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Updated: Sep 30, 2026
A Blood-based Test for the Detection of ROS1 and RET Fusion Transcripts from Circulating Ribonucleic Acid Using Digital Polymerase Chain Reaction
Published on: April 5, 2018
Clinical and Translational Implications of RET Rearrangements in Non-Small Cell Lung Cancer
Roberto Ferrara1, Nathalie Auger2, Edouard Auclin1
1Medical Oncology Department, Gustave Roussy, Villejuif, France.
Abstract:
Since the discovery in 2012 of rearranged during transfection proto-oncogene gene (RET) rearrangements in NSCLC, at least 12 different fusion variants have been identified, with kinesin family member 5B gene (KIF5B)-RET being the most frequent and the best characterized. Unlike ALK receptor tyrosine kinase gene (ALK) and ROS1 rearrangements, RET fusion genes cannot be adequately detected by immunohistochemistry (IHC), although fluorescence in situ hybridization and reverse transcriptase polymerase chain reaction are fully complementary diagnostic tools. In large retrospective studies, RET rearrangements correlate with adenocarcinoma histologic subtype, never-smoking status, younger age, more advanced disease stage, potentially higher chemosensitivity (in particular, to pemetrexed-based regimens), and coexistence of other genomic alterations. To date, several preclinical models, clinical trials, and retrospective studies have investigated multitarget inhibitors with anti-rearranged during transfection proto-oncogene (RET) activity in patients with RET-rearranged lung cancer. In the clinical setting, the benefit in terms of response (16%-47%) and progression-free survival (2-7 months) is clearly not comparable to that seen with other targeted agents in oncogene-addicted NSCLC. Furthermore, multikinase agents showed high rates of severe toxicities, leading to frequent dose reduction and drug discontinuation. To date, no definitive conclusions about a potentially different impact of anti-RET therapies according to RET fusion variants have been drawn on account of discordant data coming mostly from small subgroup analyses. Importantly, the absence of a striking clinical benefit in RET oncogene-addicted NSCLC underscores the clear need for development of more selective and potent RET inhibitors and for better characterization of concomitant genomic alterations and mechanisms of resistance to RET inhibition in patients with lung cancer.
Insights
Rearranged during transfection (RET) gene rearrangements in non-small cell lung cancer (NSCLC) have limited treatment efficacy and significant toxicities. Development of more selective RET inhibitors is needed for better patient outcomes.
Area of Science:
- Oncology
- Genomics
- Molecular Biology
Background:
- Rearranged during transfection (RET) gene rearrangements are identified in non-small cell lung cancer (NSCLC), with KIF5B-RET being the most common variant.
- Unlike ALK and ROS1, RET fusions require advanced diagnostic methods like FISH and RT-PCR, as IHC is insufficient.
- RET rearrangements are associated with specific patient demographics and clinicopathological features, including adenocarcinoma histology and never-smoking status.
Purpose of the Study:
- To review the current understanding of RET rearrangements in NSCLC.
- To evaluate the efficacy and toxicity of existing multi-target RET inhibitors.
- To highlight the need for novel, more selective RET inhibitors and further research into resistance mechanisms.
Main Methods:
- Literature review of preclinical models, clinical trials, and retrospective studies on RET-rearranged NSCLC.
- Analysis of diagnostic approaches for RET fusions.
- Evaluation of clinical outcomes and toxicities associated with current anti-RET therapies.
Main Results:
- Current multi-target RET inhibitors show modest response rates (16%-47%) and limited progression-free survival (2-7 months) in RET-rearranged NSCLC.
- These agents are associated with significant toxicities, often requiring dose modifications or discontinuation.
- Data on the impact of specific RET fusion variants on treatment response is inconclusive due to small subgroup analyses.
Conclusions:
- Existing therapies for RET-rearranged NSCLC offer limited clinical benefit and are often poorly tolerated.
- There is a critical need for the development of more potent and selective RET inhibitors.
- Further research is required to understand concomitant genomic alterations and resistance mechanisms to optimize treatment strategies.
