Response to crizotinib in a non-small-cell lung cancer patient harboring an fusion with an atypical insertion.

Fusion of the anaplastic lymphoma receptor tyrosine kinase gene () with the echinoderm microtubule-associated protein 4 gene () is the second most common actionable alteration in non-small-cell lung cancer, with a frequency of 5%. Here, we present a case of an EML4-ALK-positive patient with an atypical in-frame insertion from the gene in the canonical junction of . The patient was a 39-year-old never-smoker female diagnosed with Stage IV lung adenocarcinoma. A core biopsy was negative for and mutations but positive for ALK immunohistochemistry and fluorescence in situ hybridization. When submitted to nCounter, the sample showed a 3'/5' imbalance indicative of an rearrangement, but failed to give a positive signal for any of the variants tested. Finally, a band with a molecular weight higher than expected appeared after reverse transcriptase-polymerase chain reaction analysis. When Sanger sequencing was performed, the band revealed an atypical fusion gene with an in-frame 129 bp insertion. A 115 bp segment of the insertion corresponded to an intronic region of , a gene located in the short arm of chromosome 2, between and . The patient received crizotinib and showed a good therapeutic response that is still ongoing after 12 months. Our result suggests that short in-frame insertions of other genes in the junction do not affect the sensitivity of the EML4-ALK fusion protein to crizotinib.