1. Establishment of a pancreatic adenocarcinoma molecular gradient (PAMG) that predicts the clinical outcome of pancreatic cancer
- Author
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Nicolle, Rémy, Blum, Yuna, Duconseil, Pauline, Vanbrugghe, Charles, Brandone, Nicolas, Poizat, Flora, Roques, Julie, Bigonnet, Martin, Gayet, Odile, Rubis, Marion, Dou, Samir, 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, and Dusetti, Nelson
- Subjects
Oncology ,Male ,Research paper ,endocrine system diseases ,Personalized treatment ,Leucovorin ,lcsh:Medicine ,Tumor response ,Mice ,Antineoplastic Combined Chemotherapy Protocols ,Neoplasm Metastasis ,Precision Medicine ,lcsh:R5-920 ,Clinical Trials as Topic ,medicine.diagnostic_test ,Middle Aged ,Prognosis ,Predictive value ,Well differentiated ,Neoplasm Proteins ,Gene Expression Regulation, Neoplastic ,Oxaliplatin ,Adenocarcinoma ,Heterografts ,Female ,Translational medicine ,Fluorouracil ,lcsh:Medicine (General) ,Adult ,medicine.medical_specialty ,Adolescent ,Transcriptomic signature ,Irinotecan ,Prognostic ,Disease-Free Survival ,Young Adult ,Chemosensitivity prediction ,Internal medicine ,Pancreatic cancer ,Cell Line, Tumor ,Biopsy ,medicine ,Biomarkers, Tumor ,Animals ,Humans ,Endoscopic Ultrasound-Guided Fine Needle Aspiration ,Aged ,business.industry ,lcsh:R ,Histology ,medicine.disease ,Pancreatic Neoplasms ,Drug Resistance, Neoplasm ,business ,Transcriptome - Abstract
BACKGROUNDA significant gap in pancreatic ductal adenocarcinoma (PDAC) patient’s care is the lack of molecular parameters characterizing tumors and allowing a personalized treatment. The goal of this study was to examine whole PDAC transcriptomic profiles to define a signature that would predict aggressiveness and treatment responsiveness better than done until now.METHODS AND PATIENTSTumors were obtained from 76 consecutive resectable (n=40) or unresectable (n=36) tumors. PDAC were transplanted in mice to produce patient-drived xenografts (PDX). PDX were classified according to their histology into five groups, from highly undifferentiated to well differentiated. This classification resulted strongly associated with tumors aggressiveness. 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 tumors; ii/ 60 advanced tumors obtained by diagnostic EUS-guided biopsy needle flushing and iii/ on 28 biopsies from mFOLFIRINOX treated metastatic tumors.RESULTSA 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 tumors (e.g. 308 consecutive resected PDAC, HR=0.321 95% CI [0.207;0.5] and 60 locally-advanced or metastatic PDAC, HR=0.308 95% CI [0.113;0.836]). The PAMG signature is also associated with progression under mFOLFIRINOX treatment (Pearson correlation to tumor response: -0.67, p-value < 0.001).CONCLUSIONWe identified a transcriptomic signature (PAMG) that, unlike all other stratification schemas already proposed, classifies PDAC along a continuous gradient. It can be performed on formalin-fixed paraffin-embedded samples and EUS-guided biopsies showing a strong prognostic value and predicting mFOLFIRINOX responsiveness. We think that PAMG could unify all PDAC preexisting classifications inducing a shift in the actual paradigm of binary classifications towards a better characterization in a gradient.Trial RegistrationThe PaCaOmics study is registered atwww.clinicaltrials.govwith registration numberNCT01692873. The validation BACAP study is registered atwww.clinicaltrials.govwith registration numberNCT02818829.
- Published
- 2020