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Author Spotlight: Advancements in Molecular Biomarker Testing for Non-Squamous Non-Small Cell Lung Cancer
Published on: September 8, 2023
Molecular Characterization and Clinical Outcomes in RET-Rearranged NSCLC
Aaron C Tan1, Amanda O L Seet1, Gillianne G Y Lai1
1Division of Medical Oncology, National Cancer Centre Singapore, Singapore, Singapore.
Introduction:
RET rearrangements are an emerging targetable oncogenic fusion driver in NSCLC. However, the natural history of disease and activity of different classes of systemic therapy remain to be defined. Furthermore, molecular testing for RET is not yet routine, and the optimal method of testing is unclear. We present a comparative analysis of molecular profiling with fluorescence in situ hybridization (FISH) or next-generation sequencing (NGS) and treatment outcomes.
Methods:
This study was a retrospective analysis of patients treated at the National Cancer Centre Singapore. Baseline demographics and treatment outcomes were collected.
Results:
A total of 64 patients were included, with a median age of 62 years (range: 25-85), 56% were women, 77% were of Chinese ethnicity, 95% had adenocarcinoma, and 69% were never smokers. RET rearrangement was detected by FISH in 30 of 34 patients (88%), NGS in 40 of 43 patients (93%), and with discordant results in seven of 13 patients (54%) tested with both methods. Of 61 patients with stage IIIB/IV or recurrent disease, prevalence of central nervous system metastases was 31% and 92% received palliative systemic therapy. Overall survival was prolonged in patients treated with a selective RET tyrosine kinase inhibitor versus untreated patients (median 49.3 versus 15.3 mo; hazard ratio [HR]: 0.16, 95% confidence interval [CI]: 0.06-0.40, p < 0.001). However, it was not different in patients treated with immunotherapy versus untreated patients (median 37.7 versus 49.3 mo; HR: 1.30, 95% CI: 0.53-3.19, p = 0.53). Overall survival was also prolonged in patients with CCDC6-RET fusion versus those with KIF5B-RET fusion (median 113.5 versus 37.7 mo; HR: 0.12, 95% CI: 0.04-0.38, p = 0.009).
Conclusions:
In RET-rearranged NSCLC, selective RET tyrosine kinase inhibitor therapy is associated with improved survival outcomes, especially in patients with CCDC6-RET fusion. However, immunotherapy has poor efficacy. NGS and FISH testing methods may also result in substantial discordance.
Insights
Selective RET tyrosine kinase inhibitors improve survival in RET-rearranged NSCLC, particularly with CCDC6-RET fusions. Immunotherapy shows limited efficacy, and molecular testing methods like NGS and FISH can yield discordant results.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- RET rearrangements are an emerging targetable oncogenic driver in Non-Small Cell Lung Cancer (NSCLC).
- The natural history and optimal treatment strategies for RET-rearranged NSCLC require further definition.
- Molecular testing methods for RET rearrangements, including fluorescence in situ hybridization (FISH) and next-generation sequencing (NGS), need comparative analysis.
Purpose of the Study:
- To compare molecular profiling methods (FISH vs. NGS) for detecting RET rearrangements in NSCLC.
- To analyze treatment outcomes in patients with RET-rearranged NSCLC.
- To evaluate the efficacy of different systemic therapies, including RET tyrosine kinase inhibitors and immunotherapy.
Main Methods:
- Retrospective analysis of 64 patients with RET-rearranged NSCLC treated at the National Cancer Centre Singapore.
- Comparative analysis of molecular profiling using FISH and NGS.
- Collection of baseline demographics and treatment outcomes, including overall survival.
Main Results:
- FISH detected RET rearrangement in 88% and NGS in 93% of tested patients, with 54% discordance between methods.
- Selective RET tyrosine kinase inhibitor therapy significantly prolonged overall survival (median 49.3 vs. 15.3 months).
- Immunotherapy did not show a significant survival benefit compared to no treatment (median 37.7 vs. 49.3 months).
- CCDC6-RET fusion was associated with longer overall survival than KIF5B-RET fusion (median 113.5 vs. 37.7 months).
Conclusions:
- Selective RET tyrosine kinase inhibitors are effective in improving survival for RET-rearranged NSCLC, especially with CCDC6-RET fusions.
- Immunotherapy demonstrates poor efficacy in this patient population.
- Significant discordance can occur between FISH and NGS testing methods for RET rearrangements.
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