Auteurs

Nicolle Rémy,
[:fr]O. Gayet[:],
[:fr]P. Duconseil[:],
[:fr]C. Vanbrugghe[:],
[:fr]J. Roques[:],
[:fr]M. Bigonnet[:],
[:fr]Y. Blum[:],
[:fr]N. Elarouci[:],
[:fr]L. Armenoult[:],
[:fr]M. Ayadi[:],
[:fr]A. de Reyniès[:],
[:fr]F. Puleo[:],
[:fr]J. Augustin[:],
[:fr]J.F. Emile[:],
[:fr]M. Svrcek[:],
[:fr]T. Arsenijevic[:],
[:fr]P. Hammel[:],
[:fr]M. Giovannini[:],
[:fr]P. Grandval[:],
[:fr]L. Dahan[:],
[:fr]V. Moutardier[:],
[:fr]M. Gilabert[:],
[:fr]J.L. Van Laethem[:],
[:fr]J.B. Bachet[:],
Cros Jérome,
[:fr]J. Iovanna[:],
[:fr]N.J. Dusetti[:],

[: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 carried out 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 relationships between predicted gemcitabine sensitivity and patients’ overall survival (OS) and disease-free survival 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 who did not receive gemcitabine. Among gemcitabine-treated patients, GemPred+ patients had significantly higher OS than the GemPred-: 91.3 months [95% confidence interval (CI): 61.2-not reached] versus 33 months (95% CI: 24-35.2); hazard ratio 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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