Marc Hilmi1, Jérôme Cros2, Francesco Puleo3, Jeremy Augustin4, Jean-Francois Emile5, Magali Svrcek6, Pascal Hammel7, Tatjana Arsenijevic8, Jean-Luc Van Laethem8, Jean-Baptiste Bachet9, Remy Nicolle10. 1. Programme Cartes D'Identité des Tumeurs (CIT), Ligue Nationale Contre le Cancer, Paris, France. Electronic address: Hilmi.marc@gmail.com. 2. Department of Pathology, Assistance Publique Hopitaux de Paris, Beaujon Hopsital, INSERM U1149, Université de Paris, Clichy, France. 3. Department of Gastroenterology and Medical Oncology, Delta Hospital CHIREC, Brussels, Belgium. 4. Department of Pathology, Assistance Publique Hopitaux de Paris, Pitié Salpêtrière Hospital, Sorbonne Université, Paris, France. 5. Department of Pathology, Assistance Publique Hopitaux de Paris, Ambroise Paré Hospital, Université de Versailles Saint Quentin-En-Yvelines, Boulogne-Billancourt, France. 6. Department of Pathology, Assistance Publique Hopitaux de Paris, Saint-Antoine Hospital, Sorbonne Université, Paris, France. 7. Department of Pancreatology, Assistance Publique Hopitaux de Paris, Beaujon Hopsital, University Paris VII, Clichy, France. 8. Department of Gastroenterology and Medical Oncology, Hôpital Erasme and Laboratory of Experimental Gastroenterology, Université Libre de Bruxelles, Brussels, Belgium. 9. Department of Hepato-Gastroenterology, Assistance Publique Hopitaux de Paris, Pitié Salpêtrière Hospital, Sorbonne Université, Paris, France. 10. Programme Cartes D'Identité des Tumeurs (CIT), Ligue Nationale Contre le Cancer, Paris, France.
Abstract
BACKGROUND: Few patients with pancreatic adenocarcinoma (PAC) are eligible for surgery. Patients with early relapse have a poor prognosis and might be better candidates for a medical approach. Clinical and pathological parameters only partially predict recurrence and are only obtained after surgery. PAC subtypes based on gene expression were proposed, and we assessed if they could predict the risk and type of recurrence independently of clinicopathological parameters. METHODS: Patients with curative-intent surgery for PAC without pretreatment were selected and divided into two independent cohorts defined as discovery (n = 381) and validation (n = 149) cohorts. Transcriptomic analyses were performed on formalin-fixed paraffin-embedded surgical samples to characterise tumour and stroma compartments using previously defined signatures. We associated molecular and clinicopathological characteristics with general, distant, and local recurrences using Cox regression analyses. RESULTS: We found that tumour biology predicted distant recurrence contrary to local recurrence, which was directly related to resection margin status. Pure basal-like and stroma-activated subtypes were strongly associated with distant recurrence, independently of clinicopathological factors (hazard ratios [HRs] = 5.85, p < 0.001 and HR = 1.75, p = 0.007, respectively). By dissecting tumoural and stromal compartments, we demonstrated that the basal-like tumour component positively correlated with distant recurrence in both cohorts (HR = 1.45, p < 0.001 and HR = 1.90, p < 0.001), whereas the inactive structural stroma component was protective against distant recurrence (HR = 0.68, p < 0.001 and HR = 0.72, p < 0.001). CONCLUSIONS: In addition to suggesting a different mechanism for local and distant relapse (incomplete resection and high metastatic potential, respectively), our results show the potency of molecular phenotype to predict patient outcome regarding distant recurrences.
BACKGROUND: Few patients with pancreatic adenocarcinoma (PAC) are eligible for surgery. Patients with early relapse have a poor prognosis and might be better candidates for a medical approach. Clinical and pathological parameters only partially predict recurrence and are only obtained after surgery. PAC subtypes based on gene expression were proposed, and we assessed if they could predict the risk and type of recurrence independently of clinicopathological parameters. METHODS:Patients with curative-intent surgery for PAC without pretreatment were selected and divided into two independent cohorts defined as discovery (n = 381) and validation (n = 149) cohorts. Transcriptomic analyses were performed on formalin-fixed paraffin-embedded surgical samples to characterise tumour and stroma compartments using previously defined signatures. We associated molecular and clinicopathological characteristics with general, distant, and local recurrences using Cox regression analyses. RESULTS: We found that tumour biology predicted distant recurrence contrary to local recurrence, which was directly related to resection margin status. Pure basal-like and stroma-activated subtypes were strongly associated with distant recurrence, independently of clinicopathological factors (hazard ratios [HRs] = 5.85, p < 0.001 and HR = 1.75, p = 0.007, respectively). By dissecting tumoural and stromal compartments, we demonstrated that the basal-like tumour component positively correlated with distant recurrence in both cohorts (HR = 1.45, p < 0.001 and HR = 1.90, p < 0.001), whereas the inactive structural stroma component was protective against distant recurrence (HR = 0.68, p < 0.001 and HR = 0.72, p < 0.001). CONCLUSIONS: In addition to suggesting a different mechanism for local and distant relapse (incomplete resection and high metastatic potential, respectively), our results show the potency of molecular phenotype to predict patient outcome regarding distant recurrences.