Anti-EML4 monoclonal antibody, clone 4D21

The ALK gene encodes a transmembrane tyrosine kinase receptor. ALK is physiologically expressed in the nervous system during embryogenesis, but its expression decreases postnatally. ALK first emerged in the field of oncology in 1994 when it was identified to fuse to NPM1 in anaplastic large-cell lymphoma. Since then, ALK has been associated with other types of cancers, including non-small-cell lung cancer (NSCLC). More than 19 different ALK fusion partners have been discovered in NSCLC, including EML4, KIF5B, KLC1, and TPR. Most of these ALK fusions in NSCLC patients respond well to the ALK inhibitor, crizotinib. In this paper, we reviewed fusion partner genes with ALK, detection methods for ALK-rearrangement (ALK-R), and the ALK-tyrosine kinase inhibitor, crizotinib, used in NSCLC patients.

An 85-yr-old woman was diagnosed with endometrial adenocarcinoma, endometrioid type. Imaging studies showed a large tumor distending the endometrial canal without evidence of local invasion or extrauterine disease. A hysterectomy was performed, followed by microscopic examination of longitudinal tissue sections. Histopathological review showed only focal myometrial invasion, equivocal lymphovascular invasion, and negative bilateral sentinel lymph nodes (FIGO stage IA). A sample of the tumor was submitted for molecular testing (massively parallel sequencing on OncoPanel) and was found to harbor an inversion on Chromosome 2 resulting in an EML4-ALK gene fusion. Confirmatory immunohistochemistry showed ALK overexpression in just a portion of the tumor. Additional genomic characterization on a region of the tumor lacking ALK overexpression by immunohistochemistry was highly congruous with the genomic profile of the ALK-positive portion, showing similar patterns of copy-number variation and mutations in TP53 and KDM5C, with no evidence for an EML4-ALK gene fusion, confirming that EML4-ALK rearrangement had occurred as a sub-clonal process. EML4-ALK fusions are driver events in 2%-5% of non-small-cell lung cancers; crizotinib is an approved targeted therapy for these patients. EML4-ALK rearrangements have not previously been reported in endometrial cancer.