3. Discussion
tumor, colorectal cancer, cancers, CRC, cancer
TUMOR, METASTASIS, COLORECTAL CANCER, CANCERS, ADVERSE EVENTS, CANCER, SOLID TUMORS, HEPATOCELLULAR CARCINOMA, AMPLIFICATION, CELLULAR PROLIFERATION, CHROMOSOME ABERRATIONS
Large phase III randomized clinical trials indicated that regorafenib improved PFS and OS in refractory mCRC, with 1.4 to 2.5 months of survival and manageable adverse events [According to the 2023 ESMO guidelines, regorafenib is recommended as a third- and further-line treatment in patients pre-treated with fluoropyrimidines, oxaliplatin, irinotecan, and biologics, if available, or in earlier lines of therapy following oxaliplatin and irinotecan regimen failure [It is important to acknowledge that our study is exploratory in nature and encompasses a limited number of patients. In this study, the observed median PFS of 1.84 months for regorafenib as a second-line therapy aligns closely with the PFS outcomes reported in the regorafenib phase III CORRECT trial (1.9 months) [Overall, our study provided consistent insights into the safety profile of regorafenib as a second-line treatment while also reaffirming the feasibility of acquiring metastasis biopsies within this setting, ensuring their adequacy for subsequent comprehensive molecular profiling.Our study has identified a list of potential prognostic biomarker candidates for response or resistance to regorafenib based on PFS and objective tumor response. At the RNA level, activation of TGF-β and MAPK signaling pathways was identified as marker candidates for poor lesion response to regorafenib, while the adherens junction pathway was significantly enriched in lesions from patients with shorter PFS. The revelation that the TGF-β pathways play a central role in conferring resistance to a variety of cancer treatments is consistent with a decade of research. Notably, this pathway has been implicated in resistance to sorafenib in hepatocellular carcinoma, among other therapies [Despite being known to be associated with a poorer prognosis, there is no clear association between CMS4 and the best overall response to regorafenib in the present cohort. The lack of a direct association between the CMS4 subtype and patient response suggests that the interplay between various genetic and molecular factors is complex and requires further exploration in larger cohorts. However, intrinsically resistant lesions were highly enriched for the CMS4 subtype. Interestingly, this study also shed light on the heightened expression of three miRNAs (miR-365a-5p, miR-6510-3p, and miR-934) and a heightened incidence of mutations affecting amino acids 12 or 13 in KRAS within resistant lesions, providing potential candidates for future research into predictors of regorafenib treatment response. Two of the miRNAs (miR-365a-5p and miR-934) have already been described as targeting genes involved in cellular proliferation and cell signaling pathways [The dynamics of ctDNA throughout treatment or post-tumor resection have been established as predictive indicators of patient outcome and response to therapy, as evidenced by recent studies [At the copy number level, we report a list of CNAs associated with PFS that can serve in the future as a basis for studies investigating chromosome aberrations as potential markers of treatment response. Among several other gene candidates, MYC amplification was associated with a shorter PFS. Amplification is the most common mechanism of alteration of MYC in solid tumors and is reported to be found in approximately 10% of CRC patients [Our multi-omics analysis of lesions from mCRC patients treated with regorafenib as a second-line therapy has revealed several potential biomarkers indicative of poor prognosis and resistance to regorafenib. Intriguingly, many of these identified candidates have previously been linked to adverse outcomes and resistance not only in colorectal cancer but also in response to kinase inhibitors in a variety of other cancer types. This recurring pattern underscores the possibility of shared molecular mechanisms underlying resistance across different cancers and kinase inhibitor therapies. The candidates identified in our analysis, while promising, warrant further validation through studies involving larger sample sizes. This additional research is essential to confirm the reliability and clinical applicability of these biomarkers to improve patient outcomes in the context of regorafenib treatment for mCRC.