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

## TL;DR

High blood tumor mutational burden (bTMB) is linked to worse survival in a specific type of colorectal cancer, especially in RAS mutant tumors.

## Contribution

This study shows that bTMB is a poor prognostic marker in pMMR/MSS mCRC, contrasting with tissue-based TMB findings.

## Key findings

- High bTMB was associated with shorter overall survival in pMMR/MSS mCRC patients.
- The adverse effect of high bTMB was stronger in RAS mutant tumors compared to RAS/BRAF wild-type tumors.
- bTMB correlated strongly with circulating tumor DNA fraction, suggesting it reflects tumor burden.

## Abstract

Blood-based tumor mutational burden (bTMB) can be measured from circulating tumor DNA using liquid biopsy and is increasingly used in clinical oncology. However, its prognostic value in metastatic colorectal cancer (mCRC) remains unclear. In this real-world, single-center study, we analyzed 255 patients with pMMR/MSS mCRC who underwent routine genomic profiling with the FoundationOne® Liquid CDx assay. We found that patients with high bTMB had significantly shorter overall survival, especially those with RAS mutant tumors. These results differ from previous reports based on tissue-derived TMB, which often suggested better outcomes in high-TMB tumors. Our findings indicate that, in routine practice, bTMB may reflect tumor burden and aggressive disease biology rather than tumor immunogenicity. This study highlights the need for careful interpretation of liquid biopsy biomarkers in mCRC.

Background/Objectives: 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. Methods: 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 RAS/BRAF mutation status, were descriptive. Results: 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 RAS mutant tumors (HR 2.32) than with RAS/BRAF wild-type tumors (HR 1.81), while no prognostic impact was observed in BRAFV600E mutant tumors (HR 0.90). bTMB was strongly correlated with ctDNA fraction (p < 0.0001). Conclusions: In routine clinical practice, elevated bTMB is associated with poor prognosis in pMMR/MSS mCRC, particularly in RAS 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.