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.
背景：结直肠癌肝转移患者总体生存预后较差的分子与临床基础尚未明确。本研究旨在通过对比分析探讨结直肠癌肝转移的分子与临床特征。方法：通过机构结直肠癌分子数据库筛选2014年至2022年确诊的转移性结直肠癌患者。采用Fisher精确检验分析分类变量，通过Kaplan-Meier法和多变量Cox回归模型分析人口统计学、临床及分子数据。结果：共纳入299例转移性结直肠癌患者，其中肝转移组205例，非肝转移组94例。结肠癌患者肝转移发生率显著高于直肠癌患者（74% vs. 48%，p=0.00013）。肝转移组与非肝转移组在KRAS、BRAF、TP53等常见驱动基因突变发生率方面无显著差异。肝转移组中位总生存期呈现缩短趋势（42.2 vs. 47.6个月，p=0.27），但未达统计学显著性。肝转移被证实是前线治疗持续时间缩短的独立预测因子（HR 1.82，p<0.001），该指标可作为治疗反应的替代指标：肝转移组一线至二线治疗中位时间为13个月，显著短于非肝转移组的19.7个月（p=0.00098）。在肝转移组中，KRAS突变是生存预后不良的显著预测因子（HR 2.01，p<0.001）；而在非肝转移组中，BRAF突变具有显著预测价值（HR 3.42，p=0.006）。结论：结直肠癌肝转移与前线治疗持续时间缩短相关，提示可能存在化疗耐药性。鉴于肝转移与非肝转移患者分子改变发生率相似，治疗耐药性可能与肝脏肿瘤微环境相关。值得注意的是，本研究首次揭示：尽管分子改变发生率相似，但包括BRAF和KRAS在内的驱动基因突变对生存结局的影响可能因转移部位而异。
肿瘤(癌症)患者之家