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Year : 2021  |  Volume : 4  |  Issue : 2  |  Page : 420-422

Clinical utility of the NTRK gene fusion in current clinical practice

Department of Medical Oncology, Tata Memorial Centre, Homi Bhabha National Institute, Mumbai, Maharashtra, India

Date of Submission28-May-2021
Date of Decision31-May-2021
Date of Acceptance02-Jun-2021
Date of Web Publication30-Jun-2021

Correspondence Address:
Nandini Menon
Department of Medical Oncology, Tata Memorial Centre, Mumbai - 400 012, Maharashtra
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/crst.crst_122_21

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How to cite this article:
Shah M, Abraham G, Menon N. Clinical utility of the NTRK gene fusion in current clinical practice. Cancer Res Stat Treat 2021;4:420-2

How to cite this URL:
Shah M, Abraham G, Menon N. Clinical utility of the NTRK gene fusion in current clinical practice. Cancer Res Stat Treat [serial online] 2021 [cited 2021 Aug 5];4:420-2. Available from: https://www.crstonline.com/text.asp?2021/4/2/420/320310

Fusions involving the neurotrophic tropomyosin receptor kinase 1/2/3 (NTRK1/2/3) gene are hallmark NTRK alterations found in 0.3% of all solid malignancies[1] and 1% of all non small-cell lung cancers (NSCLCs).[2] The narrative literature review of NTRK by Batra et al.[2] provides a detailed overview of the biology, signaling pathways, detection methods, and treatment for NTRK fusion-positive cancers. However, there are certain aspects of the NTRK alterations that need to be emphasized.

The 2019 European Society of Medical Oncology guidelines[3] state that, for tumors that have a high probability of harboring NTRK fusions (high frequency, upto or >90%) such as secretory breast and salivary gland carcinomas, congenital mesoblastic nephroma, and infantile fibrosarcomas, any of the following techniques may be used for NTRK fusion testing – fluorescence in situ hybridization (FISH), immunohistochemistry (IHC), reverse transcriptase-polymerase chain reaction (RT-PCR), or RNA-based targeted next-generation sequencing (NGS). However, confirmatory techniques such as FISH, RT-PCR, or RNA-based targeted NGS are the most preferred. In cancers with a low frequency of NTRK fusions (<5% and 5%–25%) such as lung adenocarcinomas, breast cancer, melanomas, and head-and-neck squamous carcinomas, targeted RNA sequencing is the gold standard when an NGS facility is available. In resource-limited settings, where an NGS facility is not available, a pan-Trk IHC (sensitivity 95.2%, specificity 100%, with the rate of false negatives being higher for NTRK3 fusions)[4] can be used for screening, followed by targeted RNA sequencing in IHC-positive cases (a two-step approach). It is essential to note that the NTRK protein kinase is the pharmacological target of the NTRK inhibitors; therefore, the confirmation of the NTRK fusion protein expression by IHC should be performed in all cases[Figure 1].[3]
Figure 1: Algorithm for testing of neurotrophic tropomyosin receptor kinase gene fusion: Testing should be performed in patients with metastatic ROS1-positive non-small-cell lung cancers, metastatic/locally advanced tumors without a satisfactory therapy, in those who have exhausted standard lines of therapy, in cases where surgical cure is considered to be too morbid, and in patients whose clinical response to targeted therapy or immune checkpoint inhibitors is not as expected. In addition, testing should be considered in younger patients if other known oncogenic-driver mutations are absent. NTRK: Neurotrophic tropomyosin receptor kinase, FISH: Fluorescence in situ hybridization, IHC: Immunohistochemistry, NGS: Next-generation sequencing, RT-PCR: Reverse transcriptase-polymerase chain reaction

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Higher tumor mutational burden (TMB) and expression of programmed death-ligand 1 (PD-L1) are more common in tumors with NTRK fusions (approximately 23%)[5] than in those without. This implies that NTRK fusion-positive tumors with a high TMB and/or PD-L1 expression would also have a response to immune checkpoint inhibitor (ICI) therapy. However, this may not always be true, as NTRK fusions may act as resistance mechanisms to ICI therapy. NTRK fusions may be associated with serine/threonine kinase 11 (STK11) mutations,[6] which are also found in KRAS-mutant lung adenocarcinomas, which are known to have primary PD-L1 axis resistance. In addition, novel fusions such as NCOR2-NTRK1 are associated with PD-L1 axis resistance by mechanisms that are yet to be determined.[7] It has been observed that NTRK fusions are mutually exclusive with other oncogenic drivers including KRAS, NRAS, BRAF, MAP2K1, EGFR, ALK, RET, ROS1, KIT, and PDGFRA.[8] However, in a recently published Chinese study, 50% of the patients with NTRK fusions had concurrent epidermal growth factor receptor (EGFR) mutations.[9] The study suggested that NTRK1 fusion might act as a resistance mechanism against EGFR tyrosine kinase inhibitors. This highlights the fact that NTRK fusions can mediate resistance to targeted therapies/ICIs in tumors driven by other oncogenic mutations (like EGFR/PD-L1) and that it is necessary to look for NTRK fusions when a clinical response to targeted therapies/ICIs is not as expected.

There has been an increasing trend in the testing for NTRK fusions after the Phase I/II basket trials successfully demonstrated a significant increase in the objective response rate, intracranial response rate, and survival benefit with the use of first-generation NTRK inhibitors (larotrectinib and entrectinib).[1] NTRK inhibitors have demonstrated histology agnostic and age-independent activity in various cancers harboring NTRK fusions. As a result of the development of newer molecules such as repotrectinib and selitrectinib (that are able to overcome primary resistance to first-generation NTRK inhibitors) and given the fact that NTRK fusions can mediate resistance even in EGFR/PDL1-positive tumors, it becomes imperative to test for NTRK fusions in all metastatic and locally advanced tumors without a satisfactory therapy, in patients who have exhausted standard lines of therapy, in settings where surgical cure is considered to be too morbid, and in patients in whom the clinical response to targeted therapies/ICI is not as expected. The systemic and intracranial activities of NTRK inhibitors have changed the landscape for the management of ROS1-positive NSCLCs with brain metastasis in the current era, with NTRK inhibitors being preferred over the standard therapy with crizotinib, wherever feasible.[10]

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  References Top

Doebele RC, Drilon A, Paz-Ares L, Siena S, Shaw AT, Farago AF, et al. Entrectinib in patients with advanced or metastatic NTRK fusion-positive solid tumours: Integrated analysis of three phase 1-2 trials. Lancet Oncol 2020;21:271-82.  Back to cited text no. 1
Batra U, Nathany S, Sharma M. NTRK-A narrative review. Cancer Res Stat Treat 2021;4:110-4.  Back to cited text no. 2
  [Full text]  
Marchiò C, Scaltriti M, Ladanyi M, Iafrate AJ, Bibeau F, Dietel M, et al. ESMO recommendations on the standard methods to detect NTRK fusions in daily practice and clinical research. Ann Oncol 2019;30:1417-27.  Back to cited text no. 3
Hechtman JF, Benayed R, Hyman DM, Drilon A, Zehir A, Frosina D, et al. Pan-Trk Immunohistochemistry is an efficient and reliable screen for the detection of NTRK fusions. Am J Surg Pathol 2017;41:1547-51.  Back to cited text no. 4
Gatalica Z, Xiu J, Swensen J, Vranic S. Molecular characterization of cancers with NTRK gene fusions. Mod Pathol 2019;32:147-53.  Back to cited text no. 5
Skoulidis F, Goldberg ME, Greenawalt DM, Hellmann MD, Awad MM, Gainor JF, et al. STK11/LKB1 Mutations and PD-1 inhibitor resistance in KRAS-mutant lung adenocarcinoma. Cancer Discov 2018;8:822-35.  Back to cited text no. 6
Zhang L, Liu H, Tian Y, Wang H, Yang X. A novel NCOR2-NTRK1 fusion detected in a patient of lung adenocarcinoma and response to larotrectinib: A case report. BMC Pulm Med 2021;21:125.  Back to cited text no. 7
Solomon JP, Benayed R, Hechtman JF, Ladanyi M. Identifying patients with NTRK fusion cancer. Ann Oncol 2019;30:816-22.  Back to cited text no. 8
Xia H, Xue X, Ding H, Ou Q, Wu X, Nagasaka M, et al. Evidence of NTRK1 fusion as resistance mechanism to EGFR TKI in EGFR+NSCLC: Results from a large-scale survey of NTRK1 fusions in Chinese patients with lung cancer. Clin Lung Cancer 2020;21:247-54.  Back to cited text no. 9
Sehgal K, Piper-Vallillo AJ, Viray H, Khan AM, Rangachari D, Costa DB. Cases of ROS1-rearranged lung cancer: When to use crizotinib, entrectinib, lorlatinib, and beyond? Precis Cancer Med 2020;3:17.  Back to cited text no. 10


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