Prognostic Impact of Blood Tumor Mutational Burden in pMMR/MSS Metastatic Colorectal Cancer Assessed by FoundationOne® Liquid CDx

<b>Background/Objectives:</b> The prognostic significance of blood tumor mutational burden (bTMB) in metastatic colorectal cancer (mCRC) remains poorly defined. While tissue-based TMB has been associated with favorable outcomes in selected colorectal cancer subgroups, the clinical meaning of bTMB in real-world practice is unclear. This study evaluated the prognostic impact of bTMB measured through liquid biopsy in an unselected cohort of patients with mCRC. <b>Methods:</b> This monocentric, real-world study included 255 adult patients with pMMR/MSS mCRC who underwent routine comprehensive genomic profiling using the FoundationOne^® Liquid CDx assay. bTMB was quantified in mutations per megabase (mut/Mb), and patients were classified into bTMB-low and bTMB-high groups using the cohort median. The primary endpoint was overall survival (OS). Subgroup analyses, including stratification by <i>RAS/BRAF</i> mutation status, were descriptive. <b>Results:</b> The median bTMB was 5 mut/Mb. Patients in the bTMB-high group had an increased risk of death compared with those in the bTMB-low group (hazard ratio (HR) 1.88). The adverse prognostic effect for OS of high bTMB was more pronounced in patients with <i>RAS</i> mutant tumors (HR 2.32) than with <i>RAS/BRAF</i> wild-type tumors (HR 1.81), while no prognostic impact was observed in <i>BRAF^V600E</i> mutant tumors (HR 0.90). bTMB was strongly correlated with ctDNA fraction (<i>p</i> < 0.0001). <b>Conclusions:</b> In routine clinical practice, elevated bTMB is associated with poor prognosis in pMMR/MSS mCRC, particularly in <i>RAS</i> mutant tumors. These results contrast with prior tissue-based studies and indicate that bTMB may reflect tumor burden and aggressive disease biology rather than tumor immunogenicity. Prospective studies integrating bTMB with ctDNA fraction, tumor burden metrics, and longitudinal molecular dynamics are warranted to refine its clinical utility.