Clinical Impact of Molecular Subtyping of Pancreatic Cancer.

Xu Zhou,Teresa Peccerella,Thilo Hackert,Malte Buchholz,Susanne Roth,Kai Hu,Markus W Büchler,Christoph Springfeld,Peter Bailey,Kongyuan Wei,Jingyu An,John P Neoptolemos,Benedikt Brors,Thomas Gress,Roma Kurilov

doi:10.3389/fcell.2021.743908

Abstract

Pancreatic ductal adenocarcinoma is a highly lethal malignancy, which has now become the seventh most common cause of cancer death in the world, with the highest mortality rates in Europe and North America. In the past 30 years, there has been some progress in 5-year survival (rates increasing from 2.5 to 10%), but this is still extremely poor compared to all other common cancer types. Targeted therapies for advanced pancreatic cancer based on actionable mutations have been disappointing, with only 3–5% showing even a short clinical benefit. There is, however, a molecular diversity beyond mutations in genes responsible for producing classical canonical signaling pathways. Pancreatic cancer is almost unique in promoting an excess production of other components of the stroma, resulting in a complex tumor microenvironment that contributes to tumor development, progression, and response to treatment. Various transcriptional subtypes have also been described. Most notably, there is a strong alignment between the Classical/Pancreatic progenitor and Quasi-mesenchymal/Basal-like/Squamous subtype signatures of Moffit, Collinson, Bailey, Puleo, and Chan-Seng-Yue, which have potential clinical impact. Sequencing of epithelial cell populations enriched by laser capture microscopy combined with single-cell RNA sequencing has revealed the potential genomic evolution of pancreatic cancer as being a consequence of a gene expression continuum from mixed Basal-like and Classical cell populations within the same tumor, linked to allelic imbalances in mutant KRAS, with metastatic tumors being more copy number-unstable compared to primary tumors. The Basal-like subtype appears more chemoresistant with reduced survival compared to the Classical subtype. Chemotherapy and/or chemoradiation will also enrich the Basal-like subtype. Squamous/Basal-like programs facilitate immune infiltration compared with the Classical-like programs. The immune infiltrates associated with Basal and Classical type cells are distinct, potentially opening the door to differential strategies. Single-cell and spatial transcriptomics will now allow single cell profiling of tumor and resident immune cell populations that may further advance subtyping. Multiple clinical trials have been launched based on transcriptomic response signatures and molecular subtyping including COMPASS, Precision Promise, ESPAC6/7, PREDICT-PACA, and PASS1. We review several approaches to explore the clinical relevance of molecular profiling to provide optimal bench-to-beside translation with clinical impact.

Highlights

Pancreatic ductal adenocarcinoma (PDAC), a distinct form of pancreatic cancer, remains a major oncological challenge (Kleeff et al, 2016)
Olaparib – a PARP inhibitor as maintenance therapy in patients who have a germline BRCA1 or BRCA2 mutation and with metastatic pancreatic cancer that had not progressed during first-line platinum-based chemotherapy, resulting in improved progression-free survival
It is estimated that 24% of all pancreatic cancers may be sensitive to platinum therapy based on an unstable genomic structural variation subtype, and/or somatic and germline mutations in BRCA genes, and/or a BRCA-type mutational signature (Waddell et al, 2015)

Summary

INTRODUCTION

Pancreatic ductal adenocarcinoma (PDAC), a distinct form of pancreatic cancer, remains a major oncological challenge (Kleeff et al, 2016). Olaparib – a PARP inhibitor as maintenance therapy in patients who have a germline BRCA1 or BRCA2 mutation and with metastatic pancreatic cancer that had not progressed during first-line platinum-based chemotherapy, resulting in improved progression-free survival. It is estimated that 24% of all pancreatic cancers may be sensitive to platinum therapy based on an unstable genomic structural variation subtype, and/or somatic and germline mutations in BRCA genes, and/or a BRCA-type mutational signature (Waddell et al, 2015). Moffitt et al (2015) used a diverse collection of pancreatic gene expression microarray data, including normal pancreata samples as well as primary and metastatic cancer samples, to identify two tumor-specific subtypes as well as additional stromal Normal and Activated subtypes which were independently prognostic. Bailey et al (2016) described four subtypes using samples with >40% cellularity from resectable primary pancreatic cancer, based on differential transcription factor expression and downstream targets responsible for lineage specification and differentiation during development and regeneration

Methodology WGS

Findings

Methodology