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

• Published in: EBioMedicine Vol. 57; p. 102858
• Main Authors: Nicolle, Rémy, Blum, Yuna, Duconseil, Pauline, Vanbrugghe, Charles, Brandone, Nicolas, Poizat, Flora, Roques, Julie, Bigonnet, Martin, Gayet, Odile, Rubis, Marion, Elarouci, Nabila, Armenoult, Lucile, Ayadi, Mira, de Reyniès, Aurélien, Giovannini, Marc, Grandval, Philippe, Garcia, Stephane, Canivet, Cindy, Cros, Jérôme, Bournet, Barbara, Buscail, Louis, Moutardier, Vincent, Gilabert, Marine, Iovanna, Juan, Dusetti, Nelson
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01-07-2020; Elsevier
• Subjects: 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; Chemosensitivity prediction; 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 cancer; Pancreatic Neoplasms; Pancreatic Neoplasms - diagnosis; Pancreatic Neoplasms - genetics; Pancreatic Neoplasms - pathology; Precision Medicine; Prognosis; Prognostic; Research paper; Transcriptome - genetics; Transcriptomic signature; Translational medicine; Young Adult; Chemosensitivity prediction; Precision medicine; Transcriptomic signature; Pancreatic cancer; Translational medicine; Prognostic
• ISSN: 2352-3964; 2352-3964
• DOI: 10.1016/j.ebiom.2020.102858

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.