Fusion proteins in lung cancer: addressing diagnostic problems for deciding therapy

ABSTRACT

Introduction: Gene fusions are frequent chromosomal aberrations in solid tumors. In Lung cancer (LC) several druggable-fusions involving tyrosine kinase receptor genes have been described, including ALK, ROS1, RET and NTRK. In non-small cell lung cancer, testing for targetable fusions has become a part of routine clinical practice, greatly impacting therapeutic choice for patients with these aberrations. Although substantial technologies for gene fusion detection have been implemented over time including; cytogenetic, Fluorescence in situ hybridization (FISH), Immunohistochemistry (IHC), Retro-transcription Real-Time PCR (RT-qPCR), to Next Generation Sequencing (NGS), nCounter system (Nanostring technology), several critical issues remain. To date, only the companion diagnostic tests FISH and IHC for ALK-rearrangements and NGS for ROS1-rearrangments were approved. Other fusion approved tests are currently unavailable.

Areas covered: In this review, we explore current diagnostic problems of gene fusion detection relative to the technologies available, in order to clarify future standardization of analyses which determine therapeutic choices.

Expert opinion: The establishment of a gold standard, an effective diagnostic algorithm, and a standardized interpretation for the analysis of each druggable-fusions in lung cancer is essential for adequate therapeutic management.

KEYWORDS:

• ALK-rearrangements
• fluorescence in situ hybridization (FISH)
• immunohistochemistry (IHC)
• next generation sequencing (NGS)
• NTRK-rearrangements
• RET-rearrangements
• ROS1-rearrangements
• tyrosine kinase inhibitors

Article highlights

• In non-small cell lung cancer the analysis of druggable-fusions involving receptor tyrosine kinase genes, such as ALK, ROS1, RET, and NTRK rearrangements represents an integral part of clinical practice

• Several technologies for gene fusion detection are commercially available, including fluorescence in situ hybridization (FISH), immunohistochemistry (IHC), reverse transcription Real-Time PCR (RT-qPCR), Next Generation Sequencing (NGS) and the nCounter system (Nanostring technology)

• Various diagnostic problems associated with each technology could have a drastic impact on therapeutic choice

• Only for ALK- and ROS1- rearrangements were companion diagnostic tests approved by the Food and Drug Administration (FDA)

• Detection of other fusions in lung cancer is extremely necessary to define the gold standard

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper received no funding.