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

Abstract

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 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.

• Authors: Che-Jui Lee, Patrick Schöffski, Elodie Modave, Tom van Wezel, Bram Boeckx, Jozef Sufliarsky, Hans Gelderblom, Jean-Yves Blay, Maria Debiec-Rychter, Raf Sciot, Judith V M G Bovée, Diether Lambrechts, Agnieszka Wozniak
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 27 Issue 24 Pg. 6737-6748 (12 15 2021) ISSN: 1557-3265 [Electronic] United States
• PMID: 34551905 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2021 American Association for Cancer Research.

Chemical References

• Protein Kinase Inhibitors
• Proto-Oncogene Proteins
• Crizotinib
• Protein-Tyrosine Kinases

Topics

• Clinical Trials, Phase II as Topic
• Crizotinib (therapeutic use)
• Gene Rearrangement
• Humans
• Lung Neoplasms (drug therapy)
• Neoplasms (drug therapy)
• Protein Kinase Inhibitors (pharmacology, therapeutic use)
• Protein-Tyrosine Kinases
• Proto-Oncogene Proteins (genetics)