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Case Reports
.2021 Nov;26(11):919-924.
doi: 10.1002/onco.13835. Epub 2021 Jun 8.

Mosaicism for Receptor Tyrosine Kinase Activation in a Glioblastoma Involving Both PDGFRA Amplification and NTRK2 Fusion

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Case Reports

Mosaicism for Receptor Tyrosine Kinase Activation in a Glioblastoma Involving Both PDGFRA Amplification and NTRK2 Fusion

Daniel J Shepherd et al. Oncologist.2021 Nov.

Abstract

Rearrangements involving the neurotrophic receptor tyrosine kinase (NTRK) gene family have been reported in diverse tumor types, and NTRK-targeted therapies have recently been approved. In this article, we report a case of a 26-year-old man with an NTRK2-rearranged isocitrate dehydrogenase-wild-type glioblastoma who showed a robust but temporary response to the NTRK inhibitor larotrectinib. Rebiopsy after disease progression showed elimination of the NTRK2-rearranged tumor cell clones, with secondary emergence of a PDGFRA-amplified subclone. Retrospective examination of the initial biopsy material confirmed rare cells harboring PDGFRA amplification. Although mosaic amplification of multiple receptor tyrosine kinase genes in glioblastoma has been previously described, mosaicism involving a fusion gene driver event has not. This case highlights the potential efficacy of NTRK-targeted treatment in glioblastoma and the implications of molecular heterogeneity in the setting of targeted therapy. KEY POINTS: This case highlights the efficacy of the NTRK inhibitor larotrectinib in treating NTRK-rearranged glioblastoma. This is the first case to demonstrate mosaicism in glioblastoma involving both a fusion gene and amplification for receptor tyrosine kinases. Intratumoral heterogeneity in glioblastoma has significant implications for tumor resistance to targeted therapies.

© 2021 AlphaMed Press.

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Conflict of interest statement

Disclosures of potential conflicts of interest may be found at the end of this article.

Figures

Figure 1
Figure 1
Radiologic and histopathologic findings on initial presentation and biopsy.(A): Postcontrast T1‐weighted magnetic resonance images show a contrast‐enhancing tumor centered in the left frontal lobe and involving the corpus callosum (white arrowheads). Top: axial; middle: coronal; bottom: sagittal.(B): H&E‐stained slides from the initial biopsy show a hypercellular, pleomorphic neoplasm with microvascular proliferation (top right; black arrowheads). By immunohistochemistry, the neoplastic cells are positive for OLIG2 (middle left) and negative for R132H‐mutantIDH (middle right; wild‐type pattern). Fluorescence in situ hybridization using green and redNTRK2‐specific break‐apart probes flanking the breakpoint (bottom row) shows split red and green signals (white brackets: split signals, white arrowheads: nonsplit signals), confirmingNTRK translocation. Abbreviations: IDH, isocitrate dehydrogenase; NTRK, neurotrophic receptor tyrosine kinase.
Figure 2
Figure 2
Clinical course demonstrating initial clinical response to larotrectinib. Top: clinical timeline and treatment course. Bottom: postcontrast T1‐weighted sagittal magnetic resonance imaging views at indicated days pre‐ or postsurgical resection. D indicates day number with respect to date of initial resection. Abbreviations: nivo., nivolumab; rad, radiation therapy; resp., response; prog., progression; TMZ, temozolomide.
Figure 3
Figure 3
Disease progression with emergence of a PDGFRA‐amplified subclone. Top left: postcontrast T1‐weighted MRI showing increase in tumor size after initial response to larotrectinib. Top right: H&E stain on rebiopsied tissue shows a pleomorphic infiltrative neoplasm consistent with recurrent/residual glioblastoma. Bottom row: NTRK fluorescence in situ hybridization shows a non‐rearranged pattern (left), whereas numerous tumor cells show evidence for PDGFRA amplification (right) (red: PDGFRA‐specific probe; green: centromere control probe). Abbreviations: NTRK, neurotrophic receptor tyrosine kinase; PDGFRA, platelet‐derived growth factor receptor alpha.
Figure 4
Figure 4
Presence of rare PDGFRA‐amplified tumor cells in initial biopsy material. Analysis of the initial biopsy confirms mutually exclusive rare tumor cells withPDGFRA amplification (bottom, middle) among more numerousNTRK2‐rearranged tumor cells (bottom left, right). White signal:PDGFRA‐specific probe; green and red signals:NTRK2 break‐apart probes. Abbreviations: NTRK, neurotrophic receptor tyrosine kinase; PDGFRA, platelet‐derived growth factor receptor alpha.
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References

    1. Zheng Z, Liebers M, Zhelyazkova B et al. Anchored multiplex PCR for targeted next‐generation sequencing. Nat Med 2014;20:1479–1484. - PubMed
    1. Cocco E, Scaltriti M, Drilon A. NTRK fusion‐positive cancers and TRK inhibitor therapy. Nat Rev Clin Oncol 2018;15:731–747. - PMC - PubMed
    1. Mitre M, Mariga A, Chao MV. Neurotrophin signalling: Novel insights into mechanisms and pathophysiology. Clin Sci (Lond) 2016;131:13–23. - PMC - PubMed
    1. Bothwell M. Recent advances in understanding neurotrophin signaling. F1000Res 2016;5:F1000. - PMC - PubMed
    1. Vaishnavi A, Le AT, Doebele RC. TRKing down an old oncogene in a new era of targeted therapy. Cancer Discov 2015;5:25–34. - PMC - PubMed

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