Prognostic Differences of RAS Mutations: Results from the South Australian Metastatic Colorectal Registry

Background Effective targeting of RAS mutations has proven elusive until recently. Novel agents directly targeting KRAS G12C have shown promise in early-phase clinical trials that included patients with metastatic colorectal cancer. Prior reports have suggested that G12C mutation may be predictive of poor outcome. Objective Assessment of the specific characteristics and prognostic implications of individual RAS mutation subtypes in patients with metastatic colorectal cancer. Patients and methods Retrospective review of individual RAS mutation types from the South Australian Metastatic Colorectal Registry between 2006 and 2020. Results Of the 5165 patients entered onto the registry, 2305 (45%) had RAS mutation results available. 772 (33%) had a RAS mutation. The nature of the RAS mutation was available in 668 (87% of those with RAS mutation). Rare mutations (outside codons 12 and 13) made up 12.6% of the total. There were numerical differences in survival between the specific RAS mutation subgroups, with the longest median overall survival (30 months) observed in those with G12S mutations. However, there was no statistical difference in survival when comparing the various RAS mutations, including the comparison of G12C to G12S (p = 0.38). Patients with cancer harbouring rare RAS mutations had a median survival of 30 months. Conclusions Whilst the G12S mutation was associated with the longest survival numerically, the observed survival for patients with the most common RAS mutations (G12C, G12V, G12A, G12D and G13D) did not significantly differ.

Automated summary

This study retrospectively reviewed individual RAS mutation subtypes in patients with metastatic colorectal cancer in South Australia, finding that there were numerical differences in survival between different RAS mutation subgroups, but no statistically significant differences. Although patients with G12S mutation had numerically the longest survival, patients with the most common RAS mutations did not significantly differ in terms of survival.