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Evaluation of NTRK immunohistochemistry as a screening method for NTRK gene fusion detection in non-small cell lung cancer

Elfving, Hedvig ; Broström, Erika ; Moens, Lotte N.J. ; Almlöf, Jonas ; Cerjan, Dijana ; Lauter, Gilbert ; Nord, Helena ; Mattsson, Johanna S.M. ; Ullenhag, Gustav J. and Strell, Carina , et al. (2021) In Lung Cancer 151. p.53-59
Abstract

Purpose: The small molecule inhibitors larotrectinib and entrectinib have recently been approved as cancer agnostic drugs in patients with tumours harbouring a rearrangement of the neurotrophic tropomyosin receptor kinase (NTRK). These oncogenic fusions are estimated to occur in 0.1–3 % of non-small cell lung cancers (NSCLC). Although molecular techniques are most reliable for fusion detection, immunohistochemical analysis is considered valuable for screening. Therefore, we evaluated the newly introduced diagnostic immunohistochemical assay (clone EPR17341) on a representative NSCLC cohort. Methods: Cancer tissue from 688 clinically and molecularly extensively annotated NSCLC patients were comprised on tissue microarrays and stained... (More)

Purpose: The small molecule inhibitors larotrectinib and entrectinib have recently been approved as cancer agnostic drugs in patients with tumours harbouring a rearrangement of the neurotrophic tropomyosin receptor kinase (NTRK). These oncogenic fusions are estimated to occur in 0.1–3 % of non-small cell lung cancers (NSCLC). Although molecular techniques are most reliable for fusion detection, immunohistochemical analysis is considered valuable for screening. Therefore, we evaluated the newly introduced diagnostic immunohistochemical assay (clone EPR17341) on a representative NSCLC cohort. Methods: Cancer tissue from 688 clinically and molecularly extensively annotated NSCLC patients were comprised on tissue microarrays and stained with the pan-TRK antibody clone EPR17341. Positive cases were further analysed with the TruSight Tumor 170 RNA assay (Illumina). Selected cases were also tested with a NanoString NTRK fusion assay. For 199 cases, NTRK RNA expression data were available from previous RNA sequencing analysis. Results: Altogether, staining patterns for 617 NSCLC cases were evaluable. Of these, four cases (0.6 %) demonstrated a strong diffuse cytoplasmic and membranous staining, and seven cases a moderate staining (1.1 %). NanoString or TST170-analysis could not confirm an NTRK fusion in any of the IHC positive cases, or any of the cases with high mRNA levels. In the four cases with strong staining intensity in the tissue microarray, whole section staining revealed marked heterogeneity of NTRK protein expression. Conclusion: The presence of NTRK fusion genes in non-small cell lung cancer is exceedingly rare. The use of the immunohistochemical NTRK assay will result in a small number of false positive cases. This should be considered when the assay is applied as a screening tool in clinical diagnostics.

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type
Contribution to journal
publication status
published
subject
keywords
Diagnostics, Entrectinib, Gene fusion, Larotrectinib, Lung adenocarcinoma, NTRK
in
Lung Cancer
volume
151
pages
7 pages
publisher
Elsevier
external identifiers
  • scopus:85097454788
  • pmid:33310622
ISSN
0169-5002
DOI
10.1016/j.lungcan.2020.11.023
language
English
LU publication?
yes
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f1878477-5df8-4318-9ea2-9691604e6239
date added to LUP
2020-12-21 12:13:20
date last changed
2021-02-23 04:54:47
@article{f1878477-5df8-4318-9ea2-9691604e6239,
  abstract     = {<p>Purpose: The small molecule inhibitors larotrectinib and entrectinib have recently been approved as cancer agnostic drugs in patients with tumours harbouring a rearrangement of the neurotrophic tropomyosin receptor kinase (NTRK). These oncogenic fusions are estimated to occur in 0.1–3 % of non-small cell lung cancers (NSCLC). Although molecular techniques are most reliable for fusion detection, immunohistochemical analysis is considered valuable for screening. Therefore, we evaluated the newly introduced diagnostic immunohistochemical assay (clone EPR17341) on a representative NSCLC cohort. Methods: Cancer tissue from 688 clinically and molecularly extensively annotated NSCLC patients were comprised on tissue microarrays and stained with the pan-TRK antibody clone EPR17341. Positive cases were further analysed with the TruSight Tumor 170 RNA assay (Illumina). Selected cases were also tested with a NanoString NTRK fusion assay. For 199 cases, NTRK RNA expression data were available from previous RNA sequencing analysis. Results: Altogether, staining patterns for 617 NSCLC cases were evaluable. Of these, four cases (0.6 %) demonstrated a strong diffuse cytoplasmic and membranous staining, and seven cases a moderate staining (1.1 %). NanoString or TST170-analysis could not confirm an NTRK fusion in any of the IHC positive cases, or any of the cases with high mRNA levels. In the four cases with strong staining intensity in the tissue microarray, whole section staining revealed marked heterogeneity of NTRK protein expression. Conclusion: The presence of NTRK fusion genes in non-small cell lung cancer is exceedingly rare. The use of the immunohistochemical NTRK assay will result in a small number of false positive cases. This should be considered when the assay is applied as a screening tool in clinical diagnostics.</p>},
  author       = {Elfving, Hedvig and Broström, Erika and Moens, Lotte N.J. and Almlöf, Jonas and Cerjan, Dijana and Lauter, Gilbert and Nord, Helena and Mattsson, Johanna S.M. and Ullenhag, Gustav J. and Strell, Carina and Backman, Max and La Fleur, Linnéa and Brunnström, Hans and Botling, Johan and Micke, Patrick},
  issn         = {0169-5002},
  language     = {eng},
  pages        = {53--59},
  publisher    = {Elsevier},
  series       = {Lung Cancer},
  title        = {Evaluation of NTRK immunohistochemistry as a screening method for NTRK gene fusion detection in non-small cell lung cancer},
  url          = {http://dx.doi.org/10.1016/j.lungcan.2020.11.023},
  doi          = {10.1016/j.lungcan.2020.11.023},
  volume       = {151},
  year         = {2021},
}