# KRAS G12A Identifies a High-Risk Subset in Resected Stage II–III Colorectal Cancer

## TL;DR

The KRAS G12A mutation identifies a high-risk group of colorectal cancer patients with worse outcomes after surgery.

## Contribution

KRAS G12A is shown to be a distinct high-risk marker in stage II–III colorectal cancer, independent of other KRAS mutations.

## Key findings

- KRAS G12A is associated with significantly worse relapse-free and overall survival in stage II–III CRC patients.
- KRAS G12A mutations cluster with early recurrence within 12 months of surgery.
- KRAS G12A remains an independent prognostic factor in multivariable analyses.

## Abstract

Patients with stage II–III colorectal cancer (CRC) differ widely in their risk of relapse after surgery, even when they receive guideline-based adjuvant chemotherapy. Therefore, simple markers are needed to identify patients at particularly high risk after surgery. In this work, we showed that an uncommon KRAS variant, G12A, identifies a small subset of patients with stage II–III CRC who have a much higher likelihood of early recurrence and shortened survival. These findings, replicated in two independent cohorts, suggest that KRAS G12A should be recognized as a distinct high-risk marker in stage II–III disease and could be used to refine postoperative risk stratification.

Background: KRAS mutations are detected in ~40% of colorectal cancer (CRC), yet their prognostic value is heterogeneous across specific substitutions; the impact of uncommon variants, particularly in non-metastatic disease, remains uncertain. Methods: We evaluated the prognostic role of the relatively infrequent KRAS G12A substitution in two independent retrospective cohorts of stage II–III CRC treated with surgical resection without neoadjuvant therapy: an institutional series (FMU; n = 299) and a public dataset (AC-ICAM; n = 178). Tumors were genotyped for KRAS (and BRAF in AC-ICAM), and relapse-free survival (RFS) and overall survival (OS) were investigated. Results: KRAS G12A comprised 3.0% (FMU) and 3.4% (AC-ICAM). Across genotypes, G12A showed the highest univariable hazards compared to wild-type (WT) references for both RFS and OS in each cohort. Notably, RFS events among G12A clustered within 12 months of surgery. In multivariable Cox models, G12A remained independently associated with worse RFS and OS in each cohort, whereas non-G12A KRAS mutations did not differ significantly from the WT references. Conclusions: Across two cohorts, KRAS G12A identified a small but clinically meaningful high-risk subset of stage II–III CRC characterized by early recurrence and inferior survival. Recognition of this variant may inform postoperative risk stratification in the adjuvant setting.