R Nicolle1, O Gayet2, P Duconseil3, C Vanbrugghe3, J Roques2, M Bigonnet2, Y Blum1, N Elarouci1, L Armenoult1, M Ayadi1, A de Reyniès1, F Puleo4, J Augustin5, J F Emile6, M Svrcek5, T Arsenijevic4, P Hammel7, M Giovannini8, P Grandval9, L Dahan9, V Moutardier3, M Gilabert8, J L Van Laethem4, J B Bachet5, J Cros7, J Iovanna10, N J Dusetti11. 1. Tumour Identity Card Program (CIT), French League Against Cancer, Paris, France. 2. Cancer Research Center of Marseille, CRCM, Inserm, CNRS, Paoli-Calmettes Institut, Aix-Marseille University, Marseille, France. 3. Cancer Research Center of Marseille, CRCM, Inserm, CNRS, Paoli-Calmettes Institut, Aix-Marseille University, Marseille, France; Nord Hospital, Marseille, France. 4. Laboratory of Experimental Gastroenterology (Université Libre de Bruxelles), Brussels, Belgium; Department of Gastroenterology and Digestive Oncology, Erasme Hospital, Brussels, Belgium. 5. Sorbonne University, UPMC University, Department of Gastroenterology, Pitié-Salpetriére Hospital, Paris, France. 6. Ambroise Paré Hospital, Boulogne, AP-HP, France. 7. Department of Digestive Oncology, Beaujon Hospital, Paris 7 University, APHP, Clichy, France. 8. Cancer Research Center of Marseille, CRCM, Inserm, CNRS, Paoli-Calmettes Institut, Aix-Marseille University, Marseille, France; Paoli-Calmettes Institut, Marseille, France. 9. Cancer Research Center of Marseille, CRCM, Inserm, CNRS, Paoli-Calmettes Institut, Aix-Marseille University, Marseille, France; La Timone Hospital, Marseille, France. 10. Cancer Research Center of Marseille, CRCM, Inserm, CNRS, Paoli-Calmettes Institut, Aix-Marseille University, Marseille, France. Electronic address: juan.iovanna@inserm.fr. 11. Cancer Research Center of Marseille, CRCM, Inserm, CNRS, Paoli-Calmettes Institut, Aix-Marseille University, Marseille, France. Electronic address: nelson.dusetti@inserm.fr.
Abstract
BACKGROUND: Chemotherapy is the only systemic treatment approved for pancreatic ductal adenocarcinoma (PDAC), with a selection of regimens based on patients' performance status and expected efficacy. The establishment of a potent stratification associated with chemotherapeutic efficacy could potentially improve prognosis by tailoring treatments. PATIENTS AND METHODS: Concomitant chemosensitivity and genome-wide RNA profiles were performed on preclinical models (primary cell cultures and patient-derived xenografts) derived from patients with PDAC included in the PaCaOmics program (NCT01692873). The RNA-based stratification was tested in a monocentric cohort and validated in a multicentric cohort, both retrospectively collected from resected PDAC samples (67 and 368 patients, respectively). Forty-three (65%) and 203 (55%) patients received adjuvant gemcitabine in the monocentric and the multicentric cohorts, respectively. The relationship between predicted gemcitabine sensitivity and patients' overall survival (OS) and disease-free survival (DFS) were investigated. RESULTS: The GemPred RNA signature was derived from preclinical models, defining gemcitabine sensitive PDAC as GemPred+. Among the patients who received gemcitabine in the test and validation cohorts, the GemPred+ patients had a higher OS than GemPred- (p = 0.046 and p = 0.00216). In both cohorts, the GemPred stratification was not associated with OS among patients that did not receive gemcitabine. Among gemcitabine treated-patients, GemPred+ patients had significantly higher OS than the GemPred-: 91.3 months (95% CI: 61.2-not reached) vs 33 months (95% CI: 24-35.2); HR 0.403 (95% CI: 0.221-0.735, p = 0.00216). The interaction test for gemcitabine and GemPred+ stratification was significant (p = 0.0245). Multivariate analysis in the gemcitabine-treated population retained an independent predictive value. CONCLUSION: The RNA-based GemPred stratification predicts the benefit of adjuvant gemcitabine in PDAC patients.
BACKGROUND: Chemotherapy is the only systemic treatment approved for pancreatic ductal adenocarcinoma (PDAC), with a selection of regimens based on patients' performance status and expected efficacy. The establishment of a potent stratification associated with chemotherapeutic efficacy could potentially improve prognosis by tailoring treatments. PATIENTS AND METHODS: Concomitant chemosensitivity and genome-wide RNA profiles were performed on preclinical models (primary cell cultures and patient-derived xenografts) derived from patients with PDAC included in the PaCaOmics program (NCT01692873). The RNA-based stratification was tested in a monocentric cohort and validated in a multicentric cohort, both retrospectively collected from resected PDAC samples (67 and 368 patients, respectively). Forty-three (65%) and 203 (55%) patients received adjuvant gemcitabine in the monocentric and the multicentric cohorts, respectively. The relationship between predicted gemcitabine sensitivity and patients' overall survival (OS) and disease-free survival (DFS) were investigated. RESULTS: The GemPred RNA signature was derived from preclinical models, defining gemcitabine sensitive PDAC as GemPred+. Among the patients who received gemcitabine in the test and validation cohorts, the GemPred+ patients had a higher OS than GemPred- (p = 0.046 and p = 0.00216). In both cohorts, the GemPred stratification was not associated with OS among patients that did not receive gemcitabine. Among gemcitabine treated-patients, GemPred+ patients had significantly higher OS than the GemPred-: 91.3 months (95% CI: 61.2-not reached) vs 33 months (95% CI: 24-35.2); HR 0.403 (95% CI: 0.221-0.735, p = 0.00216). The interaction test for gemcitabine and GemPred+ stratification was significant (p = 0.0245). Multivariate analysis in the gemcitabine-treated population retained an independent predictive value. CONCLUSION: The RNA-based GemPred stratification predicts the benefit of adjuvant gemcitabine in PDAC patients.
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