Cancer-derived inflammation is associated with bevacizumab resistance and inferior clinical outcomes in patients with metastatic colorectal cancer

Background: Cancer-derived inflammation has been shown to attenuate the efficacy of chemotherapy (CT) in colorectal cancer. However, its role in clinical response to bevacizumab (Bev) remains unclear in patients with metastatic colorectal cancer (mCRC). Objectives: To investigate the clinical significance of the fibrinogen-to-prealbumin ratio (FPR) as a biomarker in mCRC patients receiving first-line Bev plus CT (Bev/CT). Design: A retrospective, single-center, observational study. Methods: Patients treated with first-line Bev/CT were enrolled across discovery ( n = 249), internal validation ( n = 115), and external validation ( n = 109) cohorts, along with a patient group receiving CT alone ( n = 175). Propensity score matching was performed to balance baseline characteristics between the Bev/CT- and CT-treated groups. The primary endpoints were disease control rate (DCR) and progression-free survival (PFS), and 1-year overall survival (OS) was designated as a secondary endpoint. Results: Elevated pretreatment FPR was significantly associated with increased tumor burden. FPR-H patients exhibited an unfavorable DCR compared to the FPR-L patients in the overall Bev/CT-treated population (adjusted odds ratio (OR) = 2.18, 95% confidence interval (CI) = 1.32–3.61, p < 0.01). FPR-H was also independently associated with shorter PFS in the discovery ( p log-rank < 0.01, adjusted hazard ratio (HR) = 1.51, 95% CI = 1.11–2.05), internal validation ( p log-rank < 0.01, adjusted HR = 2.47, 95% CI = 1.43–4.27), and external validation cohorts ( p log-rank < 0.001, adjusted HR = 2.28, 95% CI = 1.43–3.64), regardless of KRAS status, particularly in the microsatellite stable subgroup. Furthermore, FPR-H patients had significantly worse 1-year OS than the FPR-L subgroup in the overall population ( p log-rank < 0.001; adjusted HR = 2.86, 95% CI = 1.78–4.61). Dynamic monitoring of FPR demonstrated utility in tracking disease progression during Bev/CT treatment, with earlier detection capability compared to imaging-based assessment. In propensity score-matched analysis, patients receiving Bev/CT showed superior outcomes relative to those receiving CT alone ( p log-rank < 0.001), especially among the FPR-L subgroup ( p log-rank < 0.01). In addition, Bev/oxaliplatin-treated FPR-L cases achieved better outcomes than those receiving the Bev/irinotecan regimen, particularly in the subgroup undergoing palliative resection. Conclusion: Cancer-derived inflammation appears to play a crucial role in mediating both intrinsic and acquired resistance to Bev. The FPR emerges as a robust, independent biomarker for predicting response to Bev, monitoring disease progression, and informing personalized therapeutic decision-making in patients with mCRC.