Dynamic monitoring of EGFR mutations in circulating tumor DNA for early detection of drug resistance in NSCLC patients on EGFR-TKI therapy

Background: Non-invasive access to the circulating tumor DNA (ctDNA) in blood of NSCLC patients (pts) enables the real-time monitoring of status and level of mutated EGFR gene DNA (mEGFR) during EGFR TKI treatment instead of retrospective evaluation of re-biopsied tumor tissue. We evaluated the feasibility of the longitudinal analysis of mEGFR level in plasma to indicate the acquired resistance to EGFR TKIs in NSCLC pts. Methods: Peripheral blood was prospectively collected from 30 advanced NSCLC pts at the time of diagnosis (baseline) and then every month during the 1st line EGFR-TKI treatment (erlotinib, gefitinib, afatinib) until clinical progression. The mutated EGFR ctDNA was analyzed quantitively using cobas EGFR Mutation Test v2 (Roche, Germany). Results: In 21 (70%) pts, who responded to EGFR TKIs, the mEGFR levels showed notable dynamics during treatment: the complete clearance of mEGFR in plasma was observed in the first 2 months, regardless the type of mutation. Also, the mEGFR levels remained undetectable in plasma for following 3-13 months during EGFR-TKI therapy. In 17 (57%) pts, a rapid raise to or above mEGFR baseline preceded clinical progression by 4-28 weeks. In 5 pts, the level of activating mEGFR raised together with the T790M level in plasma. In 9 (30%) pts, the plasma mEGFR level was undetectable at diagnosis and during treatment. Conclusion: The dynamic changes of mEGFR ctDNA levels in plasma of NSCLC pts reflect well their response to EGFR TKIs. The longitudinal monitoring of mEGFR levels in plasma allows to observe disease progression on EGFR TKIs much earlier than conventional imaging techniques. The study is ongoing.