Frank A Sinicrope1, Sakti Chakrabarti2, Pierre Laurent-Puig3, Luke Huebner4, Thomas C Smyrk5, Josep Tabernero6, Enrico Mini7, Richard M Goldberg8, Aziz Zaanan9, Gunnar Folprecht10, Jean Luc Van Laethem11, Karine Le Malicot12, Qian Shi13, Steven R Alberts2, Julien Taieb9. 1. Department of Oncology, Mayo Clinic and Mayo Comprehensive Cancer Center, Rochester, MN, USA. Electronic address: sinicrope.frank@mayo.edu. 2. Department of Oncology, Mayo Clinic and Mayo Comprehensive Cancer Center, Rochester, MN, USA. 3. Centre de Recherche des Cordeliers, INSERM, CNRS, Sorbonne Université, USPC, Université Paris Descartes, Université Paris Diderot, Paris, France. 4. Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN, USA. 5. Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA. 6. Medical Oncology Department, Vall d'Hebron University Hospital and Institute of Oncology (VHIO), UVic, IOB-Quiron, Barcelona, Spain. 7. Section of Clinical Pharmacology and Oncology, Department of Health Sciences, University of Florence, Florence, Italy. 8. Department of Medicine, West Virginia University Cancer Center, Morgantown, WV, USA. 9. Department of Gastroenterology and GI Oncology, Sorbonne Paris Cité, Université Paris Descartes, Hopital Européen Georges Pompidou, Paris, France. 10. First Medical Department, University Hospital Carl Gustav Carus, Dresden, Germany. 11. Department of Gastroenterology, Erasme Hospital University, Brussels, Belgium. 12. Department of Statistics, Fédération Francophone de Cancérologie Digestive, EPICAD INSERM, France. 13. Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN, USA; Alliance Statistics and Data Center, Mayo Clinic, Rochester, MN, USA.
Abstract
BACKGROUND: Stratification of patients with stage III colon cancer into low (T1-3N1) and high (T4 and/or N2) risk groups is used to guide the duration of adjuvant chemotherapy. We determined the relative contribution of clinical and molecular features to survival by risk group. MATERIALS & METHODS: Stage III colon cancer (N = 5337) patients from two adjuvant trials of FOLFOX ± cetuximab [N0147 (Alliance), PETACC-8] were risk grouped, then subgrouped by clinical features and molecular variables [KRAS and BRAF/mismatch repair (MMR) combined variable]. Distributions of disease-free survival (DFS), overall survival (OS), and survival after recurrence (SAR) were estimated. In multivariable Cox models, backward elimination was performed for analysis of candidate predictors of outcomes. Relative contributions of model-selected variables to outcomes by risk group were calculated using χ2. RESULTS: Among low risk tumours, mutant KRAS and male gender were significantly associated with poorer OS multivariately. In high risk tumours, significantly poorer OS was observed for right sidedness and for mutant KRAS and BRAFV600E/pMMR, subgroups. Specifically, BRAFV600E/pMMR (OS: HR = 1.75; 95% CI: 1.36-2.24; Padj<.0001) and right- versus left-sidedness were associated with significantly poorer DFS, OS (HR = 1.56; 95% CI: 1.31-1.83; Padj<.0001), and SAR (HR = 1.64; 95% CI: 1.37-1.95; Padj<.0001). Poor prognosis of mutant KRAS for DFS and OS was similar among risk groups. BRAF/MMR and sidedness were associated with poorer SAR in both low and high risk tumours. Age, gender, and KRAS were the top three relative contributors to DFS and OS among low risk tumours; sidedness ranked first for DFS and OS, and second to BRAF/MMR for SAR among high risk tumours. CONCLUSION: Sidedness and BRAF/MMR contributed the most to survival outcomes among high risk tumours and should be interpreted in the context of risk group.
BACKGROUND: Stratification of patients with stage III colon cancer into low (T1-3N1) and high (T4 and/or N2) risk groups is used to guide the duration of adjuvant chemotherapy. We determined the relative contribution of clinical and molecular features to survival by risk group. MATERIALS & METHODS: Stage III colon cancer (N = 5337) patients from two adjuvant trials of FOLFOX ± cetuximab [N0147 (Alliance), PETACC-8] were risk grouped, then subgrouped by clinical features and molecular variables [KRAS and BRAF/mismatch repair (MMR) combined variable]. Distributions of disease-free survival (DFS), overall survival (OS), and survival after recurrence (SAR) were estimated. In multivariable Cox models, backward elimination was performed for analysis of candidate predictors of outcomes. Relative contributions of model-selected variables to outcomes by risk group were calculated using χ2. RESULTS: Among low risk tumours, mutant KRAS and male gender were significantly associated with poorer OS multivariately. In high risk tumours, significantly poorer OS was observed for right sidedness and for mutant KRAS and BRAFV600E/pMMR, subgroups. Specifically, BRAFV600E/pMMR (OS: HR = 1.75; 95% CI: 1.36-2.24; Padj<.0001) and right- versus left-sidedness were associated with significantly poorer DFS, OS (HR = 1.56; 95% CI: 1.31-1.83; Padj<.0001), and SAR (HR = 1.64; 95% CI: 1.37-1.95; Padj<.0001). Poor prognosis of mutant KRAS for DFS and OS was similar among risk groups. BRAF/MMR and sidedness were associated with poorer SAR in both low and high risk tumours. Age, gender, and KRAS were the top three relative contributors to DFS and OS among low risk tumours; sidedness ranked first for DFS and OS, and second to BRAF/MMR for SAR among high risk tumours. CONCLUSION: Sidedness and BRAF/MMR contributed the most to survival outcomes among high risk tumours and should be interpreted in the context of risk group.
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