Preclinical identification and clinical validation of dynamic biomarkers for trifluridine/tipiracil with or without bevacizumab in metastatic colorectal cancer

Background: Biomarkers predicting response to trifluridine/tipiracil (FTD/TPI) with or without bevacizumab (BEV) in refractory metastatic colorectal cancer (mCRC) remain unclear. We identified candidate biomarkers in preclinical models and evaluated their clinical relevance. Materials and methods: Candidate biomarkers were identified through preclinical transcriptomic analyses. Serum interleukin (IL)-8, epiregulin (EREG), amphiregulin (AREG), interferon-inducible protein 16 (IFI16), and vascular endothelial growth factor A (VEGF-A) were measured in two cohorts treated with FTD/TPI+BEV or FTD/TPI alone. Samples were collected at baseline, before cycle 2, and at progression. Biomarker changes were categorized as increased or decreased. Propensity score matching was carried out, and survival outcomes were compared according to biomarker dynamics. Results: Among 112 patients, 34 matched pairs were analyzed after propensity score matching. FTD/TPI+BEV yielded longer overall survival (OS) than FTD/TPI alone [10.5 versus 6.2 months; hazard ratio (HR) 0.53]. Increased IL-8 at cycle 2 and elevated IFI16 at progression were associated with poorer prognosis, whereas decreased AREG at cycle 2 predicted improved survival. In patients with increased IL-8, OS was longer with FTD/TPI+BEV than with FTD/TPI alone (12.8 versus 5.8 months; HR 0.43). Early EREG decrease was associated with better OS only in the FTD/TPI+BEV group. No significant interaction was observed between treatment and biomarker dynamics. Conclusion: On-treatment changes in IL-8, AREG, and EREG may serve as prognostic-and potentially predictive-biomarkers of FTD/TPI efficacy in mCRC. These findings support further evaluation of biomarker-guided treatment strategies.