Clinical outcome and molecular characterisation of chemorefractory metastatic colorectal cancer patients with long-term efficacy of regorafenib treatment

Background To investigate the potential predictors of response to regorafenib, in chemorefractory metastatic colorectal cancer (mCRC) patients with long-term efficacy from regorafenib treatment. Methods Retrospective, single institution analysis of patients with chemorefractory mCRC treated with regorafenib, in clinical practice setting. 123 patients were treated and stratified into two groups according to number of cycles received (<7 and ≥7). Overall survival (OS), progression-free survival (PFS) and safety were evaluated. 20 tumour samples (10 poor and 10 long responders) were analysed with the OncoMine Comprehensive Assay for 143 genes. Results A good Eastern Cooperative Oncology Group performance status, a lung limited metastatic disease and a long history of metastatic disease were significantly associated with better OS and PFS from treatment with regorafenib. Mutations were mostly found in TP53, KRAS and PIK3CA as well as in NRAS, ERBB2, SMAD4 and PTEN genes. BCL2L1, ERBB2, KRAS, MYC, GAS6 gene amplifications were detected as well as ALK rearrangement. No significant correlation between molecular alterations and response to regorafenib was observed. However, HER2 gene alterations were found in three poor responder patients, suggesting a potential role in regorafenib resistance. Conversely, GAS6 amplification and SMAD4 mutation, detected in two long responder patients, might suggest a role of epithelial-mesenchymal transition phenotype in regorafenib response. Conclusion A subgroup of long responder patients to regorafenib treatment was identified and a comprehensive molecular characterisation was performed; however, further research efforts are essential to confirm our data.