# A Comparative Study of Clinical and Molecular Features of Microsatellite Stable Colorectal Cancer With and Without Liver Metastases

## TL;DR

This study compares colorectal cancer with and without liver metastases, finding that liver metastases are linked to shorter treatment response and distinct survival impacts based on mutation types.

## Contribution

The study is the first to show that driver mutations like BRAF and KRAS have site-specific survival impacts in metastatic colorectal cancer.

## Key findings

- Liver metastasis is associated with shorter time on frontline therapy, suggesting chemotherapy resistance.
- KRAS mutations predict worse survival in liver metastasis, while BRAF mutations do so in non-liver metastasis.
- Molecular alteration incidence is similar in liver and non-liver metastases, pointing to tumor microenvironment as a resistance factor.

## Abstract

Liver metastasis of colorectal cancer (CRC) is associated with worse survival outcomes and inferior response to immunotherapy. However, the molecular underpinnings of this phenomenon are not well established. Our study revealed that the incidence of molecular alterations is relatively similar between liver metastases and non-liver metastases of CRC, indicating the treatment resistance seen with liver metastasis is likely driven by intrinsic tumor microenvironment characteristics of the liver. In our study, we also identified that liver metastasis of CRC is associated with shorter time on frontline therapy, a surrogate for treatment response. This suggests that inferior treatment response seen with liver metastasis is not limited to immunotherapy but also may apply to chemotherapy. We also discovered the metastatic site-specific impact of driver oncogenes, such as BRAF and KRAS mutations, pointing out that the impact of driver alterations on survival outcomes can vary depending on the site of metastasis of CRC.

Background: The molecular and clinical underpinnings of worse overall survival outcomes with liver metastasis of CRC are not well-defined. We therefore aimed to investigate molecular and clinical characteristics of liver metastasis of CRC in this comparative study. Methods: Patients diagnosed with metastatic CRC from 2014 to 2022 were identified using the institutional molecular database of CRC. Demographic, clinical, and molecular data were collected and analyzed using Fisher’s exact tests for categorical variables, Kaplan–Meier analysis, and multivariate Cox regression analysis. Results: We identified 299 total patients with metastatic CRC, including patients with liver metastasis (n = 205) and non-liver metastasis (n = 94). We observed a significantly higher incidence of liver metastasis among patients with colon cancer compared to rectal cancer (74% vs. 48%, p = 0.00013). There was no significant difference in the incidence of common driver mutations, including KRAS, BRAF, and TP53, in the liver versus non-liver metastasis cohorts. There was a trend toward worse median overall survival among patients with liver metastasis, though this was not statistically significant (42.2 vs. 47.6 months, p = 0.27). Liver metastasis was identified as a significant predictor of shorter time on frontline therapy (HR 1.82, p < 0.001), a surrogate for treatment response, with a median time of 13 months from first- to second-line treatment compared to 19.7 months in the non-liver metastasis cohort (p = 0.00098). KRAS mutations were a significant predictor of worse survival in the liver metastasis cohort only (HR 2.01, p < 0.001), while BRAF mutations were a significant predictor in the non-liver metastasis cohort (HR 3.42, p = 0.006). Conclusions: Liver metastasis of CRC is associated with shorter time on frontline therapy, indicative of potential chemotherapy resistance. Given similar incidence of molecular alterations in patients with liver metastasis and non-liver metastasis, therapeutic resistance may instead be related to the tumor microenvironment of the liver. Most notably, this is the first study to reveal that despite a similar incidence of molecular alterations, driver alterations including BRAF and KRAS mutations may have a distinct impact on survival outcomes depending on the site of metastasis.