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

Abstract

AbstractPurpose: 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 13

1. Che‐Jui Lee

   KU Leuven

   Affiliation as printed

   Department of Oncology, Laboratory of Experimental Oncology, KU Leuven, Leuven, Belgium

2. Patrick Schöffski

   Universitair Ziekenhuis Leuven · KU Leuven

   Affiliation as printed

   Department of General Medical Oncology, Leuven Cancer Institute, University Hospitals Leuven, Leuven, Belgium

   Department of Oncology, Laboratory of Experimental Oncology, KU Leuven, Leuven, Belgium

3. Elodie Modave

   VIB-KU Leuven Center for Cancer Biology · KU Leuven

   Affiliation as printed

   Center for Cancer Biology, VIB, Leuven, Belgium

   Department of Human Genetics, Laboratory of Translational Genetics, KU Leuven, Leuven, Belgium

4. Tom van Wezel Aachen Department of Pathol-ogy, Leiden University Medical Center

   Leiden University Medical Center

   Affiliation as printed

   Department of Pathol-ogy, Leiden University Medical Center, Leiden, the Netherlands

5. Bram Boeckx

   VIB-KU Leuven Center for Cancer Biology · KU Leuven

   Affiliation as printed

   Center for Cancer Biology, VIB, Leuven, Belgium

   Department of Human Genetics, Laboratory of Translational Genetics, KU Leuven, Leuven, Belgium

6. Jozef Šufliarský
   Affiliation as printed

   National Cancer Institute, Bratislava, Slovakia

7. Hans A. J. Gelderblom Aachen Department of Medical Oncology

   Leiden University Medical Center

   Affiliation as printed

   Department of Medical Oncology, Leiden University Medical Center, Leiden, the Netherlands

8. Jean‐Yves Blay

   Centre Léon Bérard

   Affiliation as printed

   Department of Medical Oncology, Center L eon B erard/Universit e Claude Bernard Lyon Institute, Lyon, France

9. Maria Dêbiec‐Rychter

   KU Leuven

   Affiliation as printed

   Department of Human Genetics, Laboratory for Genetics of Malignant Disorders, KU Leuven, Belgium

10. Raf Sciot

    KU Leuven

    Affiliation as printed

    Department of Pathology, University Hospitals Leuven and KU Leuven, Leuven, Belgium

11. Judith V.M.G. Bovée Aachen Department of Pathol-ogy, Leiden University Medical Center

    Leiden University Medical Center

    Affiliation as printed

    Department of Pathol-ogy, Leiden University Medical Center, Leiden, the Netherlands

12. Diether Lambrechts

    VIB-KU Leuven Center for Cancer Biology · KU Leuven

    Affiliation as printed

    Center for Cancer Biology, VIB, Leuven, Belgium

    Department of Human Genetics, Laboratory of Translational Genetics, KU Leuven, Leuven, Belgium

13. Agnieszka Woźniak corresponding

    KU Leuven

    Affiliation as printed

    Department of Oncology, Laboratory of Experimental Oncology, KU Leuven, Leuven, Belgium