Are targeted therapies or immunotherapies effective in metastatic pancreatic adenocarcinoma?

Abstract

Metastatic pancreatic ductal adenocarcinoma (PDAC) is a major health burden due to its increasing incidence and poor prognosis. PDAC is characterized by a low tumor mutational burden, and its molecular pathogenesis is driven by Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations. Response to DNA damage through homologous repair is defective in 15% of tumors. Chemotherapy using FOLFIRINOX (folinic acid, fluorouracil, irinotecan, oxaliplatin) or gemcitabine-nab-paclitaxel significantly improves life expectancy, but the median overall survival remains <1 year. Targeted therapies are not efficient in the overall population of patients with metastatic PDAC. Improvements in overall survival or progression-free survival, however, have been demonstrated in subgroups carrying certain mutations. Maintenance therapy with poly-ADP-ribose polymerase (PARP) inhibitors increases progression-free survival in patients with germline mutations in BRCA1/2. Sotorasib shows signs of efficacy against tumors carrying the KRAS G12C mutation, and targeted therapies may also benefit patients with KRAS-wild-type PDAC. Combining targeted therapies with chemotherapy holds promise because of potential synergistic effects. These associations, however, have not yet demonstrated clinical benefit. Checkpoint inhibitors are not effective against metastatic PDAC. Combined immunotherapies attempt to restore their efficacy but have not succeeded yet. Other immunotherapies are emerging such as therapeutic vaccines or chimeric antigen receptor (CAR) T cells, but these strategies remain to be evaluated in large trials. In the future, treatment personalization based on tumor-derived organoids could potentially further improve treatment efficiency.

Keywords: immunotherapy; pancreatic adenocarcinoma; precision oncology; targeted therapies.

Figure 1

Signaling pathways and cellular processes involved in the pathogenesis of PDAC. For each signaling pathway, genes frequently mutated in PDACs are listed. MAP, mitogen-activated protein; PDAC, pancreatic ductal adenocarcinoma; PI3K, phosphoinositide-3-kinase; TGF-β; transforming growth factor-β.

Figure 2

Interplay between DNA damage response and cell cycle control in PDAC. This figure shows the main signaling pathways involved in DNA damage response, and how they connect with cell cycle checkpoints. Genes frequently mutated in PDAC are written in italics. Targeted therapies and chemotherapies currently evaluated in PDAC are depicted, together with their molecular targets. CDK, cyclin-dependent kinase; NHEJ, non-homologous end joining; PARP, poly-ADP-ribose polymerase; PDAC, pancreatic ductal adenocarcinoma.