Early Detection of Multiple Resistance Mechanisms by ctDNA Profiling in a Patient With EGFR-mutant Lung Adenocarcinoma Treated With Osimertinib

Despite impressive initial responses, most patients with epidermal growth factor receptor (EGFR)-mutant lung adenocarcinoma develop resistance to EGFR-targeted therapies. One known mechanism of resistance is small-cell lung cancer (SCLC) transformation. Detecting this transformation and adjusting treatments in a timely manner can be difficult owing to rebiopsy challenges. We present the case of a patient with EGFR-mutant adenocarcinoma of the lung with early detection of disease recurrence by liquid biopsy profiling. Furthermore, loss-of-function mutations in RB1 and TP53, typical of SCLC, and the C797S point mutation in EGFR revealed by serial liquid biopsy increased suspicion for multiple mechanisms of resistance. In fact, SCLC transformation was later confirmed by tissue biopsy of an axillary lymph node. Molecular testing on the lymph node detected the RB1 and TP53 but not the C797S mutation, suggesting the presence of different co-existing molecular subclones in metastatic sites. The present case illustrates the benefit of serial circulating tumor DNA analysis to monitor patients' tumor progression and adapt systemic therapy. Profiling liquid biopsies in addition to histology may help identify patients at risk for SCLC transformation, improve clonal characterization of the disease, and tailor the patient's treatment earlier. (C) 2020 Elsevier Inc. All rights reserved.