Clinical Impact of Molecular Subtyping of Pancreatic Cancer

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.

Establishment of a reference single-cell RNA sequencing dataset for human pancreatic adenocarcinoma

“…Yue et al, 2020;Dijk et al, 2020;Martens et al, 2019;Rashid et al, 2020). However, this will yield a future diagnostic tool for personalized medicine (Froeling et al, 2021;Xu et al, 2021). As an advantage of scRNAseq, tumor subtypes could be determined at the cellular resolution and revealed the presence of intra-tumoral heterogeneity.…”

Single Cell RNA Sequencing: A New Frontier in Pancreatic Ductal Adenocarcinoma

“…Instead, it becomes imperative to create highly personalized treatment schemes for these patients, targeted therapies homing in on the specific molecular mechanisms driving tumor progression in each case. To this end, various researchers have called for the implementation of molecular subtyping using transcriptomic techniques—scRNA-seq in particular—in clinical trials [ 72 , 73 , 74 ]. Others still recommend profiling the tumor tissue of all patients coming in with PDAC [ 75 ] with the recent National Comprehensive Cancer Network (NCCN) guidelines for PDAC strongly recommending molecular tumor analysis [ 64 ].…”

“…Moreover, molecular technologies continue to improve to overcome whatever challenges arise, with novel approaches showing promise in stratifying patient response to treatment in many tumor types [ 72 ]. As for pancreatic cancer, several groups have developed informatics designs that purport to identify and stratify patients into clinically actionable subtypes [ 74 ] accurately; these have yet to be assessed in clinical trials. Nonetheless, these numerous studies have shown the feasibility of incorporating molecular analysis into current clinical practice to screen patients and assign them to matched chemotherapy treatments, at least within the United States [ 72 ].…”

Deconstructing Pancreatic Cancer Using Next Generation-Omic Technologies–From Discovery to Knowledge-Guided Platforms for Better Patient Management

“…The recent identification of intrinsic transcriptomic subtypes of PDAC provides an alternative strategy for patient treatment selection–reviewed in depth by Xu Z et al (2021) . Transcriptomic profiling has identified 2 broad intrinsic PDAC classes, namely Classical and Basal-like with Basal-like tumours associated with significantly poorer outcomes and late-stage disease ( Moffitt et al, 2015 ; Collisson et al, 2019 ).…”