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

Abstract

Highlights Inflammatory myofibroblastic tumor of the uterus (UMT) is a rare but aggressive malignancy that is often misdiagnosed. Immunohistochemistry (IHC) and next generation sequencing (NGS) are essential for accurate diagnosis of UMT. We report good therapeutic activity of ALK inhibition in UMT harboring ALK fusions, with responses lasting ≥12 months. After disease progression or intolerance to first-generation ALK inhibitors, second-generation inhibitors were beneficial. Support for use of second- and third-generation ALK inhibitors should be considered in tumors with ALK rearrangements.

Fertility-preserving management of an inflammatory myofibroblastic tumor: A case report and review of the literature

“…Large tumor size, presence of tumor-type necrosis, high mitotic index and lymphovascular invasion have been proposed as features associated with a more aggressive clinical course [ 3 , 5 ]. Cases of recurrent or metastatic disease have been successfully treated with tyrosine kinase inhibitors such as crizotinib, emphasizing the importance of accurate diagnosis in these patients [ 4 , 18 ].…”

Abdominal inflammatory myofibroblastic tumour: Clinicopathological and molecular analysis of 20 cases, highlighting potential therapeutic targets

“…38 Indeed, uterine myofibroblastic tumours with FN1::ALK fusions have also been reported to show variable indolent to aggressive clinical behaviour. 39,40 Another 10-20% of IMTs harbour alterations in kinase genes other than ALK, i.e. ROS1, NTRK3, PDGFRb, IGF1R and RET (Table 3).…”

Recurrent uterine inflammatory myofibroblastic tumor previously managed as leiomyosarcoma has sustained response to alectinib

“…Several cases have been described where a previous diagnosis was revised after discovering an ALK fusion on molecular testing ( Hensley et al, 2020 , Kyi et al, 2021 , Lee et al, 2019 , Zhang et al, 2020 , Testa et al, 2021 ). On review of the literature, this is the third reported case of uterine IMT with an aggressive clinical behavior containing a TNS1-ALK fusion specifically ( Kyi et al, 2021 , Lee et al, 2019 ). This is the second such case treated with alectinib.…”

“…This is the second such case treated with alectinib. In 2021, Kyi et al described a case of uterine IMT containing TNS1-ALK fusion that was treated with alectinib as second line therapy for 12 months prior to disease progression ( Kyi et al, 2021 ). There are also limited reports of leiomyosarcomas containing ALK fusions, but it cannot be discerned from the published manuscripts if IMT was considered in the differential diagnosis ( Davis et al, 2019 , Ross et al, 20172017 ).…”

“…If a tumor is determined to be an IMT, these cytotoxic regimens are not recommended in the upfront setting or as first line in the recurrent setting when ALK fusions are present ( Agulnik et al, 2022 ). Regardless of diagnosis, the presence of an ALK fusion provides an opportunity for a targeted treatment option with demonstrated clinical activity ( Kyi et al, 2021 , Testa et al, 2021 , McKeage, 2015 ). The NCCN Guidelines for Uterine Neoplasms now recommend comprehensive genomic profiling with a validated assays including at least NTRK, MSI, and TMB as it is informative for pathologic characterization and identifying rare pan-tumor targeted therapy opportunities ( Abu-Rustum, 2022 ).…”