Diagnosis and therapy of tumors with NTRK gene fusion

Tilburg, Cornelis M. van; Tabatabai, Ghazaleh; Graf, Norbert; Griesinger, Frank; Heukamp, Lukas C.; Hummel, Michael; Klingebiel, Thomas; Hettmer, Simone; Vokuhl, Christian; Merkelbach‐Bruse, Sabine; Overkamp, Friedrich; Reichardt, Peter; Scheer, Monika; Weichert, Wilko; Westphalen, C. Benedikt; Bokemeyer, Carsten; Ivanyi, Philipp; Loges, Sonja; Schirmacher, Peter; Wörmann, Bernhard; Bielack, Stefan; Seufferlein, Thomas

doi:10.1007/s00292-020-00864-y

Cited by 13 publications

(5 citation statements)

References 67 publications

(151 reference statements)

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“…The detection of a RREB1‐MKL2 fusion transcript in the current case suggests that molecular analysis for rearrangements of the RREB1 and/or the MKL2 genes, which was previously reported to be a genetic feature in ECMT, 8 or for alternative gene fusions should be performed in presumed BSNS without detectable PAX3 or MAML3 rearrangements. Our data are in line with the notion that fusions, which are highly prevalent or even pathognomonic in a specific histological setting, can occur outside their primary histological context as evidenced, for example, for ALK 27 or NTRK 28 gene fusions. In the future, more comprehensive studies are warranted to unravel the relation between the spectrum of tumor types primarily identified by histological features and RREB1‐MKL2 fusions.…”

Section: Discussionsupporting

confidence: 90%

RREB1‐MKL2 fusion in a spindle cell sinonasal sarcoma: biphenotypic sinonasal sarcoma or ectomesenchymal chondromyxoid tumor in an unusual site?

Mechtersheimer

Andrulis

Delank

et al. 2021

Genes Chromosomes & Cancer

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Biphenotypic sinonasal sarcoma (BSNS) is a rare, low grade spindle cell sarcoma, recently recognized in the WHO classification of head and neck tumors, which is characterized by a dual myogenic and neural differentiation and recurrent gene fusions, often involving PAX3‐MAML3, and less commonly PAX3 fusions with other partners such as NCOA1, NCOA2, or WWTR1. Yet, in about 4% of tumors no gene rearrangements are identified. Herein, we describe a RREB1‐MKL2 fusion in a BSNS lesion occurring in a 73‐year‐old female patient with a right maxillo‐ethmoidal angle lesion. The polypoid, moderately cellular tumor with infiltrative submucosal growth was composed of fascicles of relatively bland spindle cells embedded in a loose collagenous matrix. The tumor cells showed moderate amounts of eosinophilic cytoplasm with indistinct borders and uniform, pale, ovoid to slender nuclei. The slowly proliferating neoplastic cells co‐expressed smooth muscle actin and S100, and showed focal nuclear positivity for ß‐catenin, while lacking staining for cytokeratins, desmin, myogenin, caldesmon, glial fibrillary acid protein, and SOX‐10. Molecular analysis by targeted RNA‐based next‐generation sequencing identified an in‐frame fusion between exon 8 of RREB1 and exon 11 of MKL2, a genetic event that was reported to be a molecular hallmark of ectomesenchymal chondromyxoid tumor. Gene rearrangements in both genes were independently verified by fluorescence in situ hybridization (FISH). To evaluate its recurrent potential an additional group of 15 fusion negative BSNS were tested for abnormalities in RREB1 and MKL2 genes by FISH, but no additional positive cases were identified.

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Section: Discussionsupporting

confidence: 90%

RREB1‐MKL2 fusion in a spindle cell sinonasal sarcoma: biphenotypic sinonasal sarcoma or ectomesenchymal chondromyxoid tumor in an unusual site?

Mechtersheimer

Andrulis

Delank

et al. 2021

Genes Chromosomes & Cancer

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“…SC is characterised by a recurrent chromosomal rearrangement, t(12:15)(p13:q25), that is detected in 75–92% of tumours. This leads to fusion between E26 transformation specific translocation variant 6 ( ETV6 ) and neurotrophic receptor tyrosine kinase 3 ( NTRK3 ) [ 134 ] with potential for targeted therapy using larotrectinib and entrectinib. This fusion may also be detected in congenital fibrosarcoma, cellular mesoblastic nephroma, acute myeloid leukaemia, ALK-negative inflammatory myofibroblastic tumour and radiation-induced papillary thyroid carcinoma [ 130 , 135 ] but appears to be specific for SC in the breast context.…”

Section: Secretory Carcinoma (Sc)mentioning

confidence: 99%

Triple-Negative Breast Cancer Histological Subtypes with a Favourable Prognosis

Cserni

Quinn

Foschini

et al. 2021

Cancers

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Triple-negative breast cancers (TNBC), as a group of tumours, have a worse prognosis than stage-matched non-TNBC and lack the benefits of routinely available targeted therapy. However, TNBC is a heterogeneous group of neoplasms, which includes some special type carcinomas with a relatively indolent course. This review on behalf of the European Working Group for Breast Screening Pathology reviews the literature on the special histological types of BC that are reported to have a triple negative phenotype and indolent behaviour. These include adenoid cystic carcinoma of classical type, low-grade adenosquamous carcinoma, fibromatosis-like metaplastic carcinoma, low-grade mucoepidermoid carcinoma, secretory carcinoma, acinic cell carcinoma, and tall cell carcinoma with reversed polarity. The pathological and known molecular features as well as clinical data including treatment and prognosis of these special TNBC subtypes are summarised and it is concluded that many patients with these rare TNBC pure subtypes are unlikely to benefit from systemic chemotherapy. A consensus statement of the working group relating to the multidisciplinary approach and treatment of these rare tumour types concludes the review.

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“…In solid tumors, fusion genes of NTRK1/2/3 with other genes were reported with a prevalence of 0.3-0.5% [306]. In BC, NTRK fusions only appear in the very rare secretory BC [306].…”

Section: Tyrosine Receptor Kinase (Trk) Inhibitionmentioning

confidence: 99%

“…In solid tumors, fusion genes of NTRK1/2/3 with other genes were reported with a prevalence of 0.3-0.5% [306]. In BC, NTRK fusions only appear in the very rare secretory BC [306]. The corresponding transmembrane proteins with kinase activity (namely Trk) are constitutively activated conferring oncogenic potential [208].…”

Section: Tyrosine Receptor Kinase (Trk) Inhibitionmentioning

confidence: 99%

The Diversity of Liquid Biopsies and Their Potential in Breast Cancer Management

Keup,

Kimmig,

Kasimir-Bauer

2023

Cancers

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Analyzing blood as a so-called liquid biopsy in breast cancer (BC) patients has the potential to adapt therapy management. Circulating tumor cells (CTCs), extracellular vesicles (EVs), cell-free DNA (cfDNA) and other blood components mirror the tumoral heterogeneity and could support a range of clinical decisions. Multi-cancer early detection tests utilizing blood are advancing but are not part of any clinical routine yet. Liquid biopsy analysis in the course of neoadjuvant therapy has potential for therapy (de)escalation.Minimal residual disease detection via serial cfDNA analysis is currently on its way. The prognostic value of blood analytes in early and metastatic BC is undisputable, but the value of these prognostic biomarkers for clinical management is controversial. An interventional trial confirmed a significant outcome benefit when therapy was changed in case of newly emerging cfDNA mutations under treatment and thus showed the clinical utility of cfDNA analysis for therapy monitoring. The analysis of PIK3CA or ESR1 variants in plasma of metastatic BC patients to prescribe targeted therapy with alpesilib or elacestrant has already arrived in clinical practice with FDA-approved tests available and is recommended by ASCO. The translation of more liquid biopsy applications into clinical practice is still pending due to a lack of knowledge of the analytes’ biology, lack of standards and difficulties in proving clinical utility.

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Diagnosis and therapy of tumors with NTRK gene fusion

Cited by 13 publications

References 67 publications

RREB1‐MKL2 fusion in a spindle cell sinonasal sarcoma: biphenotypic sinonasal sarcoma or ectomesenchymal chondromyxoid tumor in an unusual site?

RREB1‐MKL2 fusion in a spindle cell sinonasal sarcoma: biphenotypic sinonasal sarcoma or ectomesenchymal chondromyxoid tumor in an unusual site?

Triple-Negative Breast Cancer Histological Subtypes with a Favourable Prognosis

The Diversity of Liquid Biopsies and Their Potential in Breast Cancer Management

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