The Impact of Molecular Subtyping on Pathological Staging of Pancreatic Cancer.

Stephan Dreyer ,Nigel B Jamieson,David K Chang,Andrew V Biankin,Antonio Pea,Alessandro Zerbi ,Roberto Salvia ,Kirsty Bisset ,Colin Mckay ,Aldo Scarpa ,Anubhav Mittal ,Amber Johns ,Fraser Duthie ,Rita T Lawlor ,Rosie Upstill-Goddard ,S Rae ,Georgios Gemenetzis ,Euan J Dickson ,Jaswinder S Samra ,Federica Marchesi ,Alessandra Pulvirenti ,Anthony J Gill

doi:10.1097/sla.0000000000005050

Abstract

The long-term outcomes following surgical resection for pancreatic ductal adenocarcinoma (PDAC) remains poor, with only 20% of patients surviving 5 years after pancreatectomy. Patient selection for surgery remains suboptimal largely due to the absence of consideration of aggressive tumor biology. The aim of this study was to evaluate traditional staging criteria for PDAC in the setting of molecular subtypes. Clinicopathological data were obtained for 5 independent cohorts of consecutive unselected patients, totaling n = 1298, including n = 442 that underwent molecular subtyping. The main outcome measure was disease-specific survival following surgical resection for PDAC stratified according to the American Joint Commission for Cancer (TNM) staging criteria, margin status, and molecular subtype. TNM staging criteria and margin status confers prognostic value only in tumors with classical pancreatic subtype. Patients with tumors that are of squamous subtype, have a poor outcome irrespective of favorable traditional pathological staging [hazard ratio (HR) 1.54, 95% confidence interval (CI) 1.04-2.28, P = 0.032]. Margin status has no impact on survival in the squamous subtype (16.0 vs 12.1 months, P = 0.374). There were no differences in molecular subtype or gene expression of tumors with positive resection margin status. Aggressive tumor biology as measured by molecular subtype predicts poor outcome following pancreatectomy for PDAC and should be utilized to inform patient selection for surgery.

Highlights

Pancreatic ductal adenocarcinoma (PDAC) has overtaken breast cancer as the 3rd most common cause of cancer related death in Western societies, and is predicted to be 2nd by 2025.1,2Transcriptomic molecular subtyping of PDAC has consistently identified a subgroup, termed squamous subtype, characterized by epigenetic changes that drive immune evasion and epithelial-to-mesenchymal transition as compared to the classical pancreatic subtype.[3,4,5] The distinct molecular features underpinning the squamous subtype is associated with aggressive tumor biology and a poorer outcome
Patients with tumors that are of squamous subtype, have a poor outcome irrespective of favorable traditional pathological staging (HR 1.54, 95%confidence intervals (CIs) 1.04 – 2.28, P = 0.032)
Pathological staging of resected PDAC has been enhanced through modifying the American Joint Commission for Cancer (AJCC) staging system (8th Edition),[7] and resection margin involvement is established as a powerful predictor of poor outcome.[8,9,10,11]

Summary

Introduction

Transcriptomic molecular subtyping of PDAC has consistently identified a subgroup, termed squamous ( known as basal) subtype, characterized by epigenetic changes that drive immune evasion and epithelial-to-mesenchymal transition as compared to the classical pancreatic subtype.[3,4,5] The distinct molecular features underpinning the squamous subtype is associated with aggressive tumor biology and a poorer outcome. Whilst these features may potentially provide novel targets for subtype-specific vulnerabilities and direct therapy for PDAC, they are not yet utilized clinically to inform prognosis.[3,6]. Patient selection for surgery remains sub-optimal largely due to the absence of consideration of aggressive tumor biology

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Results

Discussion

Conclusion