvβ[6], the overexpression of m esothelin[17,18,19,20,21,22,23], prostate-specific membrane antigen (PSMA)[24,25,26,27,28], urokinase-type plasminogen activator receptor (uPAR)[13,29,30,31], fibroblast activation protein alpha (FAP)[32,33,34], integrin subunit α5 (ITGA5)[35] and epidermal growth factor receptor (EGFR) has been described in PDAC tissue, suggesting their candidacy as imaging targets for PDAC

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Conclusion