Not all point mutations are the same: A multi-institutional study of KRAS in colorectal liver metastases

Abstract

Background: KRAS mutations correlate with reduced overall survival (OS) among surgically treated patients with colorectal liver metastases (CRLM). Nonetheless, the association of different KRAS point mutations on outcomes remains relatively unknown. Methods: In a multi-institutional cohort of 9 tertiary care centers, 1373 patients with known KRAS mutational status were identified. The association of specific point mutations with survival was analyzed using the Kaplan Meier method and multivariable Cox proportional hazards analyses. Results: In total, 915 patients with KRAS wild-type tumors and 458 patients with known point mutations (G12A, G12C, G12D, G12S, G12V, G13D, G13C, G13R, G12R, and exon 3/4) were included. The median OS of patients with KRAS mutated tumors was 39.1 months versus 57.5 months for the wild-type group (P < 0.001). Four point mutations were identified as being of prognostic interest: G12A (median survival: 32.1 months), G12V (26.2 months), G13R (5.1 months), and G12R (11.4 months). Patients with these high-risk mutations had a median OS of 26.2 months, while patients with other point mutations had a median survival of 45.5 months (P = 0.001). Importantly, high-risk mutations were independent predictors of OS in multivariable analysis (HR: 2.15, P < 0.001), along with lymph node metastases, extrahepatic disease, pre/post-operative chemotherapy, number of metastases, and R1 resection status. Furthermore, compared to other KRAS point mutations the high-risk mutation group had a significantly higher risk of early mortality (HR: 1.49, P = 0.007). Conclusion: Patients with different KRAS mutations do not form a homogenous group with regard to prognosis (figure). There exists a high-risk mutational subgroup that has significantly worse prognosis. Determining which KRAS mutation exists may have a role in determining optimal medical and surgical therapy for patients with KRAS mutated CRLM.