Molecular concordance and clonal dynamics of KRAS mutations in lung adenocarcinoma across distinct clinical scenarios

Following the approval of KRAS G12C inhibitors, the necessity of serial KRAS testing remains debated. This study evaluates the molecular concordance and dynamic evolution of KRAS mutations across different clinical scenarios and explores their diagnostic utility in differentiating multiple primary lung cancers (MPLCs) from intra-pulmonary metastases.

A total of 108 patients with paired NGS tests and ≥ 1 KRAS-positive result were categorized into three groups: Group A (same lesion sampled longitudinally, n = 16; stratified by neoadjuvant therapy status), Group B (synchronous MPLCs, n = 30), and Group C (longitudinal monitoring of distinct lesions, n = 62). Group C was further stratified into three subgroups based on lesion relationships: metastasis-to-metastasis (C1), primary-to-metastasis (C2), and primary-to-new pulmonary lesion (C3).

In Group A, the intra-lesional KRAS retention rate was 100% in upfront surgery without prior treatment, but decreased to 83.3% after neoadjuvant therapy. In Group B, 80.0% (24/30) of multifocal cases exhibited inter-lesion molecular discordance, including 7 cases with distinct KRAS amino acid subtypes that confirmed synchronous MPLCs. In Group C, molecular concordance was significantly lower between primary and new pulmonary lesions (C3) than between primary and metastatic lesions (C2) (65.5% vs. 88.5%, P = 0.046). Baseline variant allele frequency (VAF) served as a strong predictor of subsequent KRAS loss (median VAF: 8.4% vs. 22.4%, P = 0.031). Furthermore, patients with co-mutations of EGFR and KRAS were more prone to experience KRAS loss than those with isolated KRAS mutations (70.0% vs. 12.0%, P < 0.001).

KRAS mutations display scenario-dependent concordance, remaining clonally stable in true metastases while exhibiting divergence in independent primary lesions or under therapeutic selection. Repeat NGS testing should be prioritized for patients presenting with new or multifocal pulmonary lesions, lower baseline KRAS VAF, or co-occurring EGFR mutations.