Prognostic value of KRAS exon 3, exon 4, and NRAS mutations in pathological stage III colon cancer.

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224 Background: The molecular status of RAS , BRAF and MSI may serve as a biomarker for estimating survival for patients with both metastatic colorectal cancer and colon cancer (CC) undergoing curative surgery. However, there are few reports on CC patients with minor RAS mutations ( KRAS exon 3, exon 4 and NRAS , MTs), and their clinical significance remains unclear. Methods: We examined clinicopathological variables and prognosis in patients with surgically resected pathological stage III (pStage III) CC who were treated with adjuvant chemotherapy. Associations between molecular status of RAS , BRAF and MSI including minor RAS MTs and recurrence free survival (RFS), overall survival (OS) were assessed using a Cox Hazard model. Results: Between 2018 and 2022, we measured the RAS / BRAF mutation status in 2,014 patients with unresectable or resectable colorectal cancer, including recurrent cases. Of these, a total of 309 patients with pathological stage III colon cancer from the cecum to the upper rectum had their RAS / BRAF status examined, and 254 of them who received adjuvant chemotherapy were included in the analysis. Among these patients, KRAS exon 2, minor RAS , BRAF mutations, and RAS / BRAF wild-type status were detected in 37.8%, 7.1%, 11.0%, and 44.1%, respectively. The minor RAS MTs group was MSS /pMMR in all cases and had a low prevalence of pT4 (15.8%), whereas left-sided primary tumor location (77.8%) were more common than in the other groups. Three-year RFS/OS rates were 76.7%/96.6% for the KRAS exon 2 MT group, 94.4%/94.1% for the minor RAS MTs group, 71.4%/81.8% for the BRAF MT group, and 80.9%/97.3% for the WT group, respectively. The minor RAS MTs group showed a tendency toward better RFS, though there was no significant difference when compared with the KRAS exon 2 MT group (HR, 0.22; 95% CI, 0.03–1.60; P = 0.13), the BRAF MT group (HR, 0.18; 95% CI, 0.02–1.41; P = 0.06), or the WT group (HR, 0.26; 95% CI, 0.04–1.92; P = 0.16). Furthermore, a comparison of each minor RAS mutation variant with the KRAS exon 2 mutation showed no significant differences in RFS. In multivariate analysis, pN2 was an independent factor associated with RFS (HR, 2.54; 95% CI, 1.46–4.41; P < 0.001) and the presence of minor RAS MTs was also a promising factor associated with RFS, though there was no significant difference (HR, 0.22; 95% CI, 0.03–1.59; P = 0.13). Conclusions: Patients with pStage III CC and minor RAS MTs exhibit distinct clinical and pathological features, with a low incidence of postoperative recurrence and potentially favorable survival outcomes.

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