Utility of Next-Generation Sequencing in the Reconstruction of Clonal Architecture in a Patient with an Mutated Advanced Non-Small Cell Lung Cancer: A Case Report.

EGFR tyrosine kinase inhibitors (EGFR-TKIs) have revolutionized the treatment of non-small cell lung cancer (NSCLC) patients with activating mutations. However, targeted therapies impose a strong selective pressure against the coexisting tumor populations that lead to the emergence of resistant clones. Molecular characterization of the disease is essential for the clinical management of the patient, both at diagnosis and after progression. Next-generation sequencing (NGS) has been established as a technique capable of providing clinically useful molecular profiling of the disease in tissue samples and in non-invasive liquid biopsy samples (LB). Here, we describe a case report of a patient with metastatic NSCLC harboring mutation who developed two independent resistance mechanisms (-T790M and + mutations) to dacomitinib. Osimertinib given as a second-line treatment eliminated the -T790M population and simultaneously consolidated the proliferation of the + clone that eventually led to the histologic transformation to small-cell lung cancer (SCLC). Comprehensive NGS profiling revealed the presence of the + clone in the pretreatment biopsy, while -T790M was only detected after progression on dacomitinib. Implementation of NGS studies in routine molecular diagnosis of tissue and LB samples provides a more comprehensive view of the clonal architecture of the disease in order to guide therapeutic decision-making.