Prevalence of NTRK Fusions in Canadian Solid Tumour Cancer Patients

Abstract

Introduction: Neurotrophic tyrosine receptor kinase (NTRK) gene fusions occur in ~ 0.3% of all solid tumours but are enriched in some rare tumour types. Tropomyosin receptor kinase (TRK) inhibitors larotrectinib and entrectinib are approved as tumour-agnostic therapies for solid tumours harbouring NTRK fusions.

Methods: This study investigated the prevalence of NTRK fusions in Canadian patients and also aimed to help guide NTRK testing paradigms through analysis of data reported from a national clinical diagnostic testing program between September 2019 and July 2021.

Results: Of 1,687 patients included in the final analysis, NTRK fusions were detected in 0.71% (n = 12) of patients representing salivary gland carcinoma (n = 3), soft tissue sarcoma (n = 3), CNS (n = 3), and one in each of melanoma, lung, and colorectal cancer. All three salivary gland carcinomas contained ETV6-NTRK3 fusions. Thirteen (0.77%) clinically actionable incidental findings were also detected. Two of the 13 samples containing incidental findings were NTRK fusion-positive (GFOD1-NTRK2, FGFR3-TACC3 in a glioblastoma and AFAP1-NTRK2, BRAF c.1799T>A in a glioma). The testing algorithm screened most patient samples via pan-TRK immunohistochemistry (IHC), whereas samples from the central nervous system (CNS), pathognomonic cancers, and confirmed/ putative NTRK fusion-positive samples identified under research protocols were reflexed straight to next-generation sequencing (NGS).

Conclusion: These findings highlight the benefit and practicality of a diagnostic testing program to identify patients suitable for tumour-agnostic TRK inhibitor therapies, as well as other targeted therapies, due to clinically actionable incidental findings identified. Collectively, these findings may inform future guidance on selecting the appropriate testing approach per tumour type and on optimal NTRK testing algorithms.

Fig. 1

Breakdown of tests and NTRK fusion results from the clinical diagnostic testing algorithm. a Flow of all patient samples obtained from the clinical diagnostic testing program, from receipt to NGS result. b Samples which underwent reverse reflex quality control to the alternative lab and findings. ^*Measurements in same patient, either same tumour site repeated due to insufficient sample or same patient, different tumour site (i.e. metastases). ^†Insufficient tissue with cancer cells, necrotic tissue. ^‡Reflexed to KHSC from LifeLabs due to failed result by Archer due to RNA quality or quantity and reflexed to LifeLabs from KHSC due to negative result with OCAv3. CNS central nervous system, IHC immunohistochemistry, KHSC Kingston Health Sciences Centre, LL LifeLabs, NGS next-generation sequencing, NTRK neurotrophic tyrosine receptor kinase, TRK tropomyosin receptor kinase.

Fig. 2

Prevalence of tumour types analyzed in the clinical diagnostic testing program, % (n). Primary tumour types from both LifeLabs and KHSC (N=1687) combined were categorized similar to previous literature [6, 48]. Details are summarized in Supplementary Table 1. The “Other” category represents tumours with a frequency of <1% in the total sample pool. Prevalence by lab can be found in Supplementary Table 2 CUP cancer of unknown primary site, GI gastrointestinal, GIST gastrointestinal stromal tumour, KHSC Kingston Health Sciences Centre, PEComa perivascular epithelioid cell tumour, TRK tyrosine receptor kinase.

Fig. 3

Breakdown of tumour types of NTRK fusion-positive samples in the clinical diagnostic testing program. a Prevalence of NTRK fusion-positive samples by tumour type (N=12). b Frequency of NTRK fusion-positive sample per tumour type of all samples in the clinical diagnostic testing program (N=1687). c Percentage of samples which were pan-TRK positive, NGS-negative for NTRK fusion by tumour type (N=81). Only tumour types containing >5 samples meeting the criteria are shown. ^*Spindle cell tumour (n=1) and MPNST (n=2); ^†Astrocytoma, glioma, and grade IV glioblastoma; ^‡Secretory carcinoma (n=2) and unspecified (n=1). CUP cancer of unknown primary, GI gastrointestinal, GIST gastrointestinal stromal tumour, MPNST malignant peripheral nerve sheath tumour, NTRK neurotrophic tyrosine receptor kinase, TRK tropomyosin receptor kinase.