Leiden University Scholarly Publications

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Lee, C.J.; Schoffski, P.; Modave, E.; Wezel, T. van; Boeckx, B.; Sufliarsky, J.; ... ; Wozniak, A. (2021)

Comprehensive Molecular Analysis of Inflammatory Myofibroblastic Tumors Reveals Diverse Genomic Landscape and Potential Predictive Markers for Response to Crizotinib

Article in monograph or in proceedings
Purpose: The European Organization for Research and Treatment of Cancer (EORTC) clinical phase II trial 90101 "CREATE" showed high antitumor activity of crizotinib, an inhibitor of anaplastic lymphoma kinase (ALK)/ROS1, in patients with advanced inflammatory myofibroblastic tumor (IMFT). However, recent findings suggested that other molecular targets in addition to ALK/ROS1 might also contribute to the sensitivity of this kinase inhibitor. We therefore performed an in-depth molecular characterization of archival IMFT tissue, collected from patients enrolled in this trial, with the aim to identify other molecular alterations that could play a role in the response to crizotinib.Experimental Design: Twenty-four archival IMFT samples were used for histopathological assessment and DNA/RNA evaluation to identify gene fusions, copy-number alterations (CNA), and mutations in the tumor tissue. Results were correlated with clinical parameters to assess a potential association between...Show morePurpose: The European Organization for Research and Treatment of Cancer (EORTC) clinical phase II trial 90101 "CREATE" showed high antitumor activity of crizotinib, an inhibitor of anaplastic lymphoma kinase (ALK)/ROS1, in patients with advanced inflammatory myofibroblastic tumor (IMFT). However, recent findings suggested that other molecular targets in addition to ALK/ROS1 might also contribute to the sensitivity of this kinase inhibitor. We therefore performed an in-depth molecular characterization of archival IMFT tissue, collected from patients enrolled in this trial, with the aim to identify other molecular alterations that could play a role in the response to crizotinib.Experimental Design: Twenty-four archival IMFT samples were used for histopathological assessment and DNA/RNA evaluation to identify gene fusions, copy-number alterations (CNA), and mutations in the tumor tissue. Results were correlated with clinical parameters to assess a potential association between molecular findings and clinical outcomes.Results: We found 12 ALK fusions with 11 different partners in ALK-positive IMFT cases by Archer analysis whereas we did not identify any ROS1-rearranged tumor. One ALK-negative patient responding to crizotinib was found to have an ETV6-NTRK fusion in the tumor specimen. The CNA profile and mutational landscape of IMFT revealed extensive molecular heterogeneity. Loss of chromosome 19 (25% of cases) and PIK3CA mutations (9% of cases) were associated with shorter progression-free survival in patients receiving crizotinib.Conclusions: We identified multiple genetic alterations in archival IMFT material and provide further insight into the molecular profile of this ultra-rare, heterogeneous malignancy, which may potentially translate into novel treatment approaches for this orphan disease.Show less
All authors
Lee, C.J.; Schoffski, P.; Modave, E.; Wezel, T. van; Boeckx, B.; Sufliarsky, J.; Gelderblom, H.; Blay, J.Y.; Debiec-Rychter, M.; Sciot, R.; Bovee, J.V.M.G.; Lambrechts, D.; Wozniak, A.
Date
2021-12-15
Title of host publication
Clinical Cancer Research
Volume
27
Issue
24
Pages
6737 - 6748
DOI
doi:10.1158/1078-0432.CCR-21-1165