A clinical and molecular comparative analysis of KRAS exon-2 and KRAS non-exon-2 mutated colorectal cancer.

Abstract

212 Background: KRAS-mutated colorectal cancer (CRC) represents a biologically heterogeneous group of diseases. Majority of KRAS mutations seen in CRC are known to be exon-2 mutations, while exon-3 and exon-4 mutations are relatively uncommon. Currently, little is known about clinical and molecular differences between exon-2 and non-exon-2 mutant CRC. In this study, we investigated clinical characteristics along with molecular and inflammatory features of exon-2 vs non-exon-2 mutated CRC. Methods: In this study, we examined 235 and 45 patients diagnosed with CRC who had molecular testing at UPMC Hillman Cancer Center, respectively. We collected relevant demographic, clinical, laboratory, and molecular data by retrospective review of electronic medical records. Fisher's Exact test was utilized for comparative analyses, and Cox proportional hazards regression and Kaplan-Meier survival analyses were used to examine the association of these factors with overall survival (OS). Results: A total of 235 patients with exon 2 KRAS–mutated and 45 with non–exon 2 KRAS–mutated MSS CRC were included. Median age was 61 for both groups and colon was the primary tumor site in most patients (exon 2 72% vs non-exon 2 69%). Notably, non–exon 2 KRAS mutations were more common in females (exon 2 45% vs non–exon 2 64%, p = 0.022) and significantly more frequent in left-sided tumors compared to KRAS exon-2 mutations (exon 2 64% vs non–exon 2 82%, p = 0.023). Concurrence of PIK3CA co-mutations with KRAS exon-2 and non-exon 2 mutations were 11% vs 16%, respectively (p = 0.40). Median TMB was 8.86 for both groups. At baseline, high platelet counts were significantly more common in exon 2 group than those with non-exon 2 mutations (28% vs 4.4%; p = 0.01). No significant differences were observed for baseline neutrophil counts, lymphocyte counts, PLR, or albumin. There was no significant difference in OS between exon 2 and non–exon 2 groups (HR 1.40, 95% CI 0.87–2.25, p = 0.20). In exon 2 group, high WBC (HR 1.61, 95% CI 1.13–2.29, p = 0.008) and high neutrophils (HR 1.60, 95% CI 1.14–2.25, p = 0.014) were associated with worse OS. Higher NLR (p < 0.001) and PLR (p < 0.001) were also associated with poorer OS. In non-exon 2 group, only higher NLR was associated with worse OS (p = 0.023). Conclusions: Our study reveals that non–exon 2 KRAS mutations may occur more frequently in females and is associated with left-sided tumors, whereas exon 2 mutations were linked to baseline higher platelet counts. Although KRAS mutation exon subtype was not prognostic, elevated inflammatory markers—especially high WBC, neutrophils, NLR, and PLR—predicted poor outcomes among patients with exon 2 KRAS mutations and only NLR significant in non–exon 2 tumors. These findings provide further insight into clinical and biological difference of exon-2 and non-2 exon KRAS mutations seen in CRC.