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

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.

Keywords: clinical implications; molecular profiling; mutations; pancreatic adenocarcinoma.

Figure 1

Prevalence of potentially targetable mutations in PDAC. KRAS—KRAS proto-oncogene, GTPase [33,35]; TP53—tumour protein p53 [59]; SMAD4—SMAD Family Member 4 [19,67]; DDR—DNA damage repair pathway mutations [18,19]; CDKN2A—cyclin-dependent kinase inhibitor 2A [12,75]; RNF43—ring finger protein 43 [19,24]; BRAF B-Raf proto-oncogene, serine/threonine kinase [82]; MSI—microsatellite instability [84]. Dark colour signifies minimal range of mutation reported, while lighter shade signifies maximum range of mutation reported within different references.