STUMP un"stumped": anti-tumor response to anaplastic lymphoma kinase (ALK) inhibitor based targeted therapy in uterine inflammatory myofibroblastic tumor with myxoid features harboring DCTN1-ALK fusion.

Vivek Subbiah,Shreyaskumar Patel,Siraj M Ali,Jenny Berry,Zachary R Chalmers,Deepa Anand,Caitlin Mcmahon,Philip J Stephens,Jeffrey S Ross,Julia A Elvin,Chimela Ohaji,Dhakshina Moorthy Ganeshan,Juliann Chmielecki,Ralph Zinner,Vincent A Miller,Ishwaria M Subbiah ,Charles Levenback ,John D Mayfield ,Timothy J Brennan ,Elvio G Silva

doi:10.1186/s13045-015-0160-2

Abstract

BackgroundRecurrent, metastatic mesenchymal myxoid tumors of the gynecologic tract present a management challenge as there is minimal evidence to guide systemic therapy. Such tumors also present a diagnostic dilemma, as myxoid features are observed in leiomyosarcomas, inflammatory myofibroblastic tumors (IMT), and mesenchymal myxoid tumors. Comprehensive genomic profiling was performed in the course of clinical care on a case of a recurrent, metastatic myxoid uterine malignancy (initially diagnosed as smooth muscle tumor of uncertain malignant potential (STUMP)), to guide identify targeted therapeutic options. To our knowledge, this case represents the first report of clinical response to targeted therapy in a tumor harboring a DCTN1-ALK fusion protein.MethodsHybridization capture of 315 cancer-related genes plus introns from 28 genes often rearranged or altered in cancer was applied to >50 ng of DNA extracted from this sample and sequenced to high, uniform coverage. Therapy was given in the context of a phase I clinical trial ClinicalTrials.gov Identifier: (NCT01548144).ResultsImmunostains showed diffuse positivity for ALK1 expression and comprehensive genomic profiling identified an in frame DCTN1-ALK gene fusion. The diagnosis of STUMP was revised to that of an IMT with myxoid features. The patient was enrolled in a clinical trial and treated with an anaplastic lymphoma kinase (ALK) inhibitor (crizotinib/Xalkori®) and a multikinase VEGF inhibitor (pazopanib/Votrient®). The patient experienced an ongoing partial response (6+ months) by response evaluation criteria in solid tumors (RECIST) 1.1 criteria.ConclusionsFor myxoid tumors of the gynecologic tract, comprehensive genomic profiling can identify clinical relevant genomic alterations that both direct treatment targeted therapy and help discriminate between similar diagnostic entities.

Highlights

Myxoid neoplasms of the uterus are a diverse group of soft tissue tumors presenting diagnostic dilemmas for pathologists [1]
We report the case of a patient with a recurrent, metastatic uterine myxoid neoplasm staining diffusely for ALK1 and harboring a DCTN1-ALK fusion identified by comprehensive genomic profiling (CGP) who has experienced clinical and radiographic improvement with targeted inhibition of anaplastic lymphoma kinase (ALK) and additional targeted therapy
Case history A female in her 50’s Gravida 0, with a long standing history of gynecologic discomfort with history of laparoscopy and hysteroscopy that showed endometriosis and uterine fibroids presented to the clinic with increasing pelvic pressure sensations and significant cramps, symptoms concerning for an abdomino-pelvic neoplasm

Summary

Introduction

Myxoid neoplasms of the uterus are a diverse group of soft tissue tumors presenting diagnostic dilemmas for pathologists [1]. Metastatic mesenchymal myxoid tumors of the gynecologic tract present a management challenge as there is minimal evidence to guide systemic therapy. Comprehensive genomic profiling was performed in the course of clinical care on a case of a recurrent, metastatic myxoid uterine malignancy (initially diagnosed as smooth muscle tumor of uncertain malignant potential (STUMP)), to guide identify targeted therapeutic options. To our knowledge, this case represents the first report of clinical response to targeted therapy in a tumor harboring a DCTN1-ALK fusion protein

Methods

Results

Discussion

Conclusion