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. 2021 Jul 20;5(1):69.
doi: 10.1038/s41698-021-00206-y.

Genomic context of NTRK1/2/3 fusion-positive tumours from a large real-world population

C B Westphalen  1 , M G Krebs  2 , C Le Tourneau  3   4   5 , E S Sokol  6 , S L Maund  7 , T R Wilson  7 , D X Jin  6 , J Y Newberg  6 , D Fabrizio  6 , L Veronese  8 , M Thomas  8 , F de Braud  9   10
Affiliations

Genomic context of NTRK1/2/3 fusion-positive tumours from a large real-world population

C B Westphalen et al. NPJ Precis Oncol. .

Erratum in

Abstract

Neurotrophic tropomyosin receptor kinase (NTRK) gene fusions are rare oncogenic drivers in solid tumours. This study aimed to interrogate a large real-world database of comprehensive genomic profiling data to describe the genomic landscape and prevalence of NTRK gene fusions. NTRK fusion-positive tumours were identified from the FoundationCORE® database of >295,000 cancer patients. We investigated the prevalence and concomitant genomic landscape of NTRK fusions, predicted patient ancestry and compared the FoundationCORE cohort with entrectinib clinical trial cohorts (ALKA-372-001 [EudraCT 2012-000148-88]; STARTRK-1 [NCT02097810]; STARTRK-2 [NCT02568267]). Overall NTRK fusion-positive tumour prevalence was 0.30% among 45 cancers with 88 unique fusion partner pairs, of which 66% were previously unreported. Across all cases, prevalence was 0.28% and 1.34% in patients aged ≥18 and <18 years, respectively; prevalence was highest in patients <5 years (2.28%). The highest prevalence of NTRK fusions was observed in salivary gland tumours (2.62%). Presence of NTRK gene fusions did not correlate with other clinically actionable biomarkers; there was no co-occurrence with known oncogenic drivers in breast, or colorectal cancer (CRC). However, in CRC, NTRK fusion-positivity was associated with spontaneous microsatellite instability (MSI); in this MSI CRC subset, mutual exclusivity with BRAF mutations was observed. NTRK fusion-positive tumour types had similar frequencies in FoundationCORE and entrectinib clinical trials. NTRK gene fusion prevalence varied greatly by age, cancer type and histology. Interrogating large datasets drives better understanding of the characteristics of very rare molecular subgroups of cancer and allows identification of genomic patterns and previously unreported fusion partners not evident in smaller datasets.

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Conflict of interest statement

C.B.W. has received honoraria from Bayer, Celgene, Ipsen, Medscape, Roche, Servier; participated in advisory boards from Celgene, Shire/Baxalta, Rafael Pharmaceuticals, RedHill, Roche; received travel support from Bayer, Celgene, RedHill, Roche, Servier and Taiho; and received research support from Roche. M.K. has participated in advisory boards from Achilles Therapeutics, Bayer, Janssen, Octimet, OM Pharma and Roche; undertaken consultancy for Roche; received travel grants from AstraZeneca, BerGenBio and Immutep; and received research grants from BerGenBio and Roche. C.L.T. has participated in advisory boards from MSD, BMS, Merck Serono, Roche, Celgene, GSK, Rakuten, Nanobiotix, AstraZeneca and Seattle Genetics. E.S.S., D.X.J., J.Y.N. and D.F. are employees of Foundation Medicine and stockholders in Roche. S.L.M. and T.R.W. are employed by Genentech, Inc. and have equity in Roche. L.V. and M.T. are employed by Roche. F.d.B. reports advisory/consultancy fees from Bristol-Myers Squibb, Eli Lilly, Roche, Amgen, AstraZeneca, Istituto Gentili, Fondazione Internazionale Menarini, Octomet Oncology, Novartis, Merck Sharp & Dohme, Ignyta, Bayer, Noema, ACCMED, Dephaforum, Nadirex, Biotechspert, Pfizer, Tiziana Life Sciences and Pierre Fabre; has participated in speaker bureaus for Bristol-Myers Squibb, Roche, Merck Sharp & Dohme, Ignyta, Dephaforum, prIME Oncology, Pfizer and Biotechespert; has received research grants from Roche, Novartis, Merck Sharp & Dohme, Bristol-Myers Squibb, Pfizer, Kymab, Celgene and Tesaro and travel/accommodation expenses from Bristol-Myers Squibb, Roche, Celgene and Amgen.

Figures

Fig. 1
Fig. 1. Prevalence of NTRK fusion-positive specimens in FoundationCORE by indication and age group.
The prevalence of NTRK gene fusions overall and among adult (aged ≥18 years) and paediatric patients (aged <18 years; (a). The prevalence of NTRK gene fusions by age group (b). The prevalence of NTRK gene fusions by cancer type among: all patients (c), adult patients (d) and paediatric patients (e), with n numbers representing the total number of patients analysed per tumour type. Prevalence analysis of cancer types among all NTRK fusion-positive tumours in adults (f) and paediatric patients (g), where numbers represent the total number of patients with each cancer type. CNS central nervous system, CRC colorectal carcinoma, CUP unknown primary carcinoma, GI gastrointestinal, GIST gastrointestinal stromal tumour, NSCLC non-small cell lung cancer, NTRK neurotrophic tyrosine receptor kinase, PNS peripheral nervous system.
Fig. 2
Fig. 2. The spectrum of NTRK fusion partners detected among NTRK fusion-positive solid tumours.
Breakdown of NTRK gene fusions detected among adult (a) and paediatric patients (b) and the disease breakdown of the three most frequently observed NTRK fusion partners (c). CRC colorectal carcinoma, CUP unknown primary carcinoma, GI gastrointestinal, GIST gastrointestinal stromal tumour, NSCLC non-small cell lung cancer, NTRK neurotrophic tyrosine receptor kinase.
Fig. 3
Fig. 3. Co-occurrence of genes among NTRK fusion-positive cancers.
Co-occurrence of genes in all NTRK fusion-positive cancers (a). The prevalence of gene mutations was compared for NTRK fusion-positive and fusion-negative disease. Co-occurrence refers to genes that occurred in NTRK fusion-positive disease with an odds ratio greater than 1 compared with NTRK fusion-negative disease and the false discovery rate (FDR)-adjusted P-value was <0.05. Lack of co-occurrence refers to genes that did not occur in NTRK fusion-positive disease with an odds ratio less than 1 compared with NTRK fusion-negative disease and the FDR-adjusted P-value was <0.05. List of known disease-specific driver genes for different tumour types (b). The frequency of mutations found within driver genes listed in b in NTRK fusion-positive and NTRK fusion-negative colorectal cancer (CRC), breast cancer and non-small cell lung cancer (NSCLC; c). Summary of co-occurrence and mutual exclusivity of driver gene mutations and microsatellite instability-high (MSI-H) status with specific NTRK fusion-positive cancers (d). NTRK neurotrophic tyrosine receptor kinase.
Fig. 4
Fig. 4. Evaluation of and microsatellite instability (MSI) status in NTRK fusion-positive versus NTRK fusion-negative solid tumours.
MSI status in all tumours (a), CRC only (b) and non-CRC tumours (c). CRC colorectal cancer, MSI-H microsatellite instability-high, MSS microsatellite stable, NTRK neurotrophic tyrosine receptor kinase.
Fig. 5
Fig. 5. Comparisons of NTRK fusion-positive tumour types in entrectinib adult clinical studies versus FoundationCORE database.
CRC colorectal cancer, MASC mammary analogue secretory carcinoma, NSCLC non-small cell lung cancer, NTRK neurotrophic tyrosine receptor kinase.
See this image and copyright information in PMC

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