Inflammatory myofibroblastic tumors harbor multiple potentially actionable kinase fusions

Abstract

Inflammatory myofibroblastic tumor (IMT) is a neoplasm that typically occurs in children. The genetic landscape of this tumor is incompletely understood and therapeutic options are limited. Although 50% of IMTs harbor anaplastic lymphoma kinase (ALK) rearrangements, no therapeutic targets have been identified in ALK-negative tumors. We report for the first time that IMTs harbor other actionable targets, including ROS1 and PDGFRβ fusions. We detail the case of an 8-year-old boy with treatment-refractory ALK-negative IMT. Molecular tumor profiling revealed a ROS1 fusion, and he had a dramatic response to the ROS1 inhibitor crizotinib. This case prompted assessment of a larger series of IMTs. Next-generation sequencing revealed that 85% of cases evaluated harbored kinase fusions involving ALK, ROS1, or PDGFRβ. Our study represents the most comprehensive genetic analysis of IMTs to date and also provides a rationale for routine molecular profiling of these tumors to detect therapeutically actionable kinase fusions.

Significance: Our study describes the most comprehensive genomics-based evaluation of IMT to date. Because there is no "standard-of-care" therapy for IMT, the identification of actionable genomic alterations, in addition to ALK, is expected to redefine management strategies for patients with this disease.

Figure 1. Response to crizotinib in an 8 year old boy with refractory IMT harboring a TFG-ROS1 fusion

(A) Schematic representation of the TFG-ROS1 fusion. ROS1 is located on chromosome 6q22 and TFG is located on 3q12. The break point occurs in-frame between exon 4 of TFG and exon 36 of ROS1. (B) CT scans prior to the initiation of crizotinib (left panel) and after 3 cycles of crizotinib (right panel) showing dramatic reduction in the tumor mass within the left lung. (C) Changes in hemoglobin (HgB), mean corpuscular volume (MCV), and erythrocyte sedimentation rate (ESR) over the course of the patient’s treatments. Arrows below the graphs indicate the initiation of the indicated therapies. The high (H) and low (L) limits of normal for each measured parameter are indicated on the blue graphs.

Figure 2. Kinase fusions identified in IMT by targeted sequencing

Starting with 37 formalin-fixed, paraffin-embedded (FFPE) IMT samples (26 ALK IHC positive and 11 ALK IHC negative), 33 tumors were evaluable with targeted next generation sequencing. (A) Genomic alterations identified in the 37 IMT tumor samples. The columns denote the samples, the rows denote the genes. Red bars represent ALK fusions, green bars represent PDGFRβ fusions, and blue bars represent ROS1 fusions. The identified gene fusions were mutually exclusive. No other recurrent genomic alterations were identified by targeted next generation sequencing in these samples. (B) Schematic representation of the distinct ALK, PDGFRβ, and ROS1 fusions identified. In each case, the exons encompassed within each gene fusion partner are indicated.