Uterine mesenchymal tumors harboring ALK fusions and response to ALK-targeted therapy

Abstract

Inflammatory myofibroblastic tumor (IMT) of the uterus is a rare but aggressive malignancy that is often misdiagnosed. Approximately 50% of uterine IMTs (UMT) harbor rearrangements involving the ALK gene on chromosome 2p23 with subsequent overexpression of the ALK protein. Molecular characterization and wider availability of immunohistochemistry (IHC) and next generation sequencing (NGS) have improved clinical recognition and accurate diagnosis of UMT. The discovery of ALK fusions as a genomic driver led to the FDA approval of ALK inhibitors in ALK-altered lung cancers, but there are limited data to date on the spectrum of ALK fusions or patterns of response and resistance to ALK inhibitors in ALK-altered UMT. In this report we describe the genomic and histopathological characteristics and the response to ALK-targeted therapy in four patients with UMT. In all four patients, clinical activity of ALK inhibition was observed, with durable responses lasting 12 months or more. Moreover, three patients derived benefit from a second-generation ALK inhibitor after progression of disease or intolerance to the first-generation inhibitor crizotinib. Our report advocates for consideration of expanding the current National Comprehensive Cancer Network (NCCN) guidelines to include later-generation ALK inhibitors for the treatment of ALK-rearranged UMTs.

Keywords

• Sarcoma
• Uterine neoplasms
• ALK
• Tyrosine Kinase inhibitor (TKI)
• Inflammatory Myofibroblastic Tumor
• Leiomyosarcoma