TRK Fusions Are Enriched in Cancers with Uncommon Histologies and the Absence of Canonical Driver Mutations

Rosen, Ezra Y.; Goldman, Debra A.; Hechtman, Jaclyn F.; Benayed, Ryma; Schram, Alison M.; Cocco, Emiliano; Shifman, Sophie; Gong, Yixiao; Kundra, Ritika; Solomon, James P.; Bardelli, Alberto; Scaltriti, Maurizio; Drilon, Alexander; Iasonos, Alexia; Taylor, Barry S.; Hyman, David M.

doi:10.1158/1078-0432.ccr-19-3165

Cited by 122 publications

(186 citation statements)

References 31 publications

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Section: Discussionsupporting

confidence: 59%

“…The diverse histology of NTRK -fused gliomas overlaps with entities such as DIGG, GG, PXA, PA (including anaplastic), DA grades 2 and 3, and GBM in our study. In keeping with the wide spectrum of NTRK -fused CNS tumor histology, NTRK rearrangements have been previously reported in GBM [ 9 , 18 , 19 , 21 , 28 , 34 , 38 , 39 , 41 , 43 , 44 , 52 , 53 , 56 ], gliosarcoma [ 21 ], AA [ 9 , 18 , 21 , 52 ], diffuse midline glioma / DIPG [ 9 , 52 ], HGG [ 9 , 22 , 34 , 57 ], glioneuronal tumor (including high grade) [ 1 , 16 , 29 ], pilocytic astrocytoma (PA) (including anaplastic) [ 9 , 18 , 21 , 25 , 35 ], low grade astrocytroma with features of PA [ 26 ], PXA [ 55 ], GG [ 1 , 9 , 36 , 37 ], DIGG [ 6 , 9 ], LGG [ 18 , 34 , 44 , 50 , 53 ], glioma, not otherwise specified [ 9 , 18 ], neuroepithelial neoplasm [ 43 ], CNS fibroblastic tumor [ 47 ], primitive neuroectodermal tumor (PNET) [ 12 ], CNS embryonal tumor [ 14 ], and tumors with oligodendroglial or oligoastrocytic-like histology [ 12 , 21 , 29 , 37 , 55 ].…”

Section: Discussionmentioning

confidence: 54%

“…The estimated prevalence of NTRK -fusions across all tumors is less than 1% [ 34 , 38 ]. However, for certain tumors such as congenital infantile fibrosarcoma, mammary analogue secretory carcinoma, and secretory breast carcinoma, NTRK fusions occur in greater than 90% of cases and are essentially pathognomonic for those entities [ 48 ].…”

Section: Introductionmentioning

confidence: 99%

“…NTRK fusions occur in lower frequencies in a wide range of other neoplasms, including colorectal carcinoma, lung carcinoma, and papillary thyroid carcinoma, among others [ 48 ]. Approximately 0.55 to 2% of all gliomas/neuroepithelial tumors contain NTRK fusions [ 18 , 21 , 34 , 38 , 43 , 53 ], though the incidence may be up to 5.3% in pediatric high grade gliomas (HGG) [ 34 ], 4% of diffuse intrinsic pontine gliomas (DIPG), and 40% of non-brainstem HGG in patients younger than 3-years-old [ 52 ].…”

Section: Introductionmentioning

confidence: 99%

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Molecular and clinicopathologic features of gliomas harboring NTRK fusions

Torre

Vasudevaraja

Serrano

et al. 2020

acta neuropathol commun

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Fusions involving neurotrophic tyrosine receptor kinase (NTRK) genes are detected in ≤2% of gliomas and can promote gliomagenesis. The remarkable therapeutic efficacy of TRK inhibitors, which are among the first Food and Drug Administration-approved targeted therapies for NTRK-fused gliomas, has generated significant clinical interest in characterizing these tumors. In this multi-institutional retrospective study of 42 gliomas with NTRK fusions, next generation DNA sequencing (n = 41), next generation RNA sequencing (n = 1), RNA-sequencing fusion panel (n = 16), methylation profile analysis (n = 18), and histologic evaluation (n = 42) were performed. All infantile NTRK-fused gliomas (n = 7) had high-grade histology and, with one exception, no other significant genetic alterations. Pediatric NTRK-fused gliomas (n = 13) typically involved NTRK2, ranged from low-to high-histologic grade, and demonstrated histologic overlap with desmoplastic infantile ganglioglioma, pilocytic astrocytoma, ganglioglioma, and glioblastoma, among other entities, but they rarely matched with high confidence to known methylation class families or with each other; alterations involving ATRX, PTEN, and CDKN2A/2B were present in a subset of cases. Adult NTRK-fused gliomas (n = 22) typically involved NTRK1 and had predominantly high-grade histology; genetic alterations involving IDH1, ATRX, TP53, PTEN, TERT promoter, RB1, CDKN2A/2B, NF1, and polysomy 7 were common. Unsupervised principal component analysis of methylation profiles demonstrated no obvious grouping by histologic grade, NTRK gene involved, or age group. KEGG pathway analysis detected methylation differences in genes involved in PI3K/AKT, MAPK, and other pathways. In summary, the study highlights the clinical, histologic, and molecular heterogeneity of NTRK-fused gliomas, particularly when stratified by age group.

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Section: Discussionsupporting

confidence: 59%

Section: Discussionmentioning

confidence: 54%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Molecular and clinicopathologic features of gliomas harboring NTRK fusions

Torre

Vasudevaraja

Serrano

et al. 2020

acta neuropathol commun

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“…Whereas NTRK fusions are rare overall, occurring in <2% of tumors, certain cancer types, such as secretory carcinomas (SCs) of the salivary gland and of the breast, congenital mesoblastic nephroma, and infantile fibrosarcoma, are mostly driven by NTRK fusions, which are present in >90% of such tumors (Table 1). 5,7,12‐14 In these settings, NTRK fusions are both diagnostic and predictive.…”

Section: Figurementioning

confidence: 99%

Neurotrophic receptor tyrosine kinase (NTRK) fusions and their role in cancer

Ruíz-Cordero¹,

Ng²

2020

Cancer Cytopathology

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Pre‐ and post‐treatment blood‐based genomic landscape of patients with ROS1 or NTRK fusion‐positive solid tumours treated with entrectinib

Dziadziuszko

Hung²,

Wang³

et al. 2022

Molecular Oncology

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Genomic tumour profiling informs targeted treatment options. Entrectinib is a tyrosine kinase inhibitor with efficacy in NTRK fusion‐positive (‐fp) solid tumours and ROS1‐fp non‐small cell lung cancer. FoundationOne® Liquid CDx (F1L CDx), a non‐invasive in vitro next‐generation sequencing (NGS)‐based diagnostic, detects genomic alterations in plasma circulating tumour DNA (ctDNA). We evaluated the clinical validity of F1L CDx as an aid in identifying patients with NTRK‐fp or ROS1‐fp tumours and assessed the genomic landscape pre‐ and post‐entrectinib treatment. Among evaluable pre‐treatment clinical samples (N = 85), positive percentage agreements between F1L CDx and clinical trial assays (CTAs) were 47.4% (NTRK fusions) and 64.5% (ROS1 fusions); positive predictive value was 100% for both. The objective response rate for CTA+ F1L CDx+ patients was 72.2% in both cohorts. The median duration of response significantly differed between F1L CDx+ and F1L CDx− samples in ROS1‐fp (5.6 vs. 17.3 months) but not NTRK‐fp (9.2 vs. 12.9 months) patients. Fifteen acquired resistance mutations were detected. We conclude that F1L CDx is a clinically valid complement to tissue‐based testing to identify patients who may benefit from entrectinib and those with acquired resistance mutations associated with disease progression.

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TRK Fusions Are Enriched in Cancers with Uncommon Histologies and the Absence of Canonical Driver Mutations

Abstract: Debra Goldman owns stock in Johnson and Johnson Jaclyn F. Hechtman has received honoraria from Cor2Ed, WebMD, and Axiom Healthcare Strategies as well as research funding from Bayer, Loxo Oncology, and Boehringer Ingelheim.

Cited by 122 publications

References 31 publications

Molecular and clinicopathologic features of gliomas harboring NTRK fusions

Molecular and clinicopathologic features of gliomas harboring NTRK fusions

Neurotrophic receptor tyrosine kinase (NTRK) fusions and their role in cancer

Pre‐ and post‐treatment blood‐based genomic landscape of patients with ROS1 or NTRK fusion‐positive solid tumours treated with entrectinib

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