Association of KRAS variants with survival and therapeutic outcomes in biliary tract cancers

Biliary tract cancer (BTC) remains a highly aggressive malignancy with limited treatment options and poor prognosis. To explore the association between KRAS variants and survival/therapeutic outcomes of patients with BTC, we analyzed genetic and clinical data obtained from BTC patients who underwent comprehensive genomic profiling (CGP) testing in Japan.

A total of 7773 patients with BTC who were registered in the Center for Cancer Genomics and Advanced Therapeutics (C-CAT) were included in this study. The main outcome was overall survival (OS) in months. For survival analysis, OS was measured from diagnosis to last follow-up or death, and for therapeutic outcomes, from treatment initiation to last follow-up or death.

The overall frequency of KRAS mutations in BTC was 23.4%. When classified according to tumor subtype, KRAS mutations were identified in 24.9% of patients with intrahepatic cholangiocarcinoma (IHC), in 32.2% of those with extrahepatic cholangiocarcinoma (EHC), and in 9.4% of those with gall-bladder cancer (GB). Among patients with KRAS mutations, G12D mutation was the most common in IHC (41.5%), EHC (35.9%), and GB (29.8%). In all BTC subtypes (IHC, EHC, and GB), patients with KRAS mutations had worse OS compared to those with wild-type KRAS. By KRAS variant, the G12D, G12V, and Q61H mutations were associated with poor OS in patients with IHC, while the G12D and G12V mutations were associated with poor OS in patients with EHC. Furthermore, in patients with unresectable BTC who received first-line treatment with regimens including gemcitabine, cisplatin, and durvalumab therapy, the G12D mutation was associated with poor OS across all regimens evaluated in this study.

KRAS variants were significantly associated with poor prognosis and unfavorable therapeutic outcomes in BTC patients and may serve as potential prognostic and predictive factors.