ARTICLE

Targeted Therapy Using the Selective Tropomyosin Kinase Receptor Inhibitor Larotrectinib in an Infant with Infantile Fibrosarcoma with a TPM3–NTRK1 Gene Fusion with Lung and Central Nervous System Metastases: Case Report

A B S T R A C T

This case report describes the outcomes of tropomyosin receptor kinase (TRK) inhibitor treatment in an infant with an infantile fibrosarcoma (IFS) with a TPM3–NTRK1 gene fusion. The IFS on the left foot was refractory to chemotherapy and was partially resected. After 5 months, there was local recurrence and further surgery was performed. The patient developed pulmonary and central nervous system metastases. Pan-TRK antibody staining was positive and genomic profiling with next-generation sequencing confirmed a TPM3–NTRK1 gene fusion. The patient started treatment with larotrectinib in February 2019, with a durable response, including a clear reduction in brain metastases. Research on novel gene fusions and molecular testing to direct the use of targeted therapy should be encouraged, especially in refractory solid tumors.

Keywords

Infantile fibrosarcoma, kinase fusion, pediatric, sarcoma, case report

Introduction

Although rare, fibrosarcomas are the most common malignant mesenchymal tumor in the first year of life [1-3]. In children up to 2 years of age, the tumor is termed infantile fibrosarcoma (IFS) and in 80-90% of cases, it presents with the translocation t(12;15)(p13;q25). This translocation causes fusion of the neurotrophic tyrosine kinase receptor NTRK genes and the ETV6 gene (ETV6–NTRK3) resulting in chimeric transcripts with oncogenic potential [4]. The overall prognosis of IFS is good (3-year overall survival rate >90%) following initial surgery and chemotherapy, although progression or relapse are possible [5-7]. Conservative surgery is the treatment of choice for IFS because, although locally aggressive, distant metastases are rare. In unresectable tumors, the use of chemotherapy generally enables local tumor control [7]. Occasionally, some cases of IFS can regress spontaneously; in contrast, others can present with aggressive behaviour and are refractory to treatment [8-10]. Van Grotel et al. reported a case of IFS with the classic translocation in a 2-month old infant who presented with numerous lung metastases on diagnosis [9].

In another study, the authors presented an aggressive IFS with a rare LMNA–NTRK1 translocation that was refractory to treatment [10]. With the recent technological advances in genomic sequencing, new information on oncogenic events has been reported for various cancers. The high frequency of NTRK gene fusions in IFS has driven the development of targeted therapy with a tyrosine kinase receptor inhibitor, and specifically, a tropomyosin receptor kinase (TRK) inhibitor [11, 12]. Here, the authors present the case of an infant with chemotherapy-refractory IFS who presented with pulmonary and central nervous system (CNS) metastases. Molecular analyses detected a TPM3–NTRK1 gene fusion. The objectives of this case report are to discuss the molecular biology of IFS and describe the outcomes of this patient with TRK fusion IFS (TPM3–NTRK1 gene fusion) treated with larotrectinib-a selective TRK inhibitor.

Case Report

A female infant aged 1 year and 2 months old presented with a hardened tumor in the plantar region of the left foot; the tumor had been present for 2 months. On examination, the posterior two-thirds of the plantar region were bulging, but painless, with ill-defined limits and marked vascularization. The histological diagnosis was fibrosarcoma. Optical microscopy revealed fusocellular sarcoma with long, intersecting fascicles (Figure 1).

Immunohistochemistry (IHC) analysis indicated fibroblast/myofibroblast differentiation, with a proliferative index measured by Ki67 expression of around 5%. Magnetic resonance imaging (MRI) of the left foot showed a 3.8 × 5.8 × 4.3 cm lesion, without compromised regional lymph nodes. Other staging examinations, including chest computed tomography (CT), were normal. The final diagnosis was non-metastatic, unresectable IFS.

The family reported a maternal family history of a grandmother with cervical cancer at 44-year-old, and a great-uncle and great-grandmother with leukemia (over 60-year-old). On the paternal side, the family history included a great-aunt with breast cancer, three cousins with breast cancer (one was under 50-year-old), a cousin with head and neck cancer when under 10 years of age and another cousin with retinoblastoma. Given the family history, a commercial multigene panel was performed to search for germline point variants, deletions, and duplications in 83 genes associated with hereditary predisposition to cancer, using Illumina technology, with ≥50x depth. Only one intronic variant of uncertain significance was identified in the PMS2 gene, c.537 + 6G>A.

Upon diagnosis, three cycles of vincristine, actinomycin-D, and cyclophosphamide (VAC) chemotherapy were started, after which the tumor was stable at the reassessment examinations (Figure 2). The patient received two more cycles of ifosfamide and etoposide; however, upon imaging, the tumor had progressed. The chemotherapy regimen was then altered to vinblastine and methotrexate, resulting in a partial response. The patient then underwent conservative surgical resection with positive surgical margins. Five months after surgery, the patient relapsed with local recurrence and another resection of the tumor was performed, with coincident margins. Treatment with vinblastine and methotrexate was maintained.

The patient presented no evidence of disease for 21 months after the second local surgery, however, she presented with symptoms of a respiratory infection. A CT scan of the thorax showed an expansive, solid cystic formation with peripheral enhancement centered on the lower left lobe of the lung (Figure 2). The patient underwent a biopsy of the lung lesion and metastasis of the fibrosarcoma was confirmed. She underwent a left inferior lobectomy with total resection of the tumor and negative surgical margins, and a lymphadenectomy with neoplasia-free lymph nodes. The tumor fragment obtained from the lobectomy was sent for molecular analysis. Four months after the surgery for the lung metastasis, the patient presented with signs of intracranial hypertension. A brain MRI showed a large, expansive formation in the suprasellar, hypothalamic-chiasmatic region projecting into the third ventricle. On physical examination, the plantar region of the left foot had also bulged, with local disease recurrence confirmed by MRI. The patient received ventriculoperitoneal shunt surgery and partial resection of the brain tumor. Pathological examination confirmed fibrosarcoma metastasis and there was bleeding of the tumor during surgery. Postoperatively, there was lack of spontaneous eye opening, signs of decorticate posturing, anisocoria, and limb spasticity. Three weeks after neurosurgery, imaging (MRI) examination showed an increase in the size of the brain tumor (Figure 3). Corticosteroids and anticonvulsants were prescribed.

Paraffin-embedded tissue from the metastatic lung tumor was sent for reverse transcription-polymerase chain reaction (RT-PCR) screening for the ETV6–NTRK3 transcript from the translocation t(12;15)(p13;q25), but transcript was not detected. Subsequently, an IHC assay using the anti-pan-TRK monoclonal antibody (TRKA, B, C) EPR17341 was positive, indicating hyperexpression of the TRK proteins and the possible presence of a fusion in the NTRK gene family. Subsequently, the biopsy specimen was sent for comprehensive genomic profiling (FoundationOne, Cambridge, MA, USA) with next-generation sequencing (NGS), which detected a TPM3–NTRK1 fusion. Additional molecular findings included low tumor mutational burden, microsatellite stability, an alteration in the CD36 N53fs*24 gene, and loss of CDNK2A and CDKN2B. The identification of the TPM3–NTRK1 fusion prompted for the initiation of treatment with the highly specific TRK (TRKA, B, and C) inhibitor, larotrectinib.

Therapy with larotrectinib (oral solution, 100 mg/m²) was started and, after 14 days, the patient showed clinical improvement with a reduction of tumor volume in the plantar region of the foot. Three weeks after starting the targeted therapy, a cranial MRI showed a partial reduction in tumor size (RECIST -0.39) and an accentuated decrease in contrast uptake. The lesion on the foot had completely regressed 5 months after starting larotrectinib (RECIST -1). A chest CT showed no signs of pulmonary recurrence. The patient, now 6 years and 7 months old, has received larotrectinib for 24 months without signs of active disease, and with progressive improvement in motor and cognitive functions. Fatigue and weight gain (grade 2) have been noted in the past 22 months.

Discussion

IFS is defined by its clinical and histological characteristics, as well as the presence of the recurrent translocation t(12;15)(p13;q25) resulting in ETV6–NTRK3 gene fusion in 80-90% of cases [4]. However, this gene fusion is not specific to IFS and has been described in several adult and pediatric tumors [11-14]. Other NTRK gene fusions have also been described in IFS, with fusion partners other than ETV6 including LMNA–NTRK1, SQSTM1–NTRK1, TPM3–NTRK1, and EML4–NTRK3 [10, 15-19]. Pavlick et al. investigated the presence of NTRK gene fusions in 2031 different tumors in patients under 21 years of age. Nine of the 2031 tumors (0.44%) had NTRK gene fusions. Of these, four were patients with IFS: two with an ETV6–NTRK3 gene fusion, one with an LMNA–NTRK1 gene fusion, and the other with an SQSTM1–NTRK1 gene fusion [15]. All these gene fusions lead to constitutive expression in the chimeric proteins, driving oncogenesis and malignant transformation [13].

The infant with IFS presented in this case report developed refractoriness to chemotherapy and distant metastases. An initial analysis for an NTRK gene fusion was performed using RT-PCR to direct targeted treatment with a TRK inhibitor. Despite the high frequency of the translocation t(12;15) in IFS, the ETV6–NTRK3 transcript was not detected in initial RT-PCR screening. However, IHC analysis showed positive hyperexpression of TRK protein, suggesting the presence of an NTRK gene fusion [20]. These results highlight the importance of using IHC in the initial screening for NTRK gene fusions in patients with IFS, considering that, although translocation t(12;15) with ETV6–NTRK3 gene fusion is the most common mutation, we should also consider that other gene fusions may occur. IHC using a pan-TRK antibody has high sensitivity (95%) for the diagnosis of IFS and should be the first analysis used for screening. However, IHC can show TRK hyperexpression without necessarily indicating the presence of an NTRK gene fusion; therefore, more specific analyses are required to confirm this gene fusion [14, 21].

NGS analysis subsequently identified the rare TPM3–NTRK1 gene fusion. NGS is a highly specific analysis that can sequence multiple genes and potentially identify new fusions. The decision to undertake analyses to identify NTRK gene fusions should follow a diagnostic sequence that depends on the clinical and histological features of a tumor, as well as the variety of NTRK gene fusions with different partners and genomic breakdowns [21-23]. Actionable mutations are identified in many sequenced tumors, therefore the clinical utility of molecular testing for rare gene fusions and subsequent targeted therapy requires further study and long-term follow up of patient outcomes [22]. In Brazil, the cost and availability of genomic profiling is also a significant factor.

The unusual TPM3–NTRK1 gene fusion found in this case is rare in IFS, but has been previously identified in pediatric and adult solid tumors [15, 16, 18]. The TPM3 gene is located on chromosome 1q21.3 and the NTRK1 gene on 1q23.1, about 2.7 Mb apart [24]. This fusion involves a complex mechanism of breakage and inversion, usually within exon 6 in the TPM3 gene and exon 9 in the NTRK1 gene [25]. It is a fusion that has also been described in lipofibromatosis-like neural tumors, papillary thyroid carcinomas, colorectal carcinomas, glioblastomas, uterine sarcomas, and spindle cell sarcomas [13, 25-27].

Davis et al. have reported six cases of infants with fibroblastic tumors without an ETV6–NTRK3 gene fusion [18]. Of these, four presented with a TPM3–NTRK1 gene fusion, one with LMNA–NTRK1, and another with EML4–NTRK3. Of the patients with fusions involving the TPM3 gene, one had lung metastases. The patient described in this case report presented with an aggressive IFS tumor; metastases occurred in the midline region-a single extensive and expansive process centered on the lower lobe of the left lung—and subsequently, in the suprasellar, hypothalamic-chiasmatic region of the brain. Due to the rarity of IFS with a non-classical gene fusion such as TPM3–NTRK1, it is not possible to infer the importance of this fusion as a prognostic factor or as a new subgroup of sarcomas [10, 17]. In the Laetsch et al. study, of the 15 patients with TRK fusion cancer, eight cases were IFS, and of those, one had a TPM3–NTRK1 gene fusion and a good response to larotrectinib therapy [16]. Haller et al. described four patients with a subgroup of spindle cell sarcomas, all with a prominent myopericytic/hemangiopericytic pattern, two of which had a TPM3–NTRK1 gene fusion [27].

Loss (deletion) of CDNK2A and CDKN2B were identified by NGS. CDKN2A deletions associated with NTRK1 fusions, as found in this patient, have previously been described [15, 27-29]. Pavlik et al. described a patient with soft tissue schwannoma with an TPM3–NTRK1 gene fusion and homozygous loss of CDKN2A/B, and two other patients with homozygous loss of CDKN2A/B associated with other tumors and other fusions [15]. Haller et al. described four patients with NTRK1 gene fusions, three of whom (one with LMNA–NTRK1 and two with TPM2–NTRK1 fusion) also had CDKN2A deletions, raising the question as to whether fusions associated with NTRK1 may sometimes be associated with loss of CDKN2A/B in soft tissue sarcomas [27]. In a review by Doebele et al., four out of eight patients with sarcomas and NTRK1 gene fusions also presented with co-occurring CDKN2A/B deletion, although none had the TPM3–NTRK1 fusion [28]. These gene losses are known to be common in multiple sarcoma types and, specifically, CDKN2A deletion and/or p16INK4a deletion have been associated with poor prognosis in peripheral nerve sheath sarcomas [30].

Currently, precision medicine considers the molecular drivers of a tumor, as well as the histological tumor type, allowing individualized treatment through targeted therapies. In Brazil, larotrectinib was approved by the National Health Surveillance Agency (Agência Nacional de Vigilância Sanitária) in 2019. It is a potent and highly selective inhibitor of the TRKA, TRKB, and TRKC neurotrophin receptors. Administered orally, larotrectinib binds to the tyrosine kinase receptor domain of TRK and prevents its activation, resulting in cell growth inhibition and apoptosis. Regardless of the type of neurotrophin receptor and the fusion partner involved, larotrectinib has proved to be effective in the control and treatment of various types of solid tumors harboring an NTRK gene fusion in pediatric and adult patients (e.g. mesoblastic nephroma fibrosarcoma, soft tissue sarcoma, papillary thyroid cancer, secretory breast carcinoma, and lung cancer) [11, 23]. The objective response rate of larotrectinib was 93% in 15 pediatric patients with TRK fusion cancer and measurable tumors, including in one patient with IFS with a TPM3–NTRK1 gene fusion [16].

In a recent article describing the results of three phase 1 and 2 studies, the use of larotrectinib in patients of different age groups and with different tumors with an NTRK gene fusion resulted in a response rate of 79%. These results confirm the effectiveness of larotrectinib as a targeted therapy in tumors with an NTRK gene fusion, regardless of the tumor location and histology, and the patient's age (i.e. it is a tumor-agnostic therapy) [31, 32]. Larotrectinib has been used as neoadjuvant therapy in five children with locally advanced TRK fusion sarcomas; partial tumor responses following treatment allowed curative surgery to be performed with low morbidity [12]. Although cases with lasting responses to TRK inhibitors have been described, including partial and complete responses to larotrectinib, some patients may develop resistance [16]. Fortunately, second generation TRK inhibitors are being developed clinically, which appear to supersede the acquired resistance to first-generation inhibitors [16, 32].

In the case reported here, larotrectinib produced a therapeutic response in a patient with tumor harboring the TPM3–NTRK1 gene fusion, including an intracranial CNS response. The infant, who was in intensive care with brain metastasis and local disease progression, showed rapid clinical and radiological improvement 14 days after starting larotrectinib and remains without signs of local or pulmonary relapse after 24 months of treatment. In the CNS, the expansive metastatic disease decreased in size, with reduced contrast uptake demonstrating reduced disease activity. Larotrectinib has been well tolerated in pediatric patients in a phase 1 study, with elevated liver enzymes, cytopenias, and vomiting (grade 1) as the most frequent adverse events [16]. Pooled analysis of 159 patients, including 50 pediatric patients, from three phase 1/2 clinical trials confirm the tolerability of larotrectinib and indicate that long-term administration is feasible. The patient in this case report experienced weight gain (grade 2) and tiredness (grade 2) as adverse events on larotrectinib and follow up will be required. In locally advanced or metastatic solid tumors, identification of NTRK gene fusions may represent an important therapeutic opportunity. However, frequent and long-term monitoring is necessary until the resistance mechanisms to TRK inhibition have been well established.

Conflicts of Interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Data Availability

Availability of the data underlying this publication will be determined according to Bayer’s commitment to the EFPIA/PhRMA “Principles for responsible clinical trial data sharing”. This pertains to scope, time point, and process of data access. As such, Bayer commits to sharing upon request from qualified scientific and medical researchers patient-level clinical trial data, study-level clinical trial data, and protocols from clinical trials in patients for medicines and indications approved in the United States (US) and European Union (EU) as necessary for conducting legitimate research. This applies to data on new medicines and indications that have been approved by the EU and US regulatory agencies on or after January 01, 2014. Interested researchers can use the link to request access to anonymized patient-level data and supporting documents from clinical studies to conduct further research that can help advance medical science or improve patient care. Information on the Bayer criteria for listing studies and other relevant information is provided in the “Study sponsors section” of the portal. Data access will be granted to anonymized patient-level data, protocols, and clinical study reports after approval by an independent scientific review panel. Bayer is not involved in the decisions made by the independent review panel. Bayer will take all necessary measures to ensure that patient privacy is safeguarded.

Funding

Copyediting and editorial assistance for the development of this case study was provided by Matthew Naylor, Ph.D., at Open Health Communications (London, UK), with financial support from Bayer.

Consent

Written informed consent to participate in this study was provided by the participants’ legal guardian/next of kin.

Abbreviations

CDKN2A/B: Cyclin Dependent Kinase Inhibitor 2A/B
EML4: Echinoderm Microtubule Associated Protein-Like 4
ETV6: ETS Variant Transcription Factor 6
LMNA: Lamin A/C
NTRK1/3: Neurotrophic Receptor Tyrosine Kinase 1/3
SQSTM1: Sequestosome 1
TPM3: Tropomyosin 3

ARTICLE INFO

Download PDF View PDF

Article Info

Article Type

Case Report

Publication history

Received:

Accepted:

Published:

Copyright

© 2023 Fabricio T Romagnol. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Hosting by Science Repository.

DOI: 10.31487/j.COR.2021.03.03

AUTHOR INFO

Author Info

Eliana M Caran

Fabricio T Romagnol

Sérgio Cavalheiro

Marcelo de Toledo Petrilli

Henrique Manoel Lederman

Fernanda Teresa de Lima

Maria Teresa de Seixas Alves

Leticia Yasuda Carreira

Antonio Sérgio Petrilli

Corresponding Author

Fabricio T Romagnol
Instituto de Oncologia Pediátrica, Grupo de Apoio ao Adolescente e à Criança com Câncer (IOP/GRAACC), São Paulo, Brazil

FIGURES & TABLES

REFERENCE

1.     Sultan I, Casanova M, Al Jumaily U, Meazza C, Rodriguez Galindo C et al. (2010) Soft tissue sarcomas in the first year of life. Eur J Cancer 46: 2449-2456. [Crossref]

2.     Pastore G, Peris Bonet R, Carli M, Martinez Garcia C, Sanchez de Toledo J et al. (2006) Childhood soft tissue sarcomas incidence and survival in European children (1978-1997): report from the Automated Childhood Cancer Information System project. Eur J Cancer 42: 2136-2149. [Crossref]

3.    Weihkopf T, Blettner M, Dantonello T, Jung I, Klingebiel T et al. (2008) Incidence and time trends of soft tissue sarcomas in German children 1985-2004 - a report from the population-based German Childhood Cancer Registry. Eur J Cancer 44: 432-440. [Crossref]

4.     Knezevich SR, Garnett MJ, Pysher TJ, Beckwith JB, Grundy PE et al. (1998) ETV6-NTRK3 gene fusions and trisomy 11 establish a histogenetic link between mesoblastic nephroma and congenital fibrosarcoma. Cancer Res 58: 5046-5048. [Crossref]

5.     Orbach D, Rey A, Cecchetto G, Oberlin O, Casanova M et al. (2010) Infantile fibrosarcoma: management based on the European experience. J Clin Oncol 28: 318-323. [Crossref]

6.     Cecchetto G, Carli M, Alaggio R, Dall'Igna P, Bisogno G et al. (2001) Fibrosarcoma in pediatric patients: results of the Italian Cooperative Group studies (1979-1995). J Surg Oncol 78: 225-231. [Crossref]

7.     Orbach D, Brennan B, De Paoli A, Gallego S, Mudry P et al. (2016) Conservative strategy in infantile fibrosarcoma is possible: The European paediatric Soft tissue sarcoma Study Group experience. Eur J Cancer 57: 1-9. [Crossref]

8.     Sait SF, Danzer E, Ramirez D, LaQuaglia MP, Paul M (2018) Spontaneous regression in a patient with infantile fibrosarcoma. J Pediatr Hematol Oncol 40: e253-e255. [Crossref]

9.     van Grotel M, Blanco E, Sebire NJ, Slater O, Chowdhury T et al. (2014) Distant metastatic spread of molecularly proven infantile fibrosarcoma of the chest in a 2-month-old girl: case report and review of literature. J Pediatr Hematol Oncol 36: 231-233. [Crossref]

10.  Bender J, Anderson B, Bloom DA, Rabah R, McDougall R et al. (2019) Refractory and metastatic infantile fibrosarcoma harboring LMNA-NTRK1 fusion shows complete and durable response to crizotinib. Cold Spring Harb Mol Case Stud 5: a003376. [Crossref]

11.  Drilon A, Laetsch TW, Kummar S, DuBois SG, Lassen UN et al. (2018) Efficacy of larotrectinib in TRK fusion-positive cancers in adults and children. N Engl J Med 378: 731-739. [Crossref]

12.  DuBois SG, Laetsch TW, Federman N, Turpin BK, Albert CM et al. (2018) The use of neoadjuvant larotrectinib in the management of children with locally advanced TRK fusion sarcomas. Cancer 124: 4241-4247. [Crossref]

13.  Amatu A, Sartore Bianchi A, Siena S (2016) NTRK gene fusions as novel targets of cancer therapy across multiple tumour types. ESMO Open 1: e000023. [Crossref]

14.  Hung YP, Fletcher CDM, Hornick JL (2018) Evaluation of pan-TRK immunohistochemistry in infantile fibrosarcoma, lipofibromatosis-like neural tumour and histological mimics. Histopathology 73: 634-644. [Crossref]

15.  Pavlick D, Schrock AB, Malicki D, Stephens PJ, Kuo DJ et al. (2017) Identification of NTRK fusions in pediatric mesenchymal tumors. Pediatr Blood Cancer 64. [Crossref]

16.  Laetsch TW, DuBois SG, Mascarenhas L, Turpin B, Federman N et al. (2018) Larotrectinib for paediatric solid tumours harbouring NTRK gene fusions: phase 1 results from a multicentre, open-label, phase 1/2 study. Lancet Oncol 19: 705-714. [Crossref]

17.  Kao YC, Fletcher CDM, Alaggio R, Wexler L, Zhang L et al. (2018) Recurrent BRAF gene fusions in a subset of pediatric spindle cell sarcomas: Expanding the genetic spectrum of tumors with overlapping features with infantile fibrosarcoma. Am J Surg Pathol 42: 28-38. [Crossref]

18.  Davis JL, Lockwood CM, Albert CM, Tsuchiya K, Hawkins DS et al. (2018) Infantile NTRK-associated mesenchymal tumors. Pediatr Dev Pathol 21: 68-78. [Crossref]

19.  Tannenbaum Dvir S, Glade Bender JL, Church AJ, Janeway KA, Harris MH et al. (2015) Characterization of a novel fusion gene EML4-NTRK3 in a case of recurrent congenital fibrosarcoma. Cold Spring Harb Mol Case Stud 1: a000471. [Crossref]

20.  Penault Llorca F, Rudzinski ER, Sepulveda AR (2019) Testing algorithm for identification of patients with TRK fusion cancer. J Clin Pathol 72: 460-467. [Crossref]

21.  Albert CM, Davis JL, Federman N, Casanova M, Laetsch TW (2019) TRK Fusion Cancers in Children: A clinical Review and Recommendations for Screening. J Clin Oncol 37: 513-524. [Crossref]

22.  Solomon JP, Hechtman JF (2019) Detection of NTRK fusions: Merits and limitations of current diagnostic platforms. Cancer Res 79: 3163-3168. [Crossref]

23.  Hsiao SJ, Zehir A, Sireci AN, Aisner DL (2019) Detection of Tumor NTRK Gene Fusions to Identify Patients Who May Benefit from Tyrosine Kinase (TRK) Inhibitor Therapy. J Mol Diagn 21: 553-571. [Crossref]

24.  Cunningham F, Achuthan P, Akanni W, Allen J, Amode MR et al. (2019) Ensembl 2019. Nucleic Acids Res 47: D745-D751. [Crossref]

25. Agaram NP, Zhang L, Sung YS, Chen CL, Chung CT et al. (2016) Recurrent NTRK1 gene fusions define a novel subset of locally aggressive lipofibromatosis-like neural tumors. Am J Surg Pathol 40: 1407-1416. [Crossref]

26.  Chetty R (2019) Neurotrophic tropomyosin or tyrosine receptor kinase (NTRK) genes. J Clin Pathol 72: 187-190. [Crossref]

27.  Haller F, Knopf J, Ackermann A, Bieg M, Kleinheinz K et al. (2016) Paediatric and adult soft tissue sarcomas with NTRK1 gene fusions: a subset of spindle cell sarcomas unified by a prominent myopericytic/haemangiopericytic pattern. J Pathol 238: 700-710. [Crossref]

28.  Doebele RC, Davis LE, Vaishnavi A, Le AT, Estrada Bernal A et al. (2015) An Oncogenic NTRK Fusion in a Patient with Soft-Tissue Sarcoma with Response to the Tropomyosin-Related Kinase Inhibitor LOXO-101. Cancer Discov 5: 1049-1057. [Crossref]

29.  Wong V, Pavlick D, Brennan T, Yelensky R, Crawford J et al. (2016) Evaluation of a congenital infantile fibrosarcoma by comprehensive genomic profiling reveals an LMNA-NTRK1 gene fusion responsive to crizotinib. J Natl Cancer Inst 108: djv307. [Crossref]

30.  Endo M, Kobayashi C, Setsu N, Takahashi Y, Kohashi K et al. (2011) Prognostic significance of p14ARF, p15INK4b, and p16INK4a inactivation in malignant peripheral nerve sheath tumors. Clin Cancer Res 17: 3771-3782. [Crossref]

31.  Hong DS, DuBois SG, Kummar S, Farago AF, Albert CM et al. (2020) Larotrectinib in patients with TRK fusion-positive solid tumours: a pooled analysis of three phase 1/2 clinical trials. Lancet Oncol 21: 531-540. [Crossref]

32. Lassen U (2019) How I treat NTRK gene fusion-positive cancers. ESMO Open 4: e000612. [Crossref].