Molecular Testing Strategies to Identify NTRK Gene Fusions

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EP: 1.Molecular Testing Strategies to Identify NTRK Gene Fusions

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David S. Hong, MD: Increasingly, as new targeted therapies, including NTRK inhibitors such as larotrectinib and entrectinib, have emerged, molecular testing is becoming, if not required, always necessary to treat particular patients with advanced cancer. To deal with NTRK fusion, the gold standard is next-generation sequencing [NGS]. Ideally, RNA-based next-gen sequencing, because there are certain NTRK fusions—particularly NTRK3 fusion partners—that are fairly large, and RNA sequencing will pick those up relative to DNA-based NTRK NGS. There are other ways to pick up NTRK fusions, but they are somewhat limited. There are issues behind these methods of picking up NTRK-fusion patients. IHC [immunohistochemistry] staining is available in Europe and in some institutions, but there are flaws to NTRK IHC staining for the protein. It is not always specific, particularly in certain tumor types, such as sarcoma, which is 1 of the most common subsets of tumors that we see. It’s not always as sensitive.

FISH [fluorescence in situ hybridization] is also another possibility. There’s something called “break-apart FISH,” which can pick up certain NTRK-fusion partners, but the actual NTRK gene and the fusion partner need to be known to identify these patients with NTRK fusion by FISH. This can be done in certain tumor types that we know. Clear NTRK gene and the fusion partner are oftentimes seen in pediatric patients and in rare pediatric sarcomas, such as infantile fibrosarcoma. But ideally, the gold standard is next-gen sequencing with RNA-based next-gen sequencing. Foundation Medicine, for example, has that, but it’s counterintuitive. You can order a FoundationOne Heme panel, and that will be an RNA-sequencing panel that will pick up NTRK fusions. The standard FoundationOne DNA panel will also pick up the vast majority of NTRK fusions but will not always pick up everything.

Transcript edited for clarity.