Diagnostic testing approaches for the identification of patients with TRK fusion cancer prior to enrollment in clinical trials investigating larotrectinib.

Abstract

INTRODUCTION:

NTRK gene fusions are targetable oncogenic drivers independent of tumor type. Prevalence varies from highly recurrent in certain rare tumors to <1% in common cancers. The selective TRK inhibitor larotrectinib was shown to be highly active in adult and pediatric patients with tumors harboring NTRK gene fusions.

METHODS:

We examined the techniques used by local sites to detect tumor NTRK gene fusions in patients enrolled in clinical trials of larotrectinib. We also report the characteristics of the detected fusions in different tumor types.

RESULTS:

The analysis included 225 patients with 19 different tumor types. Testing methods used were next-generation sequencing (NGS) in 196 of 225 tumors (87%); this was RNA-based in 96 (43%); DNA-based in 53 (24%); DNA/RNA-based in 46 (20%) and unknown in 1 (<1%); FISH in 14 (6%) and PCR-based in 12 (5%). NanoString, Sanger sequencing and chromosome microarray were each utilized once (<1%). Fifty-four different fusion partners were identified, 39 (72%) of which were unique occurrences.

CONCLUSIONS:

The most common local testing approach was RNA-based NGS. Many different NTRK gene fusions were identified with most occurring at low frequency. This supports the need for validated and appropriate testing methodologies that work agnostic of fusion partners.

• Authors: Erin R Rudzinski, Jaclyn Hechtman, Sinchita Roy-Chowdhuri, Marion Rudolph, Christina M Lockwood, Josh Silvertown, Justyna Wierzbinska, Kui Shen, Ricarda Norenberg, Hendrik Nogai, David S Hong, Alexander Drilon, Theodore W Laetsch
• Journal: Cancer genetics (Cancer Genet) Vol. 260-261 Pg. 46-52 (01 2022) ISSN: 2210-7762 [Print] United States
• PMID: 34929613 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.

Chemical References

• Membrane Glycoproteins
• NTRK1 protein, human
• NTRK3 protein, human
• Oncogene Proteins, Fusion
• Pyrazoles
• Pyrimidines
• Receptor, trkA
• Receptor, trkB
• Receptor, trkC
• tropomyosin-related kinase-B, human
• larotrectinib

Topics

• Adult
• Child
• Clinical Trials, Phase I as Topic
• Clinical Trials, Phase II as Topic
• Diagnostic Techniques and Procedures
• Female
• High-Throughput Nucleotide Sequencing
• Humans
• In Situ Hybridization, Fluorescence
• Male
• Membrane Glycoproteins (genetics)
• Microarray Analysis
• Neoplasms (drug therapy, genetics)
• Oncogene Proteins, Fusion (genetics)
• Patient Selection
• Precision Medicine
• Pyrazoles (therapeutic use)
• Pyrimidines (therapeutic use)
• Receptor, trkA (genetics)
• Receptor, trkB (genetics)
• Receptor, trkC (genetics)
• Sequence Analysis, DNA
• Sequence Analysis, RNA