Mortality Outcome Associated with Specific KRAS, NRAS, and BRAF Hot-Spot Mutations in Metastatic Colorectal Cancer Patients: A Retrospective Cohort Study

<b>Background/Objective:</b> The prognostic value of specific hot-spot mutations within <i>KRAS</i>, <i>NRAS</i>, and <i>BRAF</i> genes in metastatic colorectal cancer (mCRC) genes remains debatable. This study explores whether certain <i>KRAS</i>, <i>NRAS</i>, and <i>BRAF</i> mutations are associated with the risk of all-cause mortality in mCRC. <b>Methods:</b> We retrospectively analyzed records of 494 patients with mCRC treated at the University of Texas Medical Branch between January 2016 and July 2023. Data on genetic mutations and clinicopathological features were collected for this analysis. We estimated survival probabilities and conducted multivariable Cox proportional hazards regression to evaluate the impact of specific mutations on all-cause mortality risk. <b>Results:</b><i>KRAS</i> c.35G>T (p.Gly12Val) and c.34G>T (p.Gly12Cys) mutations were significantly associated with an increased risk of all-cause mortality in the overall mCRC population and the treated mCRC subgroup. <i>KRAS</i> c.38G>A (p.Gly13Asp) was significantly associated with an increased risk of all-cause mortality in the treated mCRC subgroup but <i>BRAF</i> c.1799T>A (p.Val600Glu) was significantly associated with an increased risk of all-cause mortality in the overall mCRC population. No significant association was observed between <i>NRAS</i> mutations and mortality risk in mCRC, possibly due to their lower frequency or different biological effects compared to <i>KRAS</i> and <i>BRAF</i> mutations. <b>Conclusions:</b> These findings suggest that specific <i>KRAS</i> [c.35G>T (p.Gly12Val), c.34G>T (p.Gly12Cys), and c.38G>A (p.Gly13Asp)] and <i>BRAF</i> c.1799T>A (p.Val600Glu) mutations may have prognostic value in mCRC. However, given the single-center study design and lack of direct therapeutic implications, larger multicenter studies are needed to substantiate these results and better define the clinical relevance of these mutations.