Establishment of a pancreatic adenocarcinoma molecular gradient (PAMG) that predicts the clinical outcome of pancreatic cancer

EBioMedicine. 2020 Jul;57:102858. doi: 10.1016/j.ebiom.2020.102858. Epub 2020 Jul 3.

Abstract

Background: A significant gap in pancreatic ductal adenocarcinoma (PDAC) patient's care is the lack of molecular parameters characterizing tumours and allowing a personalized treatment.

Methods: Patient-derived xenografts (PDX) were obtained from 76 consecutive PDAC and classified according to their histology into five groups. A PDAC molecular gradient (PAMG) was constructed from PDX transcriptomes recapitulating the five histological groups along a continuous gradient. The prognostic and predictive value for PMAG was evaluated in: i/ two independent series (n = 598) of resected tumours; ii/ 60 advanced tumours obtained by diagnostic EUS-guided biopsy needle flushing and iii/ on 28 biopsies from mFOLFIRINOX treated metastatic tumours.

Findings: A unique transcriptomic signature (PAGM) was generated with significant and independent prognostic value. PAMG significantly improves the characterization of PDAC heterogeneity compared to non-overlapping classifications as validated in 4 independent series of tumours (e.g. 308 consecutive resected PDAC, uHR=0.321 95% CI [0.207-0.5] and 60 locally-advanced or metastatic PDAC, uHR=0.308 95% CI [0.113-0.836]). The PAMG signature is also associated with progression under mFOLFIRINOX treatment (Pearson correlation to tumour response: -0.67, p-value < 0.001).

Interpretation: PAMG unify all PDAC pre-existing classifications inducing a shift in the actual paradigm of binary classifications towards a better characterization in a gradient.

Funding: Project funding was provided by INCa (Grants number 2018-078 and 2018-079, BACAP BCB INCa_6294), Canceropole PACA, DGOS (labellisation SIRIC), Amidex Foundation, Fondation de France, INSERM and Ligue Contre le Cancer.

Keywords: Chemosensitivity prediction; Pancreatic cancer; Precision medicine; Prognostic; Transcriptomic signature; Translational medicine.

MeSH terms

  • Adenocarcinoma / diagnosis*
  • Adenocarcinoma / genetics
  • Adenocarcinoma / pathology
  • Adolescent
  • Adult
  • Aged
  • Animals
  • Antineoplastic Combined Chemotherapy Protocols / adverse effects
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology
  • Biomarkers, Tumor / genetics
  • Cell Line, Tumor
  • Clinical Trials as Topic
  • Disease-Free Survival
  • Drug Resistance, Neoplasm / genetics
  • Endoscopic Ultrasound-Guided Fine Needle Aspiration
  • Female
  • Fluorouracil / adverse effects
  • Fluorouracil / pharmacology
  • Gene Expression Regulation, Neoplastic / drug effects
  • Heterografts
  • Humans
  • Irinotecan / adverse effects
  • Irinotecan / pharmacology
  • Leucovorin / adverse effects
  • Leucovorin / pharmacology
  • Male
  • Mice
  • Middle Aged
  • Neoplasm Metastasis
  • Neoplasm Proteins / genetics*
  • Oxaliplatin / adverse effects
  • Oxaliplatin / pharmacology
  • Pancreatic Neoplasms / diagnosis*
  • Pancreatic Neoplasms / genetics
  • Pancreatic Neoplasms / pathology
  • Precision Medicine
  • Prognosis
  • Transcriptome / genetics*
  • Young Adult

Substances

  • Biomarkers, Tumor
  • Neoplasm Proteins
  • folfirinox
  • Oxaliplatin
  • Irinotecan
  • Leucovorin
  • Fluorouracil

Supplementary concepts

  • Pancreatic Carcinoma