NTRK Fusions Explained: A Tumour-Agnostic Target

What an NTRK Fusion Is

The genes NTRK1, NTRK2 and NTRK3 encode the receptor tyrosine kinases TRKA, TRKB and TRKC, which normally respond to neurotrophin growth factors in the nervous system.

A chromosomal rearrangement fuses the kinase domain of an NTRK gene to a partner such as ETV6, LMNA or TPM3. The partner drives constant expression and dimerisation, so the TRK kinase is permanently on.

Where They Occur

NTRK fusions are present in less than 1 percent of common adult cancers such as lung, colorectal and breast, but they are highly enriched, often over 90 percent, in certain rare tumours: infantile fibrosarcoma, cellular and mixed congenital mesoblastic nephroma, secretory carcinoma of the breast and salivary gland (mammary analogue secretory carcinoma).

This split means testing strategy differs: near-certain in the rare tumours, a needle in a haystack in common ones.

Detection

Pan-TRK immunohistochemistry is a reasonable screen, with caveats: normal neural tissue stains, and some fusion partners give weak or unusual patterns. RNA-based next-generation sequencing is the most reliable method and identifies the partner.

DNA panels can miss NTRK fusions, especially NTRK2 and NTRK3 with breakpoints in large introns, so a negative DNA-only result does not exclude a fusion.

TRK Inhibitors

Larotrectinib and entrectinib are approved for NTRK fusion-positive solid tumours regardless of origin, with high response rates across tumour types and good central-nervous-system activity for entrectinib. Dizziness, weight gain and, for entrectinib, some cardiac effects are seen.

Acquired resistance occurs through secondary NTRK kinase-domain mutations, particularly solvent-front and gatekeeper mutations, which the next-generation inhibitors selitrectinib and repotrectinib are designed to cover.

Interpretation Notes

An NTRK result should confirm a genuine fusion (partner identified, in-frame, kinase domain retained) rather than an NTRK point mutation or a non-functional rearrangement, which are not targetable in the same way.

In a common cancer with another strong driver already identified, an NTRK fusion is unlikely and any weak signal warrants confirmation.

Key Takeaways

• ·NTRK1/2/3 fusions create a constitutively active TRK kinase driver.
• ·Rare in common cancers, near-universal in infantile fibrosarcoma and secretory carcinomas.
• ·RNA sequencing is the most reliable detection method; DNA panels and immunohistochemistry have blind spots.
• ·Larotrectinib and entrectinib have tumour-agnostic approval; next-generation inhibitors target resistance.