Association of KRAS Variant Subtypes With Survival and Recurrence in Patients With Surgically Treated Intrahepatic Cholangiocarcinoma

IMPORTANCE KRAS variants are associated with tumor progression; however, the prevalence of KRAS variant subtypes and their association with survival and recurrence in patients with intrahepatic cholangiocarcinoma (ICC) after curative resection are largely unknown. OBJECTIVE To explore the prognostic association of KRAS variant subtypes with survival and recurrence in patients with ICC. DESIGN, SETTING, AND PARTICIPANTS In this cohort study, patients who underwent curative resection for ICC from January 2009 through December 2016 at a single hospital in China were recruited, and whole-exome sequencing, targeted sequencing, and Sanger sequencing were performed to identify KRAS variants. Kaplan-Meier and log-rank tests were used to compare overall survival (OS) and disease-free survival (DFS). Univariate and multivariate analyses were performed using the Cox proportional hazards regression model. Data were analyzed from April 2020 to January 2021. INTERVENTIONS Hepatectomy in patients with ICC. MAIN OUTCOMES AND MEASURES The association of KRAS variant subtypes with OS and DFS. RESULTS Of 1024 included patients with ICC, 621 (60.6%) were male, and the mean (SD) age was 59.2 (10.2) years. A total of 14 different subtypes of KRAS somatic variants affecting 127 patients (12.4%) were identified. G12D was the most frequent allele in this cohort, accounting for 55 of 127 identified KRAS variants (43.3%), followed by G12V (25 [19.7%]), G12C (9 [7.1%]), and G13D (8 [6.3%]). Compared with patients with wild-type KRAS, patients with variant KRAS were more likely to have high levels of carbohydrate antigen 19-9 (92 of 127 [72.4%] vs 546 of 897 [60.9%]; P =.01) and gamma-glutamyltransferase (72 of 127 [56.7%] vs 420 of 897 [46.8%]; P =.04). Multivariable analysis revealed that G12 KRAS variants but not non-G12 KRAS variants were independently associated with worse OS (hazard ratio [HR], 1.69; 95% CI, 1.31-2.18; P <.001) and DFS (HR, 1.47; 95% CI, 1.16-1.88; P =.002). Among the patients with G12 KRAS variants, the G12V KRAS variant was the strongest prognostic determinant for the worst OS (HR, 3.05; 95% CI, 1.94-4.79; P <.001) and DFS (HR, 1.79; 95% CI, 1.13-2.85; P =.01). CONCLUSIONS AND RELEVANCE In this cohort study, the distribution of KRAS variant subtypes was characterized in a large cohort of patients with ICC from China. The presence of G12 KRAS variants but not non-G12 KRAS variants was associated with worse survival and increased risk of recurrence. Patients with the G12V variant exhibited the worst outcomes in the whole cohort.

Automated summary

This cohort study in China characterized the distribution of KRAS variant subtypes in a large group of ICC patients. The presence of G12 KRAS variants, specifically the G12V variant, was associated with worse survival and increased risk of recurrence.