A comprehensive study of clinical and molecular features in patients with metastatic colorectal cancer with and without liver mets.
Authors: Magge Tara , Wang Shuaichao , Syed Masood Pasha , Nasrollahi Elham , McFarquhar Ashley , Overacre-Delgoffe Abigail E. , Singhi Aatur D. , Saeed Anwaar , Sahin Ibrahim Halil 
Published: January 2025

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Background:
Colorectal cancer (CRC) most frequently metastasizes to the liver, and patients (pts) with liver metastasis (mets) at the time of metastatic diagnosis tend to have poorer outcomes compared to pts with non-liver mets. However, the reason for this discrepancy is not well-defined. We thus aimed to identify any distinct molecular or clinical characteristics that could contribute to the poor outcomes associated with liver mets of CRC.
Methods:
Pts diagnosed with metastatic CRC from 2014-2022 were identified using the institutional molecular database of CRC. Demographic, clinical, and molecular data were collected by reviewing electronic medical records. Time to next treatment was defined as the time between 1st and 2nd line treatment. We utilized Fisher’s exact tests for categorical variables and both Kaplan-Meier analysis and multivariate Cox proportional hazards models to analyze survival data, with a p-value threshold of <0.05 for statistical significance.
Results:
We identified a total of 217 pts, including pts with liver mets (N=146) and non-liver mets (N=71) at time of diagnosis. Pts with non-liver mets were more likely to have rectal primary than those pts with liver mets (40% vs. 15%, p=0.0001), indicating a distinct pattern of recurrence. Common driver mutations such as KRAS, BRAF, and TP53 were observed at equal frequencies in the liver and non-liver cohorts. In pts without liver mets, age had a significant effect on OS (p < 0.05, HR 1.1). Pts without liver mets with colon primary had worse OS compared to rectum primary (HR= 0.48, 95% CI: 0.24–0.96, p = 0.038). For pts without liver mets, KRAS was not a predictor of outcomes, while BRAF was associated with poorer OS (p<0.001, HR 7.09, 95%CI: 2.31-21.8). Contrarily, for pts with liver mets, KRAS mutation was significantly associated with worse survival (mOS 40.4 vs 61.7 mos, HR 2.04, 95% CI: 1.26-3.30, p=0.004). BRAF mutations were also associated with worse OS for this cohort (p=0.039 and HR 2.86, 95%CI: 1.06-7.77). Median time to the next treatment was significantly shorter in pts with liver mets (13.6 mos) than in pts with non-liver mets (22.6 mos) (HR 1.82, 95% CI 1.28-2.59; p<0.001). OS was longer for pts with non-liver mets compared to those with liver mets (mOS 52.9 mos vs 46.7 mos) though it did not reach statistical significance, likely due to the small sample size.
Conclusions:
Liver metastasis of CRC is associated with systemic therapy resistance with a shorter time on treatment, indicating treatment resistance associated with liver mets is not limited to immunotherapy. Given similar molecular characteristics in pts with and without liver mets, treatment resistance may be related to the inherent tumor microenvironment of the liver. In this study, pts with distinct molecular features had poorer outcomes, highlighting the importance of developing targeted therapeutics in this population.