KRAS wild-type pancreatic ductal adenocarcinoma: molecular pathology and therapeutic opportunities

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a deadly disease, whose main molecular trait is the MAPK pathway activation due to KRAS mutation, which is present in 90% of cases.The genetic landscape of KRAS wild type PDAC can be divided into three categories. The first is represented by tumors with an activated MAPK pathway due to BRAF mutation that occur in up to 4% of cases. The second includes tumors with microsatellite instability (MSI) due to defective DNA mismatch repair (dMMR), which occurs in about 2% of cases, also featuring a high tumor mutational burden. The third category is represented by tumors with kinase fusion genes, which marks about 4% of cases. While therapeutic molecular targeting of KRAS is an unresolved challenge, KRAS-wild type PDACs have potential options for tailored treatments, including BRAF antagonists and MAPK inhibitors for the first group, immunotherapy with anti-PD-1/PD-L1 agents for the MSI/dMMR group, and kinase inhibitors for the third group.This calls for a complementation of the histological diagnosis of PDAC with a routine determination of KRAS followed by a comprehensive molecular profiling of KRAS-negative cases.

Keywords: BRAF; KRAS; MSI; dMMR; fusion genes; pancreatic cancer.

Fig. 1

The genetic landscape of KRAS wild-type pancreatic ductal adenocarcinoma (PDAC) is shown. The vast majority of cases harbored KRAS mutations, but about 8–10% of cases show other molecular alterations, including microsatellite instability (MSI) – high tumor mutational burden (hTMB), kinase fusion genes, and activation of the MAPK pathway without KRAS involvement

Fig. 2

A schematic representation of the MAPK pathway is here shown. As highlighted, B-RAF is an immediately downstream of RAS and triggers MAP 2 K1/MEK, which activates MAPK1/ERK2, important mediators of the entire MAPK pathway. The overall effects include block of apoptosis, stress response and cell proliferation

Fig. 3

This is a classic example of a conventional pancreatic ductal adenocarcinoma (PDAC) with microsatellite instability, assessed by immunohistochemistry. a An infiltrating PDAC gland is centrally located on the left (arrow), and a normal endocrine islet is on the right (asterisk). Hematoxylin-Eosin staining, original magnification X10. b Loss of expression of the MMR protein MLH1 with immunohistochemistry. The infiltrating PDAC gland is totally negative (loss of protein expression), and the same time the endocrine cells of the islet are positive, as well as lymphocytes, endothelial and stromal cells in the periphery (the expression of the MMR proteins in non-neoplastic cells is used as an internal control demonstrating the reliability of the immunohistochemical analysis). Original magnification X10. c, d Conserved expression of the MMR proteins MSH2 (c) and MSH6 (d). Original magnification X10. e Loss of expression of the MMR protein PMS2 with immunohistochemistry. The infiltrating gland is totally negative (loss of expression), and the same time the endocrine cells of the islet as well as lymphocytes, endothelial and stromal cells in the periphery are positive. Original magnification X10