Introduction
TRK Receptor Family and Signaling
NTRK Gene Fusions
Detection/validation method(s)a | Tumor type (NTRK gene fusion) | Study |
---|---|---|
FISH | Acute myeloid leukemia (ETV6-NTRK3) | Eguchi et al. [15] |
Congenital mesoblastic nephroma (ETV6-NTRK3) | El Demellawy et al. [18] | |
RT-PCR | Congenital mesoblastic nephroma (ETV6-NTRK3) | Knezevich et al. [12] |
Infantile fibrosarcoma (ETV6-NTRK3) | ||
RT-PCR and FISH | Congenital mesoblastic nephroma (ETV6-NTRK3) | Rubin et al. [13] |
MASC (ETV6-NTRK3) | Skalova et al. [19] | |
RT-PCR and IHC | Infantile fibrosarcoma (ETV6-NTRK3) | Bourgeois et al. [20] |
IHC and FISH | Colorectal cancer (LMNA-NTRK1) | Sartore-Bianchi et al. [21] |
NGS (DNA- or RNA-seq), FISH, or IHC | MASC (ETV6-NTRK3) | Drilon et al. [22] |
Colorectal cancer (LMNA-NTRK1) | ||
Glioneuronal tumor (BCAN-NTRK1) | ||
Lung cancer (SQSTM1-NTRK1) | ||
NGSb or FISH | Lung cancer (IRF2BP2-NTRK1) | Drilon et al. [23]; |
Melanoma (GON4L-NTRK1, TRIM63-NTRK1) | ||
Pancreatic cancer (CTRC-NTRK1) | ||
Thyroid cancer (IRF2BP2-NTRK1, PPL-NTRK1, TPM3-NTRK1) | ||
Soft tissue sarcoma (TPM3-NTRK1, TPM4-NTRK3) | Kummar and Lassen [24] | |
Appendiceal cancer (LMNA-NTRK1) | ||
Breast cancer (GATAD2B-NTRK1, LMNA-NTRK1, TPM3-NTRK1) | ||
Cholangiocarcinoma (LMNA-NTRK1, TPM3-NTRK1) | ||
Colon cancer (PLEKHA6-NTRK1) | ||
Infantile fibrosarcoma (SQSTM1-NTRK1, TPM3-NTRK1) | ||
NGS (DNA-seq) and IHC | Melanoma (GON4L-NTRK1, TRIM63-NTRK1, TRAF2-NTRK2, DDR2-NTRK1) | Lezcano et al. [25] |
NGS (RNA-seq) and array-comparative genome hybridization | Ganglioglioma (TLE4-NTRK2) | Prabhakaran et al. [26] |
NGS (DNA-seq and/or RNA-seq) | Fibrous tumor (TFG-NTRK3) | Chmielecki et al. [27] |
Infantile fibrosarcoma (SQSTM1-NTRK1) | ||
NGS (DNA- or RNA-seq) and IHC | Lung cancer (IRF2BP2-NTRK1, MRPL24-NTRK1, P2RY8- NTRK1) | Hechtman et al. [28] |
Melanoma (TRIM63-NTRK1, TRAF2-NTRK2) | ||
Soft tissue sarcoma (TPM4-NTRK3) | ||
Colorectal cancer (LMNA-NTRK1, ETV6-NTRK3) | ||
Glioblastoma (BCR-NTRK2, ZNF710-NTRK3) | ||
NGS (RNA-seq), IHC, and FISH | Colorectal cancer (SCYL3-NTRK1) | Milione et al. [29] |
NGS (RNA-seq) | Pancreatic cancer (CEL-NTRK1) | Edgren et al. [30] |
Glioblastoma (BCAN-NTRK1, NFASC-NTRK1) | Kim et al. [31] | |
Neuroendocrine cancer (ETV6-NTRK3) | Sigal et al. [32] | |
Lung cancer (IRF2BP2-NTRK1, TRIM24-NTRK2) | Stransky et al. [33] | |
Thyroid cancer (IRF2BP2-NTRK1, TFG-NTRK1, RBPMS-NTRK3) | ||
Squamous cell cancer of the head and neck (PAN3-NTRK2, ETV6-NTRK3) | ||
Sarcoma (TPM3-NTRK1) | ||
Glioma (AFAP1-NTRK2, SQSTM1-NTRK2) | ||
Glioblastoma (NFASC-NTRK1) | ||
NGS (RNA-seq) and FISH | Congenital mesoblastic nephroma (EML4-NTRK3) | Church et al. [34] |
Infantile fibrosarcoma (EML4-NTRK3) | ||
NGS (RNA-seq), IHC, and FISH | Colorectal cancer (TPM3-NTRK1) | Lee et al. [35] |
NGS (RNA-seq), FISH, and RT-PCR | GIST (ETV6-NTRK3) | Brenca et al. [36] |
NGS (whole-genome sequencing and RNA-seq) | Glioma (AKAP13-NTRK3) | Yoshihara et al. [37] |
Astrocytoma (NACC2-NTRK2, QK1-NTRK2) | Jones et al. [38] | |
Glioma (TPM3-NTRK1, AGBL4-NTRK2, VCL-NTRK2, BTBD1- NTRK3) | Wu et al. [17] | |
NGS (whole-exome sequencing, whole-genome sequencing, and/or RNA-seq) | Acute lymphoblastic leukemia (ETV6-NTRK3) | Roberts et al. [39] |
Large cell neuroendocrine cancer (COP1-NTRK1) | George et al. [40] | |
NGS (whole-genome sequencing and RNA-seq) | Thyroid cancer (TPM3-NTRK1) | Ronsley et al. [41] |
Targeted NGS (DNA-seq) | Uterine endometrial cancer (LRRC71-NTRK1) | Hartmaier et al. [42] |
Lung cancer (GRIPAP1-NTRK1) | ||
Intrahepatic cholangiocarcinoma (RABGAP1L-NTRK1) | Ross et al. [43] | |
GIST (ETV6-NTRK3) | Shi et al. [44] | |
Spitzoid neoplasm (TP53-NTRK1, LMNA-NTRK1) | Wiesner et al. [45] | |
Lung cancer (TPM3-NTRK1) | Zheng et al. [46] | |
Thyroid cancer (PPL-NTRK1) Glioblastoma (ARHGEF2-NTRK1, CHTOP-NTRK1) | ||
Targeted NGS (DNA- and RNA-seq) | Thyroid cancer (EML4-NTRK3, SQSTM1-NTRK3, IRF2BP2- NTRK1) | Liang et al. [47] |
Targeted NGS (DNA-seq) or FISH | Lung cancer (CD74-NTRK1, MPRIP-NTRK1) | Vaishnavi et al. [48] |
Targeted NGS (DNA- or RNA-seq) and/or FISH | Uterine sarcoma (LMNA-NTRK1, TPM3-NTRK1, RBPMS-NTRK3) | Chiang et al. [49] |
Clinical Data for TRK Inhibitors
Methods to Identify Patients with TRK Fusion Cancer
Fluorescence in situ hybridization (FISH) | Reverse transcription polymerase chain reaction (RT-PCR) | Pan-TRK immunohistochemistry (IHC) | Next-generation sequencing (NGS) | |
---|---|---|---|---|
Advantages | • Location of the target within the cell can be detected [61] | |||
• Decentralized, available in most laboratories [20] | ||||
• High sensitivity and specificity [63] | • Assays detect fusions expressed at the RNA level [62] | • Established reimbursement codes [66] | • Ability to test multiple actionable targets simultaneously [34] | |
• Several fluorophores can be used at once to detect different targets in one sample [67] | • Inexpensive [68] | • Turnaround time: ~2 days [64] | • Plays key role in diagnostic work-up of TRK fusion cancer [23] | |
• Relevance of NGS increases as number of actionable targets grows [69] | ||||
• High sensitivity and specificity potential [63] | ||||
Disadvantages | • Requires fluorescence microscopy [61] | • Cannot differentiate between fusion and wild-type TRK expression [28] | • Turnaround time: ~1–3 weeks [69] | |
• Technically complex and costly [70] | ||||
• Target sequence must be known; unable to detect novel fusion partners unless break-apart probes are used [34] | • Development of separate tests required for each NTRK gene [71] | • Scoring algorithms are not standardized [20] | ||
• Additional testing required to determine course of action [28] | • Reimbursement currently restricted [73] | |||
• Development of separate tests required for each NTRK gene [71] | ||||