1. Introduction
colorectal cancer, tumor, CRC, cancer, mCRC, tumors
METASTATIC COLORECTAL CANCER, TUMOR, METASTATIC TUMOR, ONCOGENESIS, CANCER, TUMORS, APC, TUMOR VASCULATURE, COLORECTAL CANCER
These authors contributed equally to this work.Single-agent regorafenib is approved in Canada for metastatic colorectal cancer (mCRC) patients who have failed previous lines of therapy. Identifying prognostic biomarkers is key to optimizing therapeutic strategies for these patients. In this clinical study (NCT01949194), we evaluated the safety and efficacy of single-agent regorafenib as a second-line therapy for mCRC patients who received it after failing first-line therapy with an oxaliplatin or irinotecan regimen with or without bevacizumab. Using various omics approaches, we also investigated putative biomarkers of response and resistance to regorafenib in metastatic lesions and blood samples in the same cohort. Overall, the safety profile of regorafenib seemed similar to the CORRECT trial, where regorafenib was administered as ≥ 2 lines of therapy. While the mutational landscape showed typical mutation rates for the top five driver genes (APC, KRAS, BRAF, PIK3CA, and TP53), KRAS mutations were enriched in intrinsically resistant lesions. Additional exploration of genomic-phenotype associations revealed several biomarker candidates linked to unfavorable prognoses in patients with mCRC using various approaches, including pathway analysis, cfDNA profiling, and copy number analysis. However, further research endeavors are necessary to validate the potential utility of these promising genes in understanding patients’ responses to regorafenib treatment.Colorectal cancer (CRC) is the third most common cancer in Canada and the United States and is the second most common cause of cancer mortality [First-line therapy for metastatic colorectal cancer (mCRC) in Canada is a combination of chemotherapy drugs. FOLFOX includes fluorouracil (5-FU) as a 46 h infusion, folinic acid, and oxaliplatin, whereas XELOX contains the prodrug capecitabine instead of 5-FU. In the FOLFIRI combination, oxaliplatin is replaced with the topoisomerase inhibitor irinotecan, and it is administered alone or in combination with the anti-angiogenic agent bevacizumab. Anti-angiogenic agents have been incorporated into clinical practice to treat mCRC, improving PFS and median overall survival (mOS) [The mitogen-activated protein kinase (MAPK) signaling pathway (RAS/RAF/MEK/ERK) plays an important role in mediating responses to growth signals and angiogenic factors [Regorafenib is a multikinase inhibitor, targeting both tumor cell proliferation/survival and tumor vasculature, including vascular endothelial growth factor (VEGF). Regorafenib deactivates tumors across three dimensions: angiogenesis, oncogenesis, and stromagenesis [Currently, no clinically validated biomarkers can be used to direct the treatment of mCRC patients receiving anti-angiogenic agents. The quantification of angiogenesis, both through circulating biomarkers such as VEGF and VEGFR2 and through the analysis of angiogenesis biomarkers and other microvascular density indicators in tumor tissue, has been thoroughly investigated [The efficacy of regorafenib in treating mCRC in the context of RAS or BRAF mutations remains a subject of varied and sometimes conflicting findings. Studies like those by Garcia-Alfonso et al. [Similarly, our goal is to establish a prognostic biomarker signature of clinical response or resistance to regorafenib in mCRC patients that can be rapidly translated to clinical settings. To achieve this goal, we analyzed metastatic tumor tissue and serial blood samples from 47 mCRC patients who received single-agent regorafenib as second-line therapy after failing first-line therapy with an oxaliplatin and/or irinotecan-containing regimen with or without bevacizumab. This trial (Q-CROC-06) is a sequential second-line trial based on our previous Q-CROC-01 observational trial [