A systematic review and meta-analysis of neurotrophic tyrosine receptor kinase gene fusion frequencies in solid tumors

Our plain-English summary of A systematic review and meta-analysis of neurotrophic tyrosine receptor kinase gene fusion frequencies in solid tumors, by A. Forsythe, W. Zhang, U. Phillip Strauss, et al (Therapeutic Advances in Medical Oncology, 2020).

The study

• Authors: A. Forsythe, W. Zhang, U. Phillip Strauss, M. Fellous, M. Korei, K. Keating
• Journal: Therapeutic Advances in Medical Oncology
• Published: 2020;12:1758835920975613
• Cited by: 91 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Introduction: The research objective was to systematically review evidence on neurotrophic tyrosine receptor kinase (NTRK) gene fusion frequency in solid tumors.

Methods: Using Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, a systematic literature review (SLR) was conducted of studies published from January 1987 to 2 January 2020. Selected studies were appraised for use in meta-analysis, with frequency reported as a point estimate with confidence intervals, to estimate NTRK gene fusion tumor incidence and prevalence.

Results: The SLR identified 222 studies from North America (n = 122), Europe (n = 33), Asia (n = 41), Brazil (n = 5), Australia (n = 2), and multi-continental (n = 19) reporting NTRK gene fusion frequencies across 101 histologies. Studies were prospective (n = 43) and retrospective (n = 179). Testing methods involved DNA (n = 93), RNA (n = 72), combined DNA/RNA (n = 48), protein [immunohistochemistry (IHC), n = 5], and unreported (n = 5). Sample sizes ranged from 1 to 66,871. Of the 222 studies, 107 were suitable for meta-analysis. Highest NTRK gene fusion frequencies were reported in rare cancers: infantile/congenital fibrosarcoma (90.56%, 95% CI 67.42-100.00), secretory breast cancer (92.87%, 95% CI 72.62-100.00), and congenital mesoblastic nephroma (21.52%, 95% CI 13.06-32.20). Lower frequencies were reported in non-small cell lung cancer (0.17%, 95% CI 0.09-0.25), colorectal adenocarcinoma (0.26%, 95% CI 0.15-0.36), cutaneous melanoma (0.31%, 95% CI 0.07-0.55), and non-secretory breast carcinoma (0.60%, 95% CI 0.00-1.50). Reported frequency was ~0% for some cancers: mesothelioma, renal cell carcinoma, prostate cancer, and bone sarcoma. Estimated global overall NTRK gene fusion tumour incidence and 5-year prevalence in 2018 was 0.52 and 1.52 per 100,000 persons, respectively.

Conclusion: This research confirms the rarity and varying frequency of NTRK gene fusion across tumor types. Limitations included relatively low historic NTRK gene fusion testing and reporting, limited study samples for some cancers, and suboptimal molecular testing methods. In this rapidly developing area, gold-standard testing methods and companion diagnostics are needed to capture all NTRK gene fusions.

© The Author(s), 2020.

In plain English

This was a systematic review and meta-analysis of studies on how often NTRK gene fusions, a genetic change in cancer cells, were found in solid tumors. It did not study asbestos or any other exposure. The authors searched literature from January 1987 to January 2020 and selected 222 studies. Of these, 107 entered the meta-analysis, which calculated frequencies for 98 tumor histologies (specific tumor types) in 29 tumor groups. Frequencies ranged from 0% to 92.87%; only 12 histologies reached 10% or more. The highest were secretory breast carcinoma (92.87%, 95% confidence interval 72.62 to 100.00) and infantile (congenital) fibrosarcoma (90.56%, interval 67.42 to 100.00). Common cancers had low frequencies, such as 0.17% (interval 0.09 to 0.25) in non-small cell lung cancer. Mesothelioma was listed among the cancers with a reported frequency close to 0%. The authors estimated a worldwide 2018 incidence of 0.52 and a 5-year prevalence of 1.52 per 100,000 persons. The authors noted limitations: gene fusions were not historically reported as standard, samples were small for some cancers, and test methods varied.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Systematic literature review and meta-analysis following PRISMA guidelines
• Who was studied: 222 published English-language studies of patients of any age with solid tumors, published 1 January 1987 to 2 January 2020 (179 retrospective, 43 prospective). 107 studies met the meta-analysis criteria, which required publication after 2010 and generally at least 20 patients. From them, frequencies were calculated for 98 tumor histologies in 29 tumor groups.
• Exposure: No asbestos or other exposure was studied. The review measured how often NTRK gene fusions (NTRK1, NTRK2, NTRK3) were detected in tumors.
• Main results:
  • Across the 107 meta-analysis studies, frequencies were calculated for 98 histologies from 29 tumor groups.
  • The range of reported NTRK gene fusion frequencies across tumor histologies was 0% to 92.87%.
  • Only 12 of the 98 tumor histologies had a frequency of 10% or more.
  • Highest frequencies, in rare cancers: secretory breast carcinoma 92.87% (95% CI 72.62 to 100.00); infantile (congenital) fibrosarcoma 90.56% (95% CI 67.42 to 100.00); secretory salivary gland cancer 79.68% (95% CI 62.84 to 96.51); congenital mesoblastic nephroma (all subsets) 21.52% (95% CI 13.06 to 32.20).
  • Low frequencies in common tumor types: non-small cell lung cancer 0.17% (95% CI 0.09 to 0.25); colorectal adenocarcinoma 0.26% (95% CI 0.15 to 0.36); cutaneous melanoma 0.31% (95% CI 0.07 to 0.55); invasive breast carcinoma 0.10% (95% CI 0.03 to 0.18).
  • Mesothelioma was among the cancers with a reported NTRK gene fusion frequency close to 0%. The article text does not give the number of mesothelioma cases tested.
  • Estimated worldwide overall NTRK gene fusion incidence was 0.52 per 100,000 persons and 5-year prevalence was 1.52 per 100,000 persons (2018).
• The authors' conclusion: The authors concluded that NTRK gene fusion frequency varied across tumor types and even across studies of a single histology. They found it rare in most common tumor types but more frequent in several rare ones, with an estimated 5-year prevalence below the threshold they cite for an ultra-rare disease. They added that changes in testing and reporting may change these estimates.
• Limitations the authors state:
  • Gene fusion frequencies have not historically been a standard part of reporting in cancer studies.
  • Studies may not clearly distinguish between numbers of samples and numbers of patients.
  • Some of the higher frequencies came from single studies, so no meta-analysis was possible for those histologies. Small samples may also not reflect the true frequency.
  • Testing methods varied, and 5 included studies used immunohistochemistry (IHC), which may introduce uncertainty.
  • The estimates depend on the statistical modeling used, and different meta-analysis procedures may give different values.
  • No confidence intervals were given for the overall incidence and prevalence estimates.

Topics

Medical terms in this study, explained in our Lexicon: Systematic Review, Meta-Analysis, confidence interval, Immunohistochemistry, Non-Small Cell Lung Cancer, Adenocarcinoma, Carcinoma, Mesothelioma.

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