NTRK gene fusions in solid tumors: agnostic relevance, prevalence and diagnostic strategies

Abstract

A number of innovative drugs, developed for precision medicine, have shown impressive activity in neoplastic patients with rare molecular targets, independently from the site and type of tumor. This gave rise to the concept of agnostic treatments in oncology. The detection of such rare targets is a prerequisite for these treatments and is nowadays one of the main challenges in diagnostic molecular pathology. Various algorithms, new diagnostic strategies and pathological workflows have been suggested to help pathologists in the detection of these rare molecular alterations. An emblematic example of biological targets for agnostic treatments is represented by genetic rearrangements affecting members of the Neurotrophic Tyrosine Receptor Kinase (NTRK) gene family. These gene rearrangements have an unusual dual mode of distribution: the first, at high frequency in some very rare neoplasms, and the second with extremely lower frequencies in more common tumors. Even in the context of an agnostic approach, knowledge of site, histotype and prevalence of the tumors carrying these genetic lesions may be helpful to guide the pathologist in the daily effort in search of these molecular alterations. This review examines the prevalence of NTRK gene fusions in different forms of solid tumors, based on the largest studies to date, reports a comprehensive diagnostic algorithm and an innovative pathological workflow for rapid screening.

Keywords: Neurotrophic Tyrosine; Next Generation Sequencing (NGS); Receptor Kinase (NTRK); targeted therapy; tumor agnostic treatments.

Figure 1.

Frequency of NTRK gene fusions in rare tumors (data obtained from Westphalen et al.).

Figure 2.

Prevalence of NTRK gene fusions in tumors in the adult population (data obtained from Westphalen et al, Rosen et al, Solomon et al.) CRC, colorectal cancer; CUP, cancer of unknown primary; GIST, gastrointestinal stromal tumor; NSCLC, non-small cell lung cancer.

Figure 3.

Prevalence of the different tumor types that were positive for NTRK gene fusions in the adult population (data obtained from Westphalen et al.). CRC, colorectal cancer; CUP, cancer of unknown primary; GIST, gastrointestinal stromal tumor; NSCLC, non-small cell lung cancer.

Figure 4.

Major fusion partners of NTRK genes in the adult population by frequency (modified from Westphalen et al.).

Figure 5.

Diagnostic algorithm based on the prevalence (high, > 50%: low, 1-5%; very low, < 1%) of NTRK gene fusions and the molecular tests planned in routine diagnostics.

Figure 6.

A simplified diagnostic workflow for testing rare biomarkers and select patients for tumor-agnostic treatments. A more detailed workflow for diagnostic screening in clinical practice is reported in Marchetti et al, 2019 , from which the figure was derived.