Advances in Molecular Profiling and Categorisation of Pancreatic Adenocarcinoma and the Implications for Therapy.

Rille Pihlak,Juan W Valle,Jamie M J Weaver,Mairéad G Mcnamara

doi:10.3390/cancers10010017

Rille Pihlak, Juan W Valle + Show 2 more

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https://doi.org/10.3390/cancers10010017

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Abstract

Pancreatic ductal adenocarcinoma (PDAC) continues to be a disease with poor outcomes and short-lived treatment responses. New information is emerging from genome sequencing identifying potential subgroups based on somatic and germline mutations. A variety of different mutations and mutational signatures have been identified; the driver mutation in around 93% of PDAC is KRAS, with other recorded alterations being SMAD4 and CDKN2A. Mutations in the deoxyribonucleic acid (DNA) damage repair pathway have also been investigated in PDAC and multiple clinical trials are ongoing with DNA-damaging agents. Rare mutations in BRAF and microsatellite instability (MSI) have been reported in about 1–3% of patients with PDAC, and agents used in other cancers to target these have also shown some promise. Immunotherapy is a developing field, but has failed to demonstrate benefits in PDAC to date. While many trials have failed to improve outcomes in this deadly disease, there is optimism that by developing a better understanding of the translational aspects of this cancer, future informed therapeutic strategies may prove more successful.

Highlights

Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers [1] with a five-year overall survival (OS) for all stages of around 8% in the United States (US) [2] and 3% in the UnitedKingdom (UK) [3]
This review aims to interrogate the novel mutations and signatures identified in PDAC and assess their potential clinical significance for the treatment of patients
microsatellite instability (MSI) is rare in PDAC, there have been promising results in studies of novel treatments with immunotherapy in solid tumours [22,86], and mutational testing for this deficiency in PDAC could be considered

Summary

Introduction

Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers [1] with a five-year overall survival (OS) for all stages of around 8% in the United States (US) [2] and 3% in the UnitedKingdom (UK) [3]. Even in patients who had potentially curative surgery followed by adjuvant chemotherapy with gemcitabine and capecitabine, the five-year OS was still only 28.8% in the recently reported phase III randomised ESPAC-4 trial [4]. Combination chemotherapy trials in patients with advanced PDAC have been the only studies which reported clinically meaningful significant extensions in median OS in the recent decade. The combination of 5-fluorouracil, oxaliplatin, irinotecan and leucovorin (FOLFIRINOX) from the ACCORD trial has resulted in the longest-reported OS for patients with metastatic PDAC; median OS was 11.1 months compared to 6.8 months with single-agent gemcitabine [5]. Multiple other clinical trials with either chemotherapy combinations or novel agents have failed to demonstrate a significant OS improvement [7,8,9,10]. Due to poor prognosis and very little improvement in survival, PDAC is a major cause of cancer death and it is estimated that it will become the 2nd leading cause of cancer-related death in the US by 2030 [11], being 3rd [2] and 5th [3] currently in the US and UK, respectively

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