ctDNA whole exome sequencing in pancreatic ductal adenocarcinoma unveils organ-dependent metastatic mechanisms and identifies actionable alterations in fast progressing patients

Transl Res. 2024 Sep:271:105-115. doi: 10.1016/j.trsl.2024.05.003. Epub 2024 May 21.

Abstract

Understanding progression mechanisms and developing new targeted therapies is imperative in pancreatic ductal adenocarcinoma (PDAC). In this study, 80 metastatic PDAC patients were prospectively recruited and divided into discovery (n=37) and validation (n=43) cohorts. Tumor and plasma samples taken at diagnosis were pair analyzed using whole exome sequencing (WES) in patients belonging to the discovery cohort alone. The variant allele frequency (VAF) of KRAS mutations was measured by ddPCR in plasma at baseline and response assessment in all patients. Plasma WES identified at least one pathogenic variant across the cohort, uncovering oncogenic mechanisms, DNA repair, microsatellite instability, and alterations in the TGFb pathway. Interestingly, actionable mutations were mostly found in plasma rather than tissue. Patients with shorter survival showed enrichment in cellular organization regulatory pathways. Through WES we could identify a specific molecular profile of patients with liver metastasis, which exhibited exclusive mutations in genes related to the adaptive immune response pathway, highlighting the importance of the immune system in liver metastasis development. Moreover, KRAS mutations in plasma (both at diagnosis and persistent at follow-up) correlated with shorter progression free survival (PFS). Patients presenting a reduction of over 84.75 % in KRAS VAF at response assessment had similar PFS to KRAS-negative patients. Overall, plasma WES reveals molecular profiles indicative of rapid progression, potentially actionable targets, and associations between adaptive immune response pathway alterations and liver tropism.

Keywords: Organ tropism; Pancreatic adenocarcinoma; Targeted therapy; WES; ctDNA.

MeSH terms

  • Adult
  • Aged
  • Carcinoma, Pancreatic Ductal* / genetics
  • Carcinoma, Pancreatic Ductal* / mortality
  • Carcinoma, Pancreatic Ductal* / pathology
  • Carcinoma, Pancreatic Ductal* / secondary
  • Circulating Tumor DNA* / blood
  • Circulating Tumor DNA* / genetics
  • Disease Progression*
  • Exome Sequencing*
  • Female
  • Humans
  • Male
  • Middle Aged
  • Mutation
  • Neoplasm Metastasis
  • Pancreatic Neoplasms* / genetics
  • Pancreatic Neoplasms* / pathology
  • Proto-Oncogene Proteins p21(ras) / genetics

Substances

  • Circulating Tumor DNA
  • Proto-Oncogene Proteins p21(ras)
  • KRAS protein, human