Summary
Background. Several TRK inhibitors have demonstrated clinical efficacy in patients with solid tumors harboring NTRK gene fusions. However, the natural history and prognostic implications of NTRK fusions in solid tumors remain unknown. Methods. A cohort of 77 MD Anderson Cancer Center patients (MDACC) with NTRK gene fusions was identified and retrospectively compared to a second cohort from the Cancer Genome Atlas (TCGA) database. Due to paucity of events in early stage cancers and lack of TCGA data in rare tumors, 25 randomly selected MDACC patients were matched to 122 TCGA patients without NTRK gene fusion. Next we assessed the associations between NTRK gene fusion and overall (OS) and progression-free survivals (PFS). Results. Among the 77 MDACC patients with NTRK gene fusions, 18 NTRK fusion partners were identified. There were insufficient OS events for analysis in the matched cohort. PFS was not significantly different (p = 0.49) between the NTRK-fusion positive MDACC patients (median PFS 786 weeks, 95% CI 317-NE) and the NTRK-fusion negative TCGA patients (median PFS NE). The adjusted hazard ratio comparing TCGA patients to MDACC patients was HR = 0.72 (95% CI: 0.23–2.33), which trended towards a reduced rate of progression or death experienced by TCGA patients. Conclusions. This study did not identify statistically significant associations between NTRK fusion and PFS. Nonsignificant trends estimated increases in the risk of progression or death events for patients with NTRK fusions when compared to matched controls. Our findings help illuminate the influence of NTRK fusions on the natural history of a variety of solid tumors.
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All data generated and analyzed during the current study are available from the corresponding author on reasonable request.
References
Klein R, Jing S, Nanduri V, O’Rourke E, Barbacid M (1991) The trk proto-oncogene encodes a receptor for nerve growth factor. Cell. https://doi.org/10.1016/0092-8674(91)90419-Y
Kaplan DR, Martin-Zanca D, Parada LF (1991) Tyrosine phosphorylation and tyrosine kinase activity of the trk proto-oncogene product induced by NGF. Nature. https://doi.org/10.1038/350158a0
Rubin JB, Segal RA (2003) Growth, survival and migration: the Trk to cancer. Cancer Treat Res. https://doi.org/10.1007/0-306-48158-8_1
Brenca M, Rossi S, Polano M, Gasparotto D, Zanatta L, Racanelli D et al (2016) Transcriptome sequencing identifies ETV6-NTRK3 as a gene fusion involved in GIST. J Pathol. https://doi.org/10.1002/path.4677
Haller F, Knopf J, Ackermann A, Bieg M, Kleinheinz K, Schlesner M et al (2016) Paediatric and adult soft tissue sarcomas with NTRK1 gene fusions: A subset of spindle cell sarcomas unified by a prominent myopericytic/haemangiopericytic pattern. J Pathol. https://doi.org/10.1002/path.4701
Bishop JA, Yonescu R, Batista D, Eisele DW, Westra WH (2013) Most nonparotid “acinic cell carcinomas” represent mammary analog secretory carcinomas. Am J Surg Pathol. https://doi.org/10.1097/PAS.0b013e3182841554
Prasad ML, Vyas M, Horne MJ, Virk RK, Morotti R, Liu Z et al (2016) NTRK fusion oncogenes in pediatric papillary thyroid carcinoma in northeast United States. Cancer. https://doi.org/10.1002/cncr.29887
Drilon A, Laetsch TW, Kummar S, Dubois SG, Lassen UN, Demetri GD et al (2018) Efficacy of larotrectinib in TRK fusion-positive cancers in adults and children. N Engl J Med. https://doi.org/10.1056/NEJMoa1714448
Hyman D, Kummar S, Farago A, Geoerger B, Mau-Sorensen M, Taylor M, et al (2019) Abstract CT127: Phase I and expanded access experience of LOXO-195 (BAY 2731954), a selective next-generation TRK inhibitor (TRKi). https://doi.org/10.1158/1538-7445.sabcs18-ct127
Bazhenova L, Jiao X, Lokker A, Snider J, Castellanos E, Nanda S, et al (2020) Abstract 09: Cancers with NTRK gene fusions: Molecular characteristics and prognosis. https://doi.org/10.1158/1557-3265.advprecmed20-09
Liu J, Lichtenberg T, Hoadley KA, Poisson LM, Lazar AJ, Cherniack AD et al (2018) An Integrated TCGA Pan-Cancer Clinical Data Resource to Drive High-Quality Survival Outcome Analytics. Cell. https://doi.org/10.1016/j.cell.2018.02.052
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This study was funded by National Institute of Health and Bayer Corporation.
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This retrospective study involving human participants was in accordance with the ethical standards of the institutional and national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. The Human Investigation Committee (IRB) of MD Anderson Cancer Center approved this study.
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Zhu, L., Hobbs, B., Roszik, J. et al. Investigating the natural history and prognostic nature of NTRK gene fusions in solid tumors. Invest New Drugs 40, 157–162 (2022). https://doi.org/10.1007/s10637-021-01157-8
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DOI: https://doi.org/10.1007/s10637-021-01157-8