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.

Histopathologic and Molecular Characterization of Uterine Leiomyoma–like Inflammatory Myofibroblastic Tumor

“…In ULs, chromothripsis occurs rarely, while more subtle chromosomal alterations are relatively common, especially in MED12 wild-type lesions 4. In IMT, complex chromosomal rearrangements including chromothripsis have been detected in a few metastatic tumors 43,44. In our analysis, 1 tumor (My6290m3) with strong ALK IHC positivity showed clear chromothripsis of the ALK harboring chromosome 2.…”

Inflammatory Myofibroblastic Tumour: State of the Art

“…In the absence of large randomized studies, we must rely on published clinical cases, as well as choose treatments by analogy with the responses obtained in other cancers with the same genetic mutations. In-depth molecular characterization of archival IMT tissue from 24 patients enrolled in the CREATE trial revealed extensive molecular heterogeneity including DNA damage repair mechanisms (19/24), Wnt signaling (16/24), and cell-cycle and cell death pathway (13/24) [ 42 , 48 ]. Although the authors identified 17 potentially actionable recurrent gene aberrations including ATRX , FAT1 , FCRL4 , FOXO1 , NUTM2B , PIK3CA , SMAD4 , and TP53 , no ROS1 -rearranged tumor has been identified.…”

“…Although the authors identified 17 potentially actionable recurrent gene aberrations including ATRX , FAT1 , FCRL4 , FOXO1 , NUTM2B , PIK3CA , SMAD4 , and TP53 , no ROS1 -rearranged tumor has been identified. In the CREATE trial, the patient who had the objective response in the ALK-negative cohort had an ETV6-NTRK3 fusion which may have made the IMT sensitive to crizotinib [ 48 ].…”

“…High tumor mutational burden is an emerging predictive biomarker with relevance for tumor treatment with immune checkpoint inhibitors (ICI). The only available data are ad hoc analyses of the CREATE trial showing an average of 7 mutations per Mb suggesting an intermediate mutational burden in IMT [ 48 ]. No association between 12q24.33 loss and the mutational burden was found, suggesting that the POLE deletion does not influence the mutational profile in the analyzed cohort.…”

Inflammatory myofibroblastic tumor of the mesentery with a SQSTM1::ALK fusion responding to alectinib

“…Observation of recurrent translocations at 2p23 with identification of the anaplastic lymphoma kinase ( ALK ) gene in fusion proteins led to the recognition that IMT cases with these alterations have intermediate malignant potential 6–8 . Translocations involving ALK may be present in 50%–60% of IMT cases, although there is heterogeneity 1,4,9 . In cases with absent ALK protein expression or translocation, additional target genes, such as ROS1, NTRK, RET , and PDGFR‐beta , have been identified 9 …”