KRAS-G12C Mutation in One Real-Life and Three Population-Based Nordic Cohorts of Metastatic Colorectal Cancer

Abstract

<p><strong>Background: </strong><em>KRAS</em> mutations, present in over 40% of metastatic colorectal cancer (mCRC), are negative predictive factors for anti-EGFR therapy. Mutations in <em>KRAS-</em>G12C have a cysteine residue for which drugs have been developed. Published data on this specific mutation are conflicting; thus, we studied the frequency and clinical characteristics in a real-world and population-based setting.</p><p><strong>Methods: </strong>Patients from three Nordic population-based cohorts and the real-life RAXO-study were combined. <em>RAS</em> and <em>BRAF</em> tests were performed in routine healthcare, except for one cohort. The dataset consisted of 2,559 patients, of which 1,871 could be accurately classified as <em>KRAS</em>, <em>NRAS</em>, and <em>BRAF</em>-V600E. Demographics, treatments, and outcomes were compared using logistic regression. Overall survival (OS) was estimated with Kaplan-Meier, and differences were compared using Cox regression, adjusted for baseline factors.</p><p><strong>Results: </strong>The <em>KRAS-</em>G12C frequency was 2%-4% of all tested in the seven cohorts (mean 3%) and 4%-8% of <em>KRAS</em> mutated tumors in the cohorts (mean 7%). Metastasectomies and ablations were performed more often (38% vs. 28%, p = 0.040), and bevacizumab was added more often (any line 74% vs. 59%, p = 0.007) for patients with <em>KRAS-</em>G12C- vs. other <em>KRAS</em>-mutated tumors, whereas chemotherapy was given to similar proportions. OS did not differ according to <em>KRAS</em> mutation, neither overall (adjusted hazard ratio (HR) 1.03; 95% CI 0.74-1.42, reference <em>KRAS</em>-G12C) nor within treatment groups defined as "systemic chemotherapy, alone or with biologics", "metastasectomy and/or ablations", or "best supportive care", <em>RAS</em> and <em>BRAF</em> wild-type tumors (n = 548) differed similarly to <em>KRAS</em>-G12C, as to other <em>KRAS</em>- or <em>NRAS</em>-mutated (n = 66) tumors.</p><p><strong>Conclusions: </strong>In these real-life and population-based cohorts, there were no significant differences in patient characteristics and outcomes between patients with <em>KRAS-</em>G12C tumors and those with other <em>KRAS</em> mutations. This contrasts with the results of most previous studies claiming differences in many aspects, often with worse outcomes for those with a <em>KRAS-</em>G12C mutation, although not consistent. When specific drugs are developed, as for this mutation, differences in outcome will hopefully emerge.</p><p>ill hopefully emerge.</p>