Updates on molecular targets and clinical trials with targeted therapies for pancreatic cancer.

Abstract

Pancreatic ductal adenocarcinoma (PDA) is highly aggressive and has few treatment options. To personalize therapy, it is critical to delineate molecular subtypes and understand inter- and intra-tumoral heterogeneity. KRAS mutations are present in 90 % of PDA, while 10 % are KRAS wild type and are potentially targetable with epidermal growth factor receptor (EGFR) blockade. KRAS^G12C inhibitors have shown activity in G12C mutated cancers, and novel G12D and pan-RAS inhibitors are in clinical trials. Fewer than 1 % of PDA harbor microsatellite instability high (MSI-High) status and are susceptible to immune checkpoint blockade. Albeit rare, and occurring in KRAS wild type PDAs, BRAF V600E mutations, HER2 amplification, and RET, NTRK, and NRG1 fusions are targetable with cancer agnostic FDA approved therapies. In this review, we highlight clinically relevant molecular alterations and clinical trials with focus on targeted therapies that can improve pancreatic cancer patients' outcomes through precision medicine.