NTRK is emerging as an actionable biomarker and oncogenic driver across a wide range of tumour types1–9

NTRK  fusions have been identified in at least
25 tumour types in adult and paediatric patients, including:1–9

Central nervous system cancers

  • High-grade glioma (adult and paediatric)

Head and neck cancers 

  • Head and neck cancer
  • Mammary analogue secretory carcinoma

Thyroid cancers

  • Papillary thyroid cancer (paediatric)
  • Thyroid cancer

Thoracic cancers

  • Lung cancer

Sarcomas

  • Sarcoma
  • Infantile fibrosarcoma (paediatric)

Breast cancers

  • Breast cancer
  • Secretory breast carcinoma (adult and paediatric)

Blood cancers

  • Acute lymphoblastic leukaemia
  • Acute myeloid leukaemia
  • Histiocytosis
  • Multiple myeloma
  • Dendritic cell neoplasms

Gastrointestinal cancers

  • Gastrointestinal stromal tumour
  • Cholangiocarcinoma
  • Pancreatic cancer
  • Colorectal cancer

Genitourinary cancers

  • Renal cell carcinoma
  • Cellular and mixed congenital mesoblastic nephroma (paediatric)

Skin cancers

  • Melanoma
  • Spitzoid tumours

This figure is correct as of September 2019.

NTRK fusion+ cancer currently has no known defining clinical or pathological features. Only high-quality molecular testing such as next-generation sequencing (NGS) can confirm its presence1

background-lines1.png

ESMO proposal: NTRK testing10

786210555_FIGURE 1 no title.png

 

It is important to ensure that the diagnostic test covers NTRK 1, 2, 3 fusion genes and is validated with appropriate reference standards.

Figure adapted from Marchio C. et al , 2019.

High-quality molecular testing is needed to uncover NTRK fusion+ cancer1,11,12

background-lines4.png

TRK fusion proteins drive cancer through aberrant signalling1,3–6

TRKs play an important role in healthy tissue

  • The NTRK (neurotrophic tropomyosin receptor kinase) receptor family is encoded by the three NTRK genes that code for three proteins1
  • In healthy tissue, the NTRK pathway is involved in the development and functioning of the nervous system as well as cell survival3,13
NTRK-Gene.png

NTRK gene fusions create oncogenic proteins3

  • Each of the three NTRK genes can combine with multiple other gene partners to create oncogenic fusion proteins1–3,14
  • So far, 25 distinct fusions have been identified1
graph-ntrkFusions.png

The oncogenic fusion proteins drive cancer through aberrant signalling1,3–6

  • The oncogenic fusion proteins constitutively activate a signalling cascade implicated in cell proliferation, survival and angiogenesis1,3–6
TRK-fusion-protein.png

Footnotes:

ESMO, European Society for Medical Oncology; FISH, DNA fluorescence in situ hybridisation; IHC, immunohistochemistry; NGS, next-generation sequencing; RT-PCR, reverse-transcriptase polymerase chain reaction.

1

Vaishnavi A, Le AT, Doebele RC. Cancer Discov 2015;5:25–34.

2

Lange AM, Lo HW. Cancers (Basel) 2018;10.

3

Amatu A, Sartore-Bianchi A, Siena S. ESMO Open 2016;1:e000023.

4

Khotskaya YB, et al. Pharmacol Ther 2017;173:58–66.

5

de Lartigue J. TRK inhibitors advance rapidly in “tumor-agnostic” paradigm. OncologyLive 2017;18. Available at: https://www.onclive.com/publications/oncology-live/2017/vol-18-no-15/trk-inhibitors-advance-rapidly-in-tumoragnostic-paradigm (Accessed July 2020).

6

Robbins HL, Hague A. Front Endocrinol (Lausanne) 2016;6:1–22.

7

Dupain C, et al. Mol Ther Nucleic Acids 2017;6:315–326.

8

Kummar S, Lassen UN. Target Oncol 2018;13:545–556.

9

Cocco E, Scaltriti M, Drilon A. Nat Rev Clin Oncol 2018;15:731–747. 

10

Marchio C. et al. Ann Oncol 2019;30:1417–1427.

11

Murphy DA, et al. Appl Immunohisochem Mol Morphol 2017;25:513–523.

12

Rogers TM, et al. Sci Rep 2017;7:1–8.

13

Chong CR, et al. Clin Cancer Res 2017;23:204–213.

14

Stransky N, et al. Nat Commun 2014;5:4846.