Jun Yin1, Romain Cohen2, Zhaohui Jin3, Heshan Liu1, Levi Pederson1, Richard Adams4, Axel Grothey5, Timothy S Maughan6, Alan Venook7, Eric Van Cutsem8, Cornelis Punt9, Miriam Koopman10, Alfredo Falcone11, Niall C Tebbutt12, Matthew T Seymour13, Carsten Bokemeyer14, Eduardo Diaz Rubio15, Richard Kaplan16, Volker Heinemann17, Benoist Chibaudel18, Takayuki Yoshino19, John Zalcberg20, Thierry Andre21, Aimery De Gramont22, Qian Shi1, Heinz-Josef Lenz23. 1. Division of Clinical Trials and Biostatistics, Mayo Clinic, Rochester, MN, USA. 2. Sorbonne University, Department of Medical Oncology, Saint-Antoine Hospital, AP-HP, F-75012, Paris, France. 3. Department of Oncology, Mayo Clinic, Rochester, MN, USA. 4. Cardiff University and Velindre Cancer Centre, Cardiff, UK. 5. West Cancer Center and Research Institute, OneOncology, Germantown, TN. 6. CRUK/MRC Oxford Institute for Radiation Oncology, Oxford, United Kingdom St James's Hospital, and University of Leeds, Leeds, UK. 7. Department of Medicine, The University of California San Francisco, San Francisco, California, United States of America. 8. Digestive Oncology, University Hospitals Gasthuisberg Leuven and University of Leuven Leuven, Belgium. 9. Department of Epidemiology, Julius Center for Health Sciences and Primary Care, University Medical Center, Utrecht University, The Netherlands. 10. Department of Medical Oncology, University Medical Center Utrecht, Utrecht University, The Netherlands. 11. Department of Oncology, University of Pisa, Italy. 12. Department of Medical Oncology, Austin Health, Melbourne. 13. NIHR Clinical Research Network, Leeds UK. St James's Hospital, and University of Leeds, Leeds, United Kingdom. 14. Department of Oncology, Haematology and Bone Marrow Transplantation with Section of Pneumology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. 15. Universidad Complutense Instituto de Investigacion Sanitaria del Hospital Clinico San Carlos, Madrid, Spain. 16. MRC Clinical Trials Unit at UCL, University College London, London, UK. 17. University Hospital Grosshadern, Ludwig Maximilian University of Munich, Munich, Germany. 18. Institut Franco-Britannique, Levallois-Perret, France. 19. National Cancer Center Hospital East, Japan. 20. Monash University, Melbourne, Australia. 21. Hôpital Saint-Antoine, Paris, France. 22. Department of Medical Oncology, Franco-British Institute, Levallois-Perret, France. 23. Department of Gastrointestinal Onocology, Keck School of Medicine at USC, Los Angeles, CA, USA.
Abstract
BACKGROUND: Unplanned subgroup analyses from several studies have suggested primary tumor sidedness (PTS) as a potential prognostic and predictive parameter in metastatic colorectal cancer (mCRC). We aimed to investigate the impact of PTS on outcomes of mCRC patients. METHODS: PTS data of 9,277 mCRC patients from 12 first-line randomized trials in the ARCAD database were pooled. Overall survival (OS) and progression-free survival (PFS) were assessed using Kaplan-Meier and Cox models adjusting for age, sex, performance status, prior radiation/chemo, and stratified by treatment arm. Predictive value was tested by interaction term between PTS and treatment (cetuximab plus chemotherapy vs. chemotherapy alone). All statistical tests were 2-sided. RESULTS: Compared to right-sided metastatic colorectal cancer patients (n = 2421, 26.1%), left-sided metastatic colorectal cancer patients (n = 6856, 73.9%) had better OS (median = 21.6 v 15.9 months; adjusted hazard ratio [HRadj] = 0.71, 95% confidence interval [CI] = 0.67-0.76, P<.001) and PFS (median = 8.6 v 7.5 months; HRadj = 0.80, 95% CI = 0.75-0.84, P<.001). Interaction between PTS and KRAS mutation was statistically significant (Pinteraction<.001): left-sidedness was associated with better prognosis among KRAS wild-type (WT) (OS HRadj = 0.59, 95% CI = 0.53-0.66; PFS HRadj =0.68, 95% CI = 0.61-0.75), but not among KRAS mutated tumors. Among KRAS-WT tumors, survival benefit from anti-EGFR was confirmed for left-sidedness (OS HRadj = 0.85, 95% CI = 0.75-0.97, P = .01; PFS HRadj = 0.77, 95% CI = 0.67-0.88, P<.001), but not for right-sidedness. CONCLUSIONS: The prognostic value of PTS is restricted to the KRAS-WT population. PTS is predictive of anti-EGFR efficacy, with a statistically significant improvement of survival for left-sidedness mCRC patients. These results suggest treatment choice in mCRC should be based on both PTS and KRAS status.
BACKGROUND: Unplanned subgroup analyses from several studies have suggested primary tumor sidedness (PTS) as a potential prognostic and predictive parameter in metastatic colorectal cancer (mCRC). We aimed to investigate the impact of PTS on outcomes of mCRC patients. METHODS: PTS data of 9,277 mCRC patients from 12 first-line randomized trials in the ARCAD database were pooled. Overall survival (OS) and progression-free survival (PFS) were assessed using Kaplan-Meier and Cox models adjusting for age, sex, performance status, prior radiation/chemo, and stratified by treatment arm. Predictive value was tested by interaction term between PTS and treatment (cetuximab plus chemotherapy vs. chemotherapy alone). All statistical tests were 2-sided. RESULTS: Compared to right-sided metastatic colorectal cancerpatients (n = 2421, 26.1%), left-sided metastatic colorectal cancerpatients (n = 6856, 73.9%) had better OS (median = 21.6 v 15.9 months; adjusted hazard ratio [HRadj] = 0.71, 95% confidence interval [CI] = 0.67-0.76, P<.001) and PFS (median = 8.6 v 7.5 months; HRadj = 0.80, 95% CI = 0.75-0.84, P<.001). Interaction between PTS and KRAS mutation was statistically significant (Pinteraction<.001): left-sidedness was associated with better prognosis among KRAS wild-type (WT) (OS HRadj = 0.59, 95% CI = 0.53-0.66; PFS HRadj =0.68, 95% CI = 0.61-0.75), but not among KRAS mutated tumors. Among KRAS-WT tumors, survival benefit from anti-EGFR was confirmed for left-sidedness (OS HRadj = 0.85, 95% CI = 0.75-0.97, P = .01; PFS HRadj = 0.77, 95% CI = 0.67-0.88, P<.001), but not for right-sidedness. CONCLUSIONS: The prognostic value of PTS is restricted to the KRAS-WT population. PTS is predictive of anti-EGFR efficacy, with a statistically significant improvement of survival for left-sidedness mCRC patients. These results suggest treatment choice in mCRC should be based on both PTS and KRAS status.