A Comparative Study of Clinical and Molecular Features of Microsatellite Stable Colorectal Cancer With and Without...

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.