Julien Taieb1, Hampig Raphael Kourie1, Jean-François Emile2, Karine Le Malicot3, Ralyath Balogoun4,5, Josep Tabernero6, Enrico Mini7, Gunnar Folprecht8, Jean-Luc Van Laethem9, Claire Mulot4,5, Olivier Bouché10, Thomas Aparicio11, Pierre Michel12, Josef Thaler13, John Bridgewater14, Eric Van Cutsem15, Géraldine Perkins15, Come Lepage3,16, Ramon Salazar17, Pierre Laurent-Puig4,5. 1. Sorbonne Paris Cité, Université Paris Descartes, Department of Hepatogastroenterology and GI Oncology, Hôpital Européen Georges Pompidou, Paris, France. 2. Pathology Department, Ambroise Paré Hospital, Boulogne-Billancourt, France. 3. Fédération Francophone de Cancérologie Digestive (FFCD), Dijon, France. 4. Université Paris Descartes, Sorbonne Paris Cité, France. 5. Assistance Publique-Hôpitaux de Paris, Department of Biology, Hôpital Européen Georges Pompidou, INSERM UMR-S1147, Paris, France. 6. Medical Oncology Department, Vall d'Hebron University Hospital and Institute of Oncology (VHIO), CIBERONC, Universitat Autònoma de Barcelona, Spanish Gastrointestinal Tumours TTD Group, Barcelona, Spain. 7. Section of Internal Medicine, Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy. 8. Medical Department I, University Hospital Carl Gustav Carus, Dresden, Germany. 9. Department of Gastroenterology, Hôpital Universitaire Erasme, Brussels, Belgium. 10. Department of Hepato-Gastroenterology, Reims University Hospital, Reims, France. 11. Gastroenterology Department, CHU Saint Louis, Assistance Publique-Hôpitaux de Paris and Université Paris 7, Sorbonne Paris Cité, Paris, France. 12. Department of Gastroenterology, Rouen University Hospital, University of Rouen, Rouen, France. 13. Department of Internal Medicine IV, Klinikum Wels-Grieskirchen, Wels, Austria. 14. UCL Cancer Institute, University College London, London, England. 15. Digestive Oncology, University Hospitals Leuven and KU Leuven, Leuven, Belgium. 16. Hepato-Gastroenterology Department, Dijon University Hospital and INSERM U 866, Dijon, France. 17. Catalan Institute of Oncology (IDIBELL), Universitat de Barcelona, CIBERONC, Spanish Gastrointestinal Tumours TTD Group, Barcelona, Spain.
Abstract
Importance: We know of no data on the prognostic value of primary tumor location (PTL) according to BRAF, RAS, and microsatellite instability (MSI) status in patients who have undergone resection for colon cancer (CC) and have been treated with current standard adjuvant chemotherapy. Objective: To determine the prognostic and predictive value of PTL according to BRAF, RAS, and MSI status in patients with stage III CC receiving adjuvant treatment withFOLFOX (folinic acid [leucovorin calcium], fluorouracil, and oxaliplatin) with or without cetuximab. Design, Setting, and Participants: This post hoc analysis included patients with available tumor blocks of resected stage III colon adenocarcinoma who participated in the Pan-European Trials in Alimentary Tract Cancer (PETACC)-8 phase 3 randomized trial. Among the 2559 patients who underwent randomization, 1900 were screened by next-generation sequencing, which showed that 1869 had full information concerning PTL. We categorized primary tumor site as located proximal (right) or distal (left) to the splenic flexure. Main Outcomes and Measures: The associations between PTL (right- vs left-sided) and disease-free survival (DFS), survival after relapse (SAR), and overall survival (OS) were assessed by Cox models and adjusted for clinical and pathological features, treatment, and MSI, BRAF, and RAS status. Results: Among the 1869 patients (1056 [57%] male; mean [SD] age, 59.4 [9.5] years) with full molecular data analyzed, 755 (40%) had a right-sided tumor, 164 (10%) had MSI, 942 (50%) had RAS mutations, and 212 (11%) had BRAF mutations. Right-sided tumor location was not prognostic for DFS in the whole population but was associated with a shorter SAR (hazard ratio [HR], 1.54; 95% CI, 1.23-1.93; P = .001) and OS (HR, 1.25; 95% CI, 1.02-1.54; P = .03). When looking at DFS in the different molecular subgroups, we found similar results for microsatellite-stable tumors and tumors with MSI; a better DFS in right-sided vs left-sided tumors in patients with RAS mutations (HR, 0.80; 95% CI, 0.64-1.00; P = .046); and a worse DFS in right-sided vs left-sided tumors in patients with RAS and BRAF double wild type (HR, 1.39; 95% CI, 1.01-1.92; P = .04). These results were found independently of the treatment received, and no beneficial effect of cetuximab on DFS or OS was observed in left-sided tumors. Conclusions and Relevance: Although right-sided tumor location is associated with poor survival in patients with metastatic CC as previously reported, the association with disease recurrence appears to vary for patients with stage III CC and RAS or BRAF mutations vs those with double wild type.
RCT Entities:
Importance: We know of no data on the prognostic value of primary tumor location (PTL) according to BRAF, RAS, and microsatellite instability (MSI) status in patients who have undergone resection for colon cancer (CC) and have been treated with current standard adjuvant chemotherapy. Objective: To determine the prognostic and predictive value of PTL according to BRAF, RAS, and MSI status in patients with stage III CC receiving adjuvant treatment with FOLFOX (folinic acid [leucovorin calcium], fluorouracil, and oxaliplatin) with or without cetuximab. Design, Setting, and Participants: This post hoc analysis included patients with available tumor blocks of resected stage III colon adenocarcinoma who participated in the Pan-European Trials in Alimentary Tract Cancer (PETACC)-8 phase 3 randomized trial. Among the 2559 patients who underwent randomization, 1900 were screened by next-generation sequencing, which showed that 1869 had full information concerning PTL. We categorized primary tumor site as located proximal (right) or distal (left) to the splenic flexure. Main Outcomes and Measures: The associations between PTL (right- vs left-sided) and disease-free survival (DFS), survival after relapse (SAR), and overall survival (OS) were assessed by Cox models and adjusted for clinical and pathological features, treatment, and MSI, BRAF, and RAS status. Results: Among the 1869 patients (1056 [57%] male; mean [SD] age, 59.4 [9.5] years) with full molecular data analyzed, 755 (40%) had a right-sided tumor, 164 (10%) had MSI, 942 (50%) had RAS mutations, and 212 (11%) had BRAF mutations. Right-sided tumor location was not prognostic for DFS in the whole population but was associated with a shorter SAR (hazard ratio [HR], 1.54; 95% CI, 1.23-1.93; P = .001) and OS (HR, 1.25; 95% CI, 1.02-1.54; P = .03). When looking at DFS in the different molecular subgroups, we found similar results for microsatellite-stable tumors and tumors with MSI; a better DFS in right-sided vs left-sided tumors in patients with RAS mutations (HR, 0.80; 95% CI, 0.64-1.00; P = .046); and a worse DFS in right-sided vs left-sided tumors in patients with RAS and BRAF double wild type (HR, 1.39; 95% CI, 1.01-1.92; P = .04). These results were found independently of the treatment received, and no beneficial effect of cetuximab on DFS or OS was observed in left-sided tumors. Conclusions and Relevance: Although right-sided tumor location is associated with poor survival in patients with metastatic CC as previously reported, the association with disease recurrence appears to vary for patients with stage III CC and RAS or BRAF mutations vs those with double wild type.
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