Molecular Biomarkers & Diagnosis

Dynamic Changes of EGFR Activating Mutations as an Early Predictor of Progression in Non�Small Cell Lung Cancer Patients Treated with EGFR Tyrosine Kinase Inhibitors

Abstract

Izidor Kern, Tanja Cufer, Mitja Rot, Katja Mohorcic, Igor Pozek, John F Palma, Sidney A Scudder, Partha M Das and Aleksander Sadikov

Serial monitoring of circulating tumor DNA may predict resistance to first-line epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors before CT-confirmed progression. Our objective was to evaluate dynamic changes in plasma EGFR-activating mutations as an early predictor of disease progression before clinical or radiological evidence. For this observational study, 35 patients with advanced, EGFR-positive, nonsquamous, non-small cell lung cancer were enrolled. All patients were initiating or receiving EGFR tyrosine kinase inhibitors and had received at least one follow-up CT scan. Peripheral blood samples were collected at each clinical visit, and CT scans were scheduled every 8 to 16 weeks after tyrosine kinase inhibitor initiation and upon clinical/symptom progression. Of the 35 patients, 16 experienced reappearance of EGFRactivating mutations and disease progression. Of these, 12 patients experienced reappearance of EGFR-activating mutations before CT-confirmed progression, 3 had CT-confirmed progression one visit (8 weeks) before detectable EGFR-activating mutations, and 1 had EGFR-activating mutations reappear concurrently with CT-confirmed progression. EGFR-activating mutations reappeared at a mean of 10 weeks (median, 16 weeks) before routinely scheduled CT-confirmed progression. Using study-specific definitions, we observed 5 false positives and no false negatives. This study demonstrates that dynamic changes in circulating tumor DNA can predict resistance to EGFR-TKIs before CT-confirmed progression. Further prospective trials of this promising approach with potential benefits to patient care should be considered.