Dynamic plasma KRAS and EGFR ctDNA profiling identifies treatment response and nascent resistance in metastatic lung cancer

Background: Liquid biopsy enables minimally invasive tumor genomic assessment. We evaluated serial circulating tumor DNA (ctDNA) monitoring for KRAS and EGFR in metastatic lung cancer to characterize mutational dynamics, correlate changes with clinical events, and assess plasma testing for early resistance detection. Aims: Describe longitudinal KRAS and EGFR plasma patterns during systemic therapy and relate ctDNA kinetics to treatment changes and outcomes. Methods: Thirty-five metastatic lung cancer patients were prospectively enrolled (31.4% female; median age 70, IQR 41-84). Plasma was collected at baseline and, for 20 patients, at weeks 4, 8, 12 and 24 and thereafter until progression or death. KRAS and EGFR status was assessed with targeted ctDNA assays using the Idylla platform. Results: Tissue-plasma concordance was fair to moderate for KRAS and EGFR (Cohen's kappa 0.35 and 0.43). Serial monitoring showed marked interpatient heterogeneity and dynamic shifts in mutant allele fractions. Two patients had early KRAS increases at week 4; one died and the other progressed to second-line therapy and developed a second KRAS codon 12 mutation (G12R alongside baseline G12C) at week 8, consistent with clonal diversification. Another patient showed oscillating KRAS detection-present at baseline and week 8 but absent at weeks 4 and 12-suggesting transient clonal suppression and re-expansion related to treatment scheduling. One patient's EGFR levels tracked therapy: high at baseline and week 4, cleared at week 8 after switching to Amivantamab, then reappeared at week 12 after treatment discontinuation for toxicity. EGFR mutations were observed in one patient only (8.3%); others remained EGFR wild type throughout follow-up. Conclusions: Longitudinal plasma KRAS and EGFR testing captured evolving mutational landscapes that anticipated progression and reflected treatment effects, including emergence of secondary clones and transient suppression of mutant fractions. Serial ctDNA profiling is a pragmatic adjunct to tissue genotyping for early resistance detection and therapeutic guidance. Larger cohorts are needed to quantify predictive performance and integrate ctDNA kinetics into clinical decision algorithms.