B Borelli1, E Fontana2, M Giordano3, C Antoniotti1, S Lonardi4, F Bergamo4, F Pietrantonio5, F Morano6, E Tamburini7, A Boccaccino1, D Santini8, G Zucchelli1, N Pella9, E Maiello10, A Passardi11, A Zaniboni12, C Ugolini13, G Fontanini3, A Falcone1, G Nyamundanda14, A Sadanandam15, C Cremolini16. 1. Department of Translational Research and New Technologies in Medicine and Surgery, Unit of Medical Oncology, Azienda Ospedaliero-Universitaria Pisana, University of Pisa, Pisa, Italy. 2. Division of Molecular Pathology, The Institute of Cancer Research, London, UK; Sarah Cannon Research Institute, London, UK. 3. Department of Surgical, Medical, Molecular Pathology and Critical Area, University of Pisa, Pisa, Italy. 4. Unit of Medical Oncology 1, Department of Oncology, Istituto Oncologico Veneto, IRCCS, Padua, Italy. 5. Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy; Oncology and Hemato-Oncology Department, University of Milan, Milan, Italy. 6. Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy. 7. Oncology Unit, Ospedale degli Infermi, Rimini, Italy. 8. Department of Medical Oncology, University Campus Biomedico, Rome, Italy. 9. Department of Oncology, University and General Hospital, Udine, Italy. 10. Oncology Unit, Foundation IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy. 11. Department of Medical Oncology, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCSS, Meldola, Italy. 12. Medical Oncology Unit, Fondazione Poliambulanza, Brescia, Italy. 13. Unit of Pathological Anatomy, Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy. 14. Division of Molecular Pathology, The Institute of Cancer Research, London, UK. 15. Division of Molecular Pathology, The Institute of Cancer Research, London, UK. Electronic address: anguraj.sadanandam@icr.ac.uk. 16. Department of Translational Research and New Technologies in Medicine and Surgery, Unit of Medical Oncology, Azienda Ospedaliero-Universitaria Pisana, University of Pisa, Pisa, Italy. Electronic address: chiaracremolini@gmail.com.
Abstract
INTRODUCTION: The consensus molecular subtypes (CMS) demonstrated prognostic value in metastatic colorectal cancer (mCRC). Similarly, a prognostic impact was suggested for the pre-consensus CRCAssigner (CRCA) classifier in early stages. The potential predictive role of these classifiers with regard to the choice of the first-line therapy has not been established. We investigated the prognostic and predictive impact of CMS and CRCA subtypes among mCRC patients treated in the TRIBE2 study. METHODS: Among 679 randomized patients, 426 and 428 (63%) samples were profiled according to CMS and CRCA classifications, respectively. The prognostic and predictive impact of both CMS and CRCA subtypes was investigated with univariate and multivariate analyses for progression-free survival (PFS), PFS 2 (PFS2), and overall survival (OS). RESULTS: Significant associations of CMS and CRCA subtypes with PFS, PFS2, and OS were demonstrated; the CMS classifier confirmed its independent prognostic value in the multivariable model (P value for PFS/PFS2/OS = 0.01/0.07/0.08). The effect of treatment intensification was independent of CMS subtypes (P value for interaction for PFS/PFS2/OS = 0.88/0.75/0.55). A significant interaction effect between CRCA subtypes and treatment arm was demonstrated in PFS (P = 0.02), PFS2 (P = 0.01), and OS (P = 0.008). The benefit of FOLFOXIRI seemed more relevant in the stem-like (PFS, hazard ratio = 0.60; P = 0.03) and mixed subtypes (hazard ratio = 0.44; P = 0.002). These findings were confirmed in a subgroup of patients of the previous TRIBE study. CONCLUSIONS: We confirmed the independent prognostic role of CMS classification in mCRC independently of RAS/BRAF status. CRCA classification may help identifying subgroups of patients who may derive more benefit from FOLFOXIRI/bevacizumab.
RCT Entities:
INTRODUCTION: The consensus molecular subtypes (CMS) demonstrated prognostic value in metastatic colorectal cancer (mCRC). Similarly, a prognostic impact was suggested for the pre-consensus CRCAssigner (CRCA) classifier in early stages. The potential predictive role of these classifiers with regard to the choice of the first-line therapy has not been established. We investigated the prognostic and predictive impact of CMS and CRCA subtypes among mCRC patients treated in the TRIBE2 study. METHODS: Among 679 randomized patients, 426 and 428 (63%) samples were profiled according to CMS and CRCA classifications, respectively. The prognostic and predictive impact of both CMS and CRCA subtypes was investigated with univariate and multivariate analyses for progression-free survival (PFS), PFS 2 (PFS2), and overall survival (OS). RESULTS: Significant associations of CMS and CRCA subtypes with PFS, PFS2, and OS were demonstrated; the CMS classifier confirmed its independent prognostic value in the multivariable model (P value for PFS/PFS2/OS = 0.01/0.07/0.08). The effect of treatment intensification was independent of CMS subtypes (P value for interaction for PFS/PFS2/OS = 0.88/0.75/0.55). A significant interaction effect between CRCA subtypes and treatment arm was demonstrated in PFS (P = 0.02), PFS2 (P = 0.01), and OS (P = 0.008). The benefit of FOLFOXIRI seemed more relevant in the stem-like (PFS, hazard ratio = 0.60; P = 0.03) and mixed subtypes (hazard ratio = 0.44; P = 0.002). These findings were confirmed in a subgroup of patients of the previous TRIBE study. CONCLUSIONS: We confirmed the independent prognostic role of CMS classification in mCRC independently of RAS/BRAF status. CRCA classification may help identifying subgroups of patients who may derive more benefit from FOLFOXIRI/bevacizumab.