DNA and RNA EGFR Variant Allele Fractions and Clinical Outcomes in Lung Adenocarcinoma.

BACKGROUND: Despite surgery or EGFR-targeted therapy, EGFR-mutant lung adenocarcinoma frequently recurs. Conventional staging and binary EGFR mutation status lack sufficient precision for risk stratification. Although variant allele fraction (VAF) reflects tumor clonality and allelic imbalance, the prognostic significance of DNA- and RNA-derived VAF in early-stage disease remains unclear. METHODS: We analyzed multi-omics data from patients with EGFR-mutant LUAD in the Taiwan Cancer Moonshot Program (RFS, n=133; TKI, n=48) and an independent Singaporean validation cohort (RFS, n=54; TKI, n=17). Whole-exome and RNA sequencing were integrated to quantify DNA and RNA VAFs. Patients were stratified into risk groups based on combined VAF measures. Associations with relapse-free survival (RFS) in stage I-III disease and progression-free survival (PFS) during TKI therapy were evaluated using multivariable Cox model adjusted for clinical covariates. RESULTS: VAF-based stratification identified a Low-risk group with a 5-year relapse rate of 11%, independent of pathological stage (p<0.001). Within this group, elevated TP53 RNA VAF was associated with increased relapse risk and younger age at diagnosis. Exploratory analyses comparing timing of TKI therapy indicated context-dependent associations: High-risk patients had shorter PFS when TKI therapy was deferred until relapse (p=0.047). In the adjuvant setting, mid- and high-risk patients showed numerically improved PFS with TKI therapy compared with low-risk patients (p=0.13). CONCLUSIONS: Integration of DNA and RNA EGFR VAFs refines risk stratification beyond stage and mutation status alone and may inform the timing of TKI therapy. Prospective validation is warranted.