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

Adenocarcinoma / diagnosis Adolescent Adult Aged Animals Antineoplastic Combined Chemotherapy Protocols / adverse effects 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 Gene Expression Regulation, Neoplastic / drug effects Heterografts Humans Irinotecan / adverse effects Leucovorin / adverse effects Male Mice Middle Aged Neoplasm Metastasis Neoplasm Proteins / genetics Oxaliplatin / adverse effects Pancreatic Neoplasms / diagnosis Precision Medicine Prognosis Transcriptome / genetics Young Adult Pancreatic Neoplasms

Chemosensitivity prediction Pancreatic cancer Precision medicine Prognostic Transcriptomic signature Translational medicine

Journal

EBioMedicine

ISSN: 2352-3964

Titre abrégé: EBioMedicine

Pays: Netherlands

ID NLM: 101647039

Informations de publication

Date de publication:
Jul 2020

Historique:

received: 02 04 2020

revised: 09 06 2020

accepted: 11 06 2020

pubmed: 7 7 2020

medline: 26 5 2021

entrez: 7 7 2020

Statut: ppublish

Résumé

A significant gap in pancreatic ductal adenocarcinoma (PDAC) patient's care is the lack of molecular parameters characterizing tumours and allowing a personalized treatment. 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. 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). PAMG unify all PDAC pre-existing classifications inducing a shift in the actual paradigm of binary classifications towards a better characterization in a gradient. 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.

Sections du résumé

BACKGROUND 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 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 RESULTS

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 CONCLUSIONS

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 BACKGROUND

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.

Identifiants

DOI: 10.1016/j.ebiom.2020.102858 PMID: 32629389 PMC: PMC7334821

pubmed: 32629389

pii: S2352-3964(20)30233-4

doi: 10.1016/j.ebiom.2020.102858

pmc: PMC7334821

pii:

doi:

Substances chimiques

Biomarkers, Tumor 0

Neoplasm Proteins 0

folfirinox 0

Oxaliplatin 04ZR38536J

Irinotecan 7673326042

Leucovorin Q573I9DVLP

Fluorouracil U3P01618RT

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

Pagination

102858

Informations de copyright

Déclaration de conflit d'intérêts

Conflicts of interest The authors declare no competing financial interests

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