Roberto Moretto1, Mirella Giordano2, Anello M Poma3, Alessandro Passardi4, Alessandra Boccaccino5, Filippo Pietrantonio6, Gianluca Tomasello7, Giuseppe Aprile8, Sara Lonardi9, Veronica Conca5, Cristina Granetto10, Antonio Frassoldati11, Matteo Clavarezza12, Alessandro S Bertolini13, Marco M Germani5, Clara Ugolini3, Gabriella Fontanini3, Gianluca Masi5, Alfredo Falcone5, Chiara Cremolini14. 1. Unit of Medical Oncology 2, Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy. 2. Department of Translational Research and New Technology in Medicine and Surgery, University of Pisa, Pisa, Italy. 3. Department of Surgical, Medical and Molecular Pathology and Critical Care Medicine, University of Pisa, Pisa, Italy. 4. Department of Medical Oncology, IRCCS Istituto Romagnolo per Lo Studio Dei Tumori (IRST) "Dino Amadori", Meldola, Italy. 5. Unit of Medical Oncology 2, Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy; Department of Translational Research and New Technology in Medicine and Surgery, University of Pisa, Pisa, Italy. 6. Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy; Oncology and Hemato-oncology Department, University of Milan, Milan, Italy. 7. Oncology Unit, Oncology Department, ASST of Cremona, Cremona, Italy; UOC Medical Oncology, IRCCS Foundation Ca' Granda Maggiore Hospital Policlinic, Milan, Italy. 8. Department of Oncology, University and General Hospital, Udine, Italy; Department of Oncology, San Bortolo General Hospital, Vicenza, Italy. 9. Early Phase Clinical Trial Unit, Department of Oncology, Veneto Institute of Oncology IOV-IRCCS, Padua, Italy; Medical Oncology Unit 1, Department of Oncology, Veneto Institute of Oncology IOV-IRCCS, Padua, Italy. 10. Medical Oncology, Azienda Ospedaliera S., Croce e Carle Ospedale di Insegnamento, Cuneo, Italy. 11. Clinical Oncology, Oncology Department, Azienda Ospedaliero Universitaria di Ferrara, Ferrara, Italy. 12. Medical Oncology, Ente Ospedaliero Ospedali Galliera, Genova, Italy. 13. Medical Oncology, ASST Della Valtellina e Alto Lario, Sondrio, Italy. 14. Unit of Medical Oncology 2, Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy; Department of Translational Research and New Technology in Medicine and Surgery, University of Pisa, Pisa, Italy. Electronic address: chiaracremolini@gmail.com.
Abstract
BACKGROUND: Recent data from the TRIBE2 study have failed to suggest a higher magnitude of benefit from upfront FOLFOXIRI/bevacizumab in patients with BRAF-mutant metastatic colorectal cancer (mCRC) as previously reported in the TRIBE study. PATIENTS AND METHODS: Clinical characteristics and gene expression signatures of patients with BRAF-mutant mCRC enrolled in the TRIBE2 study were evaluated with the aim of understanding that patients may derive benefit from the intensification of the upfront chemotherapy. RESULTS: Of 46 BRAF-mutant tumour samples analysed, 24 (52%) and 22 (48%) were classified as BM1 and BM2, respectively, and 27 (59%) and 19 (41%) were assigned to ligand-independent (LI) and ligand-dependent (LD) Wnt pathway subgroups, respectively. No prognostic impact was shown for both BM1/BM2 and LI/LD subtypes. No interaction was evident between BM1/BM2 or LI/LD signatures and the benefit provided by FOLFOXIRI/bevacizumab. Significant interaction effect was evident in terms of progression-free survival between treatment arm and primary tumour sidedness (P = 0.05) and Eastern Cooperative Oncology Group performance status (ECOG-PS; P < 0.001). CONCLUSIONS: Gene expression analysis failed to identify patients with BRAF-mutant mCRC candidate to upfront FOLFOXIRI/bevacizumab. ECOG-PS >0 and left-sidedness seem associated with no benefit from the intensified treatment.
BACKGROUND: Recent data from the TRIBE2 study have failed to suggest a higher magnitude of benefit from upfront FOLFOXIRI/bevacizumab in patients with BRAF-mutant metastatic colorectal cancer (mCRC) as previously reported in the TRIBE study. PATIENTS AND METHODS: Clinical characteristics and gene expression signatures of patients with BRAF-mutant mCRC enrolled in the TRIBE2 study were evaluated with the aim of understanding that patients may derive benefit from the intensification of the upfront chemotherapy. RESULTS: Of 46 BRAF-mutant tumour samples analysed, 24 (52%) and 22 (48%) were classified as BM1 and BM2, respectively, and 27 (59%) and 19 (41%) were assigned to ligand-independent (LI) and ligand-dependent (LD) Wnt pathway subgroups, respectively. No prognostic impact was shown for both BM1/BM2 and LI/LD subtypes. No interaction was evident between BM1/BM2 or LI/LD signatures and the benefit provided by FOLFOXIRI/bevacizumab. Significant interaction effect was evident in terms of progression-free survival between treatment arm and primary tumour sidedness (P = 0.05) and Eastern Cooperative Oncology Group performance status (ECOG-PS; P < 0.001). CONCLUSIONS: Gene expression analysis failed to identify patients with BRAF-mutant mCRC candidate to upfront FOLFOXIRI/bevacizumab. ECOG-PS >0 and left-sidedness seem associated with no benefit from the intensified treatment.