Genomic Profiling of Circulating Tumor DNA in Relapsed EGFR-mutated Lung Adenocarcinoma Reveals an Acquired FGFR3-TACC3 Fusion

Progression during treatment with EGFR inhibitors is driven by the T790M resistance mutation in < 63% of cases, although many alternate mechanisms of resistance have been reported. Circulating tumor DNA (ctDNA) analysis is an effective noninvasive alternative to tissue profiling and is capable of detecting diverse resistance mechanisms to targeted therapy in clinical practice. We report a case of EGFR-mutated nonesmall-cell lung cancer (NSCLC) with progression during cetuximab plus afatinib treatment. Hybrid capture-based assay of ctDNA was performed as an alternative to tissue biopsy and identified an acquired FGFR3TACC3 fusion and the primary EGFR L858R mutation. The onset of resistance in the present case correlates with the acquisition of the FGFR3-TACC3 kinase fusion, previously described as a driver mutation in NSCLC and other tumors. This observation is consistent with the previous description of RET and ALK fusions being associated with acquired resistance to targeted therapy in NSCLC. This clinically novel observation indicates that a hybrid capture-based ctDNA assay can detect genomic alterations leading to acquired resistance in the context of pairwise comparison of hybrid capture-based tissue and ctDNA assays. (C) 2016 The Authors. Published by Elsevier Inc.