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. 2022 Mar 9;12(3):668.
doi: 10.3390/diagnostics12030668.

Detection of NTRK Fusions and TRK Expression and Performance of pan-TRK Immunohistochemistry in Routine Diagnostics: Results from a Nationwide Community-Based Cohort

Bart Koopman  1 , Chantal C H J Kuijpers  2 , Harry J M Groen  3 , Wim Timens  1 , Ed Schuuring  1 , Stefan M Willems  1 , Léon C van Kempen  1
Affiliations

Detection of NTRK Fusions and TRK Expression and Performance of pan-TRK Immunohistochemistry in Routine Diagnostics: Results from a Nationwide Community-Based Cohort

Bart Koopman et al. Diagnostics (Basel). .

Abstract

Gene fusions involving NTRK1, NTRK2, and NTRK3 are rare drivers of cancer that can be targeted with histology-agnostic inhibitors. This study aimed to determine the nationwide landscape of NTRK/TRK testing in the Netherlands and the usage of pan-TRK immunohistochemistry (IHC) as a preselection tool to detect NTRK fusions. All pathology reports in 2017-2020 containing the search term 'TRK' were retrieved from the Dutch Pathology Registry (PALGA). Patient characteristics, tumor histology, NTRK/TRK testing methods, and reported results were extracted. NTRK/TRK testing was reported for 7457 tumors. Absolute testing rates increased from 815 (2017) to 3380 (2020). Tumors were tested with DNA/RNA-based molecular assay(s) (48%), IHC (47%), or in combination (5%). A total of 69 fusions involving NTRK1 (n = 22), NTRK2 (n = 6) and NTRK3 (n = 41) were identified in tumors from adult (n = 51) and pediatric (n = 18) patients. In patients tested with both IHC and a molecular assay (n = 327, of which 29 NTRK fusion-positive), pan-TRK IHC had a sensitivity of 77% (95% confidence interval (CI), 56-91) and a specificity of 84% (95% CI, 78-88%). These results showed that pan-TRK IHC has a low sensitivity in current routine practice and warrants the introduction of quality guidelines regarding the implementation and interpretation of pan-TRK IHC.

Keywords: NTRK; TRK; fusion; molecular diagnostics; nationwide; routine; testing.

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Conflict of interest statement

H.J.M.G. reports advisory board presence for Bayer, Lilly, Merck, and Novartis, outside the submitted work. W.T. reports consulting fees to the institution from Merck Sharp Dohme, and Bristol-Myers-Squibb, board membership for Dutch Society of Pathology, and the Council for Research and Innovation of the Federation of Medical Specialists, outside the submitted work. E.S. reports providing lectures for Bio-Rad, Novartis, Roche, Biocartis, Illumina, Pfizer, AstraZeneca, and Agena Bioscience, advisory board presence for AstraZeneca, Roche, Pfizer, Novartis, Bayer, Lilly, BMS, Amgen, Biocartis, Illumina, Agena Bioscience, and MSD/Merck, and research grants from Pfizer, Biocartis, Invitae-ArcherDX, AstraZeneca, Agena Bioscience, BMS, Bio-Rad, Roche, Boehringer Ingelheim, all outside the submitted work and all financial supports transferred to Institute. S.M.W. reports unrestricted research grants from Bayer, MSD, Roche, Pfizer, Novartis, Amgen and AstraZeneca, outside the submitted work. L.C.v.K reports grants and non-financial support from Roche, advisory board presence for AstraZeneca, Novartis, Merck, Janssen-Cilag, Bayer, BMS, nanoString and Pfizer, grants and non-financial support from Invitae, non-financial support from Biocartis, grants from Bayer, non-financial support from nanoString, all outside the submitted work. All remaining authors (B.K., C.C.H.J.K.) have declared no conflict of interest.

Figures

Figure 1
Figure 1
Indications and number of TRK overexpression and/or NTRK fusions testing in the Netherlands, 2017–2020. (A,B) Number of tumors tested for TRK overexpression or NTRK fusions, by year (A) and tissue origin (B). (C) Distribution of reasons for NTRK/TRK testing, by year. (D) Distribution of NTRK tests, by year. (E–G) Protein (E), DNA (F) and RNA (G) assays used to test for TRK overexpression or NTRK fusions. Abbreviations: CNS, central nervous system; CTL, comprehensive thyroid and lung; FISH, fluorescence in situ hybridization; FP, FusionPlex.
Figure 2
Figure 2
NTRK1-3 fusions identified in the Dutch population, 2017–2020. (A) Fusion partners and exonic breakpoints were identified in 69 patients with NTRK1 (green), NTRK2 (red), and NTRK3 (blue) fusions. The kinase domain is annotated and shown in pink. A blurred white breakpoint indicates that the exact breakpoint was not known or specified. At the right, a bar graph depicts the number of times the specific fusion gene was detected. (B) Frequency of NTRK1 (green), NTRK2 (red), and NTRK3 (blue) fusions and types of malignant or benign tumors. Abbreviations: CUP, cancer of unknown primary; NOS, not otherwise specified; PTC, papillary thyroid carcinoma, STUMP, Spitzoid Tumor of Uncertain Malignant Potential.
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References

    1. Cocco E., Scaltriti M., Drilon A. NTRK Fusion-Positive Cancers and TRK Inhibitor Therapy. Nat. Rev. Clin. Oncol. 2018;15:731–747. doi: 10.1038/s41571-018-0113-0. - DOI - PMC - PubMed
    1. Skálová A., Vanecek T., Sima R., Laco J., Weinreb I., Perez-Ordonez B., Starek I., Geierova M., Simpson R.H.W., Passador-Santos F., et al. Mammary Analogue Secretory Carcinoma of Salivary Glands, Containing the ETV6-NTRK3 Fusion Gene: A Hitherto Undescribed Salivary Gland Tumor Entity. Am. J. Surg. Pathol. 2010;34:599–608. doi: 10.1097/PAS.0b013e3181d9efcc. - DOI - PubMed
    1. Tognon C., Knezevich S.R., Huntsman D., Roskelley C.D., Melnyk N., Mathers J.A., Becker L., Carneiro F., MacPherson N., Horsman D., et al. Expression of the ETV6-NTRK3 Gene Fusion as a Primary Event in Human Secretory Breast Carcinoma. Cancer Cell. 2002;2:367–376. doi: 10.1016/S1535-6108(02)00180-0. - DOI - PubMed
    1. Rubin B.P., Chen C.J., Morgan T.W., Xiao S., Grier H.E., Kozakewich H.P., Perez-Atayde A.R., Fletcher J.A. Congenital Mesoblastic Nephroma t(12;15) Is Associated with ETV6-NTRK3 Gene Fusion: Cytogenetic and Molecular Relationship to Congenital (Infantile) Fibrosarcoma. Am. J. Pathol. 1998;153:1451–1458. doi: 10.1016/S0002-9440(10)65732-X. - DOI - PMC - PubMed
    1. Knezevich S.R., McFadden D.E., Tao W., Lim J.F., Sorensen P.H. A Novel ETV6-NTRK3 Gene Fusion in Congenital Fibrosarcoma. Nat. Genet. 1998;18:184–187. doi: 10.1038/ng0298-184. - DOI - PubMed

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