NTRK-fused tumors of the central nervous system

Ashley L Sumrall MD FACP FASCO

Neuro-Oncology

Updated 10.07.2024
Expires For CME 10.07.2027

NTRK-fused tumors of the central nervous system

Author: Ashley L Sumrall MD FACP FASCO

See Contributor Disclosures

Editor: Rimas V Lukas MD

NTRK-fused tumors of the central nervous system

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Introduction

Overview

The newly available class of drugs characterized by NTRK inhibitory action (entrectinib, larotrectinib, and repotrectinib) has created interest in tumors of the nervous system harboring a rearrangement of any of the neurotrophic tropomyosin receptor kinase (NTRK) genes. These genes (NTRK1, NTRK2, and NTRK3) code for three transmembrane high-affinity tyrosine-kinase receptors for nerve growth factors (TRK-A, TRK-B, and TRK-C) involved in nervous system development (13). NTRK fusions have been detected with variable frequencies in various pediatric and adult cancers, including central nervous system tumors. Testing for these fusions has become increasingly important, and different mechanisms may be used. Matching a treatment to a tumor has become the Holy Grail of oncology, representing the ultimate goal of personalized medicine. This quest involves identifying each tumor’s unique genetic and molecular characteristics to tailor the most effective treatment, thereby maximizing patient outcomes and minimizing side effects.

Key points

	•There are no WHO Classification CNS tumor entities defined by the presence or absence of NTRK fusions. Attempts to clarify the frequency of NTRK gene rearrangements has yielded variable percentages.
	• NTRK gene rearrangements may be seen in tumors affecting children or adults.
	• NTRK gene mutations differ from rearrangements and fusions.

Historical note and terminology

When reflecting on the characterization of primary CNS tumors over the years, the utilization of biomarkers has lagged behind other tumor types. Although the worlds of breast cancer and lung cancer incorporated biomarkers into the classification of tumors, the World Health Organization Classification of primary CNS tumors was not impacted much until 2016 (20). When the 2016 WHO Classification was published, multiple molecular markers were considered mandatory, revolutionizing the schema for classification overnight. In 2021, the WHO continued to incorporate biomarkers to restructure tumor classification (21). As availability for tumor testing has expanded, including the widespread use of next-generation sequencing of tumor samples, our definitions of tumors have continued to expand. Various molecular aberrations, such as NTRK fusions, can easily be identified now. This is important because new medications are available that may target fusions or mutations, offering better options than traditional cytotoxic chemotherapy. However, no primary CNS tumor entities defined by the presence (or absence) of NTRK fusions are included in the most recent WHO classification.

Clinical manifestations

Presentation and course

	• Patients may present to medical attention with various neurologic signs and symptoms, such as head pain, cognitive deficits, or motor weakness.
	• No reported clinical or radiographic features are pathognomonic for NTRK-fusion nervous system tumors.
	• NTRK fusion testing must be performed on tumor tissue.

Patients with primary CNS tumors may come to medical attention in various ways depending on factors such as tumor location, histologic type, and degree of adjacent edema. For intracranial tumors, affected individuals may experience headaches, seizures, cognitive changes, visual changes, or more subtle presentations (02). For tumors located in the brainstem or spinal cord, symptoms will vary based on location but may include motor dysfunction, balance changes, pain, or paresthesias.

Headache is a nonspecific complaint for many patients and is only reported as a presenting complaint for some. There is significant variance in the medical literature, but headaches are listed as reported symptoms in one quarter to one half of patients with intracranial gliomas (30). Isolated headaches often do not trigger imaging of the brain, so patients may go on to develop additional symptoms or findings before diagnosis. This may direct the patient to a neurologist for evaluation. Individuals with more subtle presentations may seek care initially through primary care physicians or urgent care centers (30).

Thus far, there is no documentation of any impact NTRK fusions may have on symptomatology. There are no reports of specific clinical or radiographic findings that may predict the presence of an NTRK fusion (16). There have been reports of these tumors affecting all age groups, including infants. Men and women are both affected. Tumor locations have included cerebral hemispheres, cerebellum, thalamus, and spinal cord (16).

Given the information available thus far, it would be impossible to differentiate a glioma without molecular abnormalities from a glioma with an NTRK fusion without obtaining diagnostic tissue. Even with available tissue, NTRK fusion testing is still not performed universally for all CNS tumors.

Prognosis and complications

The prognosis for individuals with primary CNS tumors varies depending on the subtype and location of the tumor. Often, the condition is a low-grade or high-grade glioma. In either scenario, these represent an incurable condition. With high-grade gliomas, patients may expect an overall survival measured in 5 years or less. Glioblastoma IDH wild-type, the most common type of malignant primary brain tumor, brings a dismal prognosis as survival rarely surpasses 2 years (36).

The clinical course experienced by a patient depends on the diagnostic and therapeutic tools employed. Most patients with primary CNS tumors will undergo surgical biopsy or resection as an initial step. Goals of surgical resection include a maximal safe resection without injuring adjacent healthy tissue. Neurosurgeons utilize techniques such as functional MRI, intra-operative MRI, awake craniotomy, and fluorescent dyes to optimize outcomes.

Following surgery, individuals will often require significant rehabilitation. This may begin in an inpatient setting if the patient is significantly affected or may be provided on an outpatient basis. Neurologic complications commonly reported in patients with brain tumors in the early rehabilitation setting include cognitive dysfunction (80%), motor dysfunction (78%), visuoperceptual deterioration (53%), sensory problems (38%), and bowel or bladder dysfunction (37%). Most patients will have multiple affected systems (25). Multidisciplinary care including specialists trained in physiatry, physical therapy, occupational therapy, speech therapy, and neuropsychology can optimize outcomes (25). Radiation therapy is often initiated shortly after diagnosis and may be accompanied by chemotherapy (36). These therapies may produce fatigue, short-term memory impairment, nausea, constipation, immunosuppression, or other complications.

Additional complications of having a tumor and undergoing treatment with conventional modalities include motor dysfunction, cognitive dysfunction, memory loss, mood disorder, pain, seizures, fatigue, communication impairment, bowel or bladder impairment, and sexual dysfunction (25).

Biological basis

	• NTRK genes, represented by NTRK-1, NTRK-2, and NTRK-3, encode TRK-A, TRK-B, and TRK-C proteins, respectively. The tyrosine kinase receptors have an intracellular domain exhibiting tyrosine-dependent kinase activity, which is connected to an extracellular domain comprising two immunoglobulin-like high-affinity receptors and three leucine-rich motifs.
	• NTRK2 appears to be the most frequently involved gene in primary CNS tumors.
	• All three fusion partners (NTRK-1, NTRK-2, NTRK-3) have been identified in pediatric and adult tissue samples.

Etiology and pathogenesis

Mechanism of NTRK. Tyrosine receptor kinases are a class of cell-membrane high-affinity receptors with similar structures and intracellular signaling pathways, yet they differ in activation and regulation mechanisms. These receptors bind specific growth factors and are crucial for cell survival. Their altered performances are well-documented as playing an oncogenic role and as potential therapeutic targets (13). Within this family of kinases, NTRK genes are represented by NTRK-1, NTRK-2, and NTRK-3, located on chromosomes 1 (1q22), 9 (9q22), and 15 (15q25). These three genes encode the TRK-A, TRK-B, and TRK-C proteins, respectively (35; 13). They were first classified as oncogenes in colorectal cancer by Pulciani and colleagues in 1982 and later described as high-affinity neurotrophin receptors in 1989 (28; 22).

The tyrosine kinase receptors have an intracellular domain exhibiting tyrosine-dependent kinase activity, which is connected to an extracellular domain comprising two immunoglobulin-like high-affinity receptors and three leucine-rich motifs. When TRK receptors are activated by their ligands (ie, neurotrophins), the intracellular domain changes, and phosphorylation of multiple tyrosine residues results. Nerve growth factor binds to NTRK1; brain-derived neurotrophic factor and neurotrophin-4 and neurotrophin-5 bind to NTRK2; and neurotrophin-3 binds NTRK1 and NTRK3 (31). Binding of neurotrophic factors to their receptors activates the downstream effectors of NTRK, and downstream signaling within the cell occurs. The NTRK inhibitors interact with the chimeric receptors’ intracellular domain, inhibiting the recruitment of the signaling pathway, and antitumor activity occurs (31; 23).

A team from the University of California in San Diego assessed 13,467 tumor samples available from The Cancer Genome Atlas (adult tumors) and the St Jude PeCan database (pediatric tumors) for the prevalence of NTRK fusions in different tumor types. NTRK fusions were observed in 0.31% of adult tumors and 0.34% of pediatric tumors. The most common gene partners were NTRK3 (0.16% of adult tumors) followed by NTRK1 (0.14% of pediatric tumors) (23).

NTRK fusions in CNS tumors affecting pediatric patients. We continue to have few therapeutic options for children and young adults battling CNS tumors. Given that the overall NTRK-fusion rate of almost 4% was observed in unselected cohorts of pediatric gliomas, it seems reasonable to routinely screen tumors for the presence of NTRK fusions (23; 01).

NTRK alterations have been widely described in pediatric brain tumors, both in low-grade and high-grade lesions. Pediatric high-grade gliomas are rare but devastating. One particular subset of non-brainstem high-grade gliomas has been identified in younger children (younger than 3 years old) with high frequencies (up to 40%) of NTRK fusions (TPM3-NTRK1 and ETV6-NTRK3) without significant additional alterations (37; 23). NTRK alterations have also been described in non-gliomas, such as low-grade and high-grade glioneuronal tumors (18).

Of the 3,501 pediatric tumor samples from the St Jude PeCan database, 0.34% (n = 12) presented an NTRK fusion. Ten of the 12 samples were from gliomas, with seven high-grade gliomas and three low-grade gliomas. All fusion partners were seen, and NTRK-1 was the most common partner gene (23).

NTRK fusions in CNS tumors affecting adult patients. It has been challenging to arrive at an accurate frequency of NTRK fusions for adult patients. Of the nearly 10,000 adult tumor samples in the TCGA database, 0.31% (n = 31 samples) exhibited an NTRK fusion. Fusions were seen in five low-grade glioma samples and a single glioblastoma sample (23). Published case reports of patients with NTRK fusions have estimated the incidence at 1% to 3%, although this may be higher than what is truly present (11).

Most series of profiled tumors focus on high-grade gliomas, such as glioblastoma, given the incurable nature of this aggressive tumor. All three NTRK genes have had fusions demonstrated in IDH-WT glioblastoma. NTRK2 appears to be the most frequently involved gene (estimates range from 1% to 11% of glioblastoma multiforme). NTRK1 fusions are much rarer (about 1%), and NTRK3 fusions seem to be extremely rare (one single case reported) (12; 32; 17; 03; 11). Among low-grade gliomas, all three NTRK genes have had fusions demonstrated (11; 13).

Epidemiology

	• More than 50 NTRK fusion partners have been identified.
	• Tumors with NTRK fusions also frequently (more than 50%) exhibit additional genomic alterations in genes associated with NTRK pathways.

According to the Central Brain Tumor Registry of the United States (CBTRUS), primary CNS tumors have an average annual age-adjusted incidence of 24.83 per 100,000 (24). Just over a quarter of those tumors are malignant. Primary brain tumors have an overall incidence rate in females of 27.62 versus males at 21.60 per 100,000. Glioblastoma and astrocytoma are slightly more common in males than females (27). The 5-year relative survival rate for individuals with malignant nervous system tumors was 35.7% (24).

NTRK fusions, although rare, are particularly notable in CNS tumors, given the need for therapies for these serious conditions. Over fifty NTRK fusion partners have been identified, highlighting the highly variable nature of this rearrangement. Despite the presence of many fusion partners, the structural pattern remains consistent: the 3′ end of the NTRK gene fuses with the 5′ end of a partner gene. This produces a chimeric protein that retains the NTRK tyrosine kinase domain, enabling it to activate standard intracellular pathways independently of ligands due to the partner gene's influence. Such oncogenic activation via gene fusion is similar to other kinase-domain oncogenes, such as ALK and ROS1. Gene fusions involving receptor tyrosine kinases are a common oncogenic mechanism across different tumor types, leading to oncogene addiction while varying between neoplasms (13).

NTRK fusions are rare (less than 1%) in large tumor series, but they have been noted to be nearly pathognomonic for certain rare cancers, such as breast secretory carcinomas, mammary analogue secretory carcinoma of the salivary glands, infantile fibrosarcomas, and congenital or infantile mesoblastic nephroma, with a near 100% prevalence. Tumors with NTRK fusions also frequently (more than 50%) exhibit additional genomic alterations in genes associated with NTRK pathways, like MAPK, PI3K signaling cascades, TP53-related genes, cell-cycle regulators, and other tyrosine kinases, although significant mitogenic driver changes are typically exclusive (23; 13).

Diagnostic workup

	• Imaging. Contrast-enhanced MRI of the brain is the standard approach to identify and characterize mass lesions in the brain. CT may be substituted for patients who cannot undergo MRI.
	• Surgical approach. Individuals with brain masses worrisome for glioma will undergo biopsy or resection of the abnormal tissue.
	• Tissue testing. Tissue will be prepared and examined by the pathologist. This includes histologic examination and additional biomarker evaluation.

After the diagnosis of glioma is confirmed, most samples will be tested for isocitrate dehydrogenase (IDH) gene mutations and other biomarkers (26). Samples may be tested for NTRK fusions via a variety of methods (13). In testing, one must reflect on the process that leads to creation of a chimeric TRK protein (13). Immunohistochemical staining can directly assess the protein product. Fluorescence in-situ hybridization and DNA-based next-generation sequencing can be used to examine the sample’s DNA. To examine the RNA, reverse transcription-polymerase chain reaction, real-time-PCR, and RNA-based next-generation sequencing analyses can be performed (13).

Most clinicians consider immunohistochemistry a screening tool. Immunohistochemistry can, thus, be used as an effective screening tool for most tumor types, but specificity in CNS neoplasms seems to be low due to the physiological expression of NTRK in neural tissues. For instance, one group of researchers reported an unsatisfactory specificity value of 20.8% in gliomas. Given this information, immunohistochemistry screening is felt to be inadequate if used alone (33). Fluorescence in-situ hybridization may be used, but all three NTRK genes would require independent assays. Information would not be available for the fusion partner with this method (33). Reverse transcription-polymerase chain reaction would require knowledge of the fusion partner before testing, making it an ineffective screening tool. Next-generation sequencing of RNA or DNA may be analyzed, but each technique has barriers. Ideally, integrated DNA or RNA next-generation sequencing assays could offer complete molecular profiling of a tumor (33; 13).

Investigators at Memorial Sloan Kettering Cancer Center embarked on a large project, attempting to detect NTRK fusions by analyzing over 38,000 tissue samples. Immunohistochemistry and DNA-based and RNA-based next-generation sequencing were used, and 87 patients with oncogenic NTRK1-3 fusions were identified. DNA-based sequencing showed impressive sensitivity and specificity values, but false negatives were seen if fusions involved breakpoints not covered by the assay. Immunohistochemistry was very sensitive for NTRK-1 and NTRK-2, but a lower sensitivity of 79% was seen for NTRK3 fusions. These investigators summarized that the appropriate assay for NTRK fusion detection depended on multiple factors: tumor type, genes involved, available tissue, accessibility of clinical assays, and need for comprehensive genomic testing (34).

Given that each technique exhibits advantages and disadvantages, it is difficult to designate one testing method as a "gold standard." For tumors affecting the nervous system, NTRK fusion assessment should be approached with a clear workflow. Limitations of tissue could play into this algorithm. Also, limitation of availability of next-generation sequencing may affect the ability to use this tool. The optimal method of determining NTRK fusion presence and identification of fusion partners remains elusive (13; 34).

Current testing methods to determine NTRK fusion status:

	• Immunohistochemistry. This method is widely available. A quick turnaround of a few days is expected, cost is limited, and minimal tissue is required. Unfortunately, this method may have low sensitivity or specificity in certain settings. No information is provided about fusion partners.
	• Fluorescence in-situ hybridization. This method is more costly than immunohistochemistry and has a longer turnaround time for results. Minimal tissue is required, and testing demonstrates high sensitivity and specificity. Fluorescence in-situ hybridization testing can be used as confirmatory testing. No information is provided about fusion partners.
	• Reverse transcription-polymerase chain reaction. Reverse transcription-polymerase chain reaction can be used to test for NTRK fusions, but fusion partner information is needed before testing.
	• Real-time -polymerase chain reaction. This method is more costly than immunohistochemistry and has a longer turnaround time for results. Testing demonstrates high sensitivity and specificity. Rare or novel fusions can be missed as a predetermined panel is used for testing. No information is provided about fusion partners.
	• RNA next-generation sequencing. This method requires specific facilities and expertise for interpretation. There is high sensitivity and specificity. Fusion partners are identified.
	• DNA next-generation sequencing. This method requires specific facilities and expertise for interpretation. There is high sensitivity and specificity. Fusion partners and other molecular information are identified.

Management

	• Patients with NTRK fusion CNS tumors will have undergone surgical treatment before identification of NTRK fusion.
	• For low- and high-grade gliomas, patients should initiate care per standard guidelines. This will often include radiation therapy and, possibly, chemotherapy.
	• Entrectinib targets TRK fusion proteins, as well as ROS1 and ALK.
	• Larotrectinib is specific for only TRK fusion proteins and was the first FDA-approved NTRK inhibitor.
	• The second-generation TRK inhibitors selitrectinib and repotrectinib are designed to overcome acquired resistance mechanisms to the first-generation NTRK inhibitors. Neither drug is FDA-approved for patients with CNS tumors.

Individuals with tumors with NTRK fusions should undergo standard-of-care management for primary nervous system tumors. This includes maximal safe resection of the offending lesion followed by consideration of radiation therapy. For some tumors, in particular consideration of glioma, chemotherapy may be offered (14). There have been no large studies examining when to initiate therapy targeting NTRK fusions at this time. Many clinicians believe that selective inhibition of TRK signaling may benefit patients whose tumors vary in histologies but share underlying oncogenic NTRK gene alterations (15).

NTRK inhibitors are receiving approvals by agencies independent of histology, given high efficacy rates in pediatric and adult tumors harboring NTRK fusions. Two first-generation agents have been approved in the United States: entrectinib and larotrectinib (15; 19).

Entrectinib was the first drug developed against NTRK fusions and was noted to penetrate the blood-brain barrier. In addition to targeting NTRK, this molecule also targets ROS1 and ALK (19). In phase-I and II trials (ALKA-372-001, STARTRK-1, STARTRK-2, and STARTRK-NG), entrectinib showed significant results in pediatric and adult solid tumors (05; 04). STARTRK-NG (NCT02650401) was a phase 1/2 trial where patients younger than 22 years of age took oral entrectinib daily. At the time of data cutoff, 43 patients were evaluated for response, and the median age was 7 years. Few dose-limiting toxicities were seen, and the most common treatment-related adverse event was weight gain (48.8%). The objective response rate was 57.7% (95% CI 36.9-76.7), and a median duration of response was not reached at the time of publication (04). It was approved by the US FDA in 2019 (16).

Larotrectinib is highly specific for NTRK fusions only, and its efficacy has been tested in several trials. It is given orally and well-tolerated, with well-documented efficacy against CNS tumors (07; 10). In addition to trials including metastatic CNS tumors, individuals with primary CNS tumors were studied in SCOUT and NAVIGATE clinical trials. Enrollment criteria allowed for patients who had progressed or were nonresponsive to available therapies and were unfit for standard chemotherapy or for whom no standard or curative therapy was available. In initial reports, nine patients with primary CNS tumors experienced disease control (10). It was approved in 2018 by the US FDA (16). As of July 2020, 33 patients with TRK fusion-positive CNS tumors were identified (median age: 8.9 years; range: 1.3-79.0). The most common histologies were high-grade glioma (n = 19) and low-grade glioma (n = 8). The objective response rate was 30% for all patients. Twenty-three of 28 patients (82%) with measurable disease had tumor shrinkage. The median time to response was 1.9 months (range 1.0 to 3.8 months). The 12-month rate for progression-free survival was 56% (95% CI: 38-74), and the 12-month rate for overall survival was 85% (95% CI: 71-99). Responses were durable, and treatment was well-tolerated (06).

Despite durable responses to NTRK inhibitors, the possibility of acquired resistance mechanisms looms. Reports of acquired secondary mutations in the TRK kinase domain after treatment with first-generation NTRK inhibitors have been described (08). Second-generation NTRK inhibitors have been developed, and ongoing studies are being performed (08; 16). The first two patients with TRK fusion-positive cancers who developed acquired resistance mutations on larotrectinib were treated with selitrectinib, a second-generation NTRK inhibitor. This first-in-human experiment led to rapid tumor responses. Neither patient had a CNS tumor (08).

Repotrectinib is a second-generation NTRK inhibitor that has been FDA-approved for ROS1-positive non-small cell lung cancer. It was designed to overcome resistance mechanisms to first-generation NTRK inhibition, and it targets NTRK fusion proteins, ROS1, and ALK (09; 16). Zurletrectinib is the latest entry to the NTRK inhibitor family. Preclinical data show stronger in vivo brain penetration and intracranial activity than prior second-generation NTRK inhibitors (29).

Outcomes

Clinical vignette #1. A 3-year-old male was found to have a primary spinal cord lesion on imaging of the back and underwent a debulking with T6-T12 laminectomy. Pathology was interpreted as an intramedullary ganglioglioma, and surveillance was recommended. Twenty-five years later, he underwent an open biopsy that confirmed recurrence. Again, surveillance was recommended. Three years later, he developed a right foot drop. An MRI of the thoracic spine showed a 12.9 x 2.2 x 2 cm intramedullary spinal cord mass from T7 to T12 with heterogeneous enhancement. He underwent another laminectomy with partial resection of the tumor. Histologically, it was suspected to be a ganglioglioma. After additional examination, it was determined to be an infiltrative high-grade glioma with wild-type IDH, 1p19q codeletion, MGMT methylation, and a GTF2I-NTRK2 fusion.

In December 2019, he started larotrectinib. He tolerated therapy well and has continued without significant adverse events. As of October 2024, he had completed 29 cycles of therapy.

Infiltrative high-grade glioma with wild-type IDH (1)

Preoperative MRI of the thoracic spine. (Contributed by Dr. Ashley L Sumrall.)
Infiltrative high-grade glioma with wild-type IDH (2)

Postoperative MRI of the thoracic spine. (Contributed by Dr. Ashley L Sumrall.)
Infiltrative high-grade glioma with wild-type IDH (3)

MRI of the thoracic spine after 1 year of NTRK inhibitor. (Contributed by Dr. Ashley L Sumrall.)
Infiltrative high-grade glioma with wild-type IDH (4)

MRI of the thoracic spine after 29 cycles of NTRK inhibitor. (Contributed by Dr. Ashley L Sumrall.)

Clinical vignette #2. A 45-year-old female presented to her primary care physician with dizziness and headaches. Imaging showed a lobulated mass originating in the fourth ventricle. Biopsy suggested a low-grade neuroepithelial lesion with necrotic features. A craniotomy with tumor resection was completed. Pathology confirmed atypical central neurocytoma, grade II. Surveillance followed for 2 years when a local recurrence occurred, and 15 Gray of stereotactic radiation was given. She had significant difficulties due to her prior procedures and therapy. When her tumor recurred 3 years later, extensive discussion followed about possible repeat resection, radiation, or chemotherapy. Ultimately, it was decided to biopsy the tissue for tumor profiling. Pathology confirmed metastatic atypical central neurocytoma, IDH wild-type, with a QKI:NTRK2 fusion.

In January 2024, she started larotrectinib. She tolerated therapy well and continued without significant adverse events. As of October 2024, she had completed nine cycles of therapy.

Metastatic atypical central neurocytoma, IDH wild-type (1)

Preoperative MRI. (Contributed by Dr. Ashley L Sumrall.)
Metastatic atypical central neurocytoma, IDH wild-type (2)

Postoperative MRI. (Contributed by Dr. Ashley L Sumrall.)
Metastatic atypical central neurocytoma, IDH wild-type (3)

MRI with tumor progression. (Contributed by Dr. Ashley L Sumrall.)
Metastatic atypical central neurocytoma, IDH wild-type (4)

MRI after three cycles of NTRK inhibitor. (Contributed by Dr. Ashley L Sumrall.)
Metastatic atypical central neurocytoma, IDH wild-type (5)

MRI after nine cycles of NTRK inhibitor. (Contributed by Dr. Ashley L Sumrall.)

As encouraging as these vignettes may be, there are unanswered questions on the management of these tumors. The ideal duration of treatment has not been described, and patients are treated until the disease progresses, the drug is not tolerated, or the patient prefers to stop therapy. It is unknown if patients may take a "holiday" from treatment or if this would promote a resistance mechanism. With the joy of finding an NTRK fusion and the ability to use an inhibitor comes the uncertainty of the future for the affected patient.

CNS tumor management is difficult, regardless of the presence of NTRK fusions or other molecular alterations. Surgical resection is almost never curative, and standard treatment with radiation offers additional negative consequences. Cytotoxic chemotherapy has limited utility for most tumor subtypes. Despite the rarity of NTRK fusions, the potential clinical benefit for an individual with a tumor possessing one of these fusions is remarkable. It is imperative that clinicians who care for individuals of all ages with CNS tumors are aware of diagnostic and therapeutic approaches to these tumors.

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38: References especially recommended by the author or editor for general reading.

Contributors

All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.

Author

Ashley L Sumrall MD FACP FASCO

Dr. Sumrall of the University of North Carolina at Chapel Hill has no relevant financial relationships to disclose.
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Editor

Rimas V Lukas MD

Dr. Lukas of Northwestern University Feinberg School of Medicine received honorariums from Novartis and Novocure for speaking engagements, honorariums from Cardinal Health, Novocure, and Merck for advisory board membership, and research support from BMS as principal investigator.
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Age range of presentation: 0 to 65+ years
Sex preponderance: No sex preponderance

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NTRK-fused tumors of the central nervous system

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NIH: Metastatic Brain Tumors

NTRK-fused tumors of the central nervous system

NTRK-fused tumors of the central nervous system

Introduction

Overview

Key points

Historical note and terminology

Clinical manifestations

Presentation and course

Prognosis and complications

Biological basis

Etiology and pathogenesis

Epidemiology

Prevention

Differential diagnosis

Confusing conditions

Associated or underlying disorders

Diagnostic workup

Management

Outcomes

Special considerations

Pregnancy

Anesthesia

Media

References

Contributors

Author

Editor

Patient Profile

ICD & OMIM codes

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Also in This Category

Neoplastic and infectious aneurysms

NF2-related schwannomatosis

Tumors of the skull base

Ganglioglioma

Paraneoplastic syndromes

Overview of neuropathology updates for infiltrating gliomas

Anti-LGI1 encephalitis

Brain metastases

	• Metastatic CNS tumors are more common than primary tumors. Given that NTRK fusions occur in tumor types that may spread to the brain (eg, thyroid cancer), possession of a pathologically confirmed diagnosis is important.
	• NTRK fusions and NTRK mutations are not the same.
	• NTRK mutations and other gene alterations can be identified in tissue samples.

NTRK-fused tumors of the central nervous system

Introduction

Overview

Key points

Historical note and terminology

Clinical manifestations

Presentation and course

Prognosis and complications

Biological basis

Etiology and pathogenesis

Epidemiology

Prevention

Differential diagnosis

Confusing conditions

Associated or underlying disorders

Diagnostic workup

Management

Outcomes

Special considerations

Pregnancy

Anesthesia

Media

References

Contributors

Author

Editor

Patient Profile

ICD & OMIM codes

This is an article preview. Start a Free Account to access the full version.

Questions or Comment?

Also in This Category

Neoplastic and infectious aneurysms

NF2-related schwannomatosis

Tumors of the skull base

Ganglioglioma

Paraneoplastic syndromes

Overview of neuropathology updates for infiltrating gliomas

Anti-LGI1 encephalitis

Brain metastases

This is an article preview.
Start a Free Account
to access the full version.