Comprehensive Molecular Analysis of Inflammatory Myofibroblastic Tumors Reveals Diverse Genomic Landscape and Potential Predictive Markers for Response to Crizotinib
| Autor: | Patrick Schöffski, Hans Gelderblom, Elodie Modave, Jean-Yves Blay, Judith V.M.G. Bovée, Che-Jui Lee, Diether Lambrechts, Jozef Sufliarsky, Agnieszka Wozniak, Tom van Wezel, Raf Sciot, Maria Debiec-Rychter, Bram Boeckx |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Gene Rearrangement
Cancer Research Lung Neoplasms Crizotinib business.industry Cancer Disease Protein-Tyrosine Kinases medicine.disease Malignancy Clinical Trials Phase II as Topic Oncology Neoplasms Proto-Oncogene Proteins Chromosome 19 ROS1 Cancer research Humans Medicine Anaplastic lymphoma kinase business Protein Kinase Inhibitors Gene medicine.drug |
| Zdroj: | Clinical Cancer Research, 27(24), 6737-6748. AMER ASSOC CANCER RESEARCH |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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