"Evaluation of ROS1 expression and rearrangements in a large cohort of early-stage lung cancer"
Anne Pernille Harlem Dyrbekk1,2,3, Abdirashid Ali Warsame4, Pål Suhrke5
1University of Oslo, NO-0316, Oslo, Norway. a.p.h.dyrbekk@studmed.uio.no.
Background:
ROS1 fusion is an infrequent, but attractive target for therapy in patients with metastatic non- small-cell lung cancer. In studies on mainly late-stage disease, the prevalence of ROS1 fusions is about 1-3%. In early-stage lung cancer ROS1 might also provide a fruitful target for neoadjuvant or adjuvant therapy. In the present study, we investigated the prevalence of ROS1 fusion in a Norwegian cohort of early-stage lung cancer. We also explored whether positive ROS1 immunohistochemical (IHC) stain was associated with certain mutations, clinical characteristics and outcomes.
Methods:
The study was performed using biobank material from 921 lung cancer patients including 542 patients with adenocarcinoma surgically resected during 2006-2018. Initially, we screened the samples with two different IHC clones (D4D6 and SP384) targeting ROS1. All samples that showed more than weak or focal staining, as well as a subgroup of negative samples, were analyzed with ROS1 fluorescence in situ hybridization (FISH) and next-generation sequencing (NGS) with a comprehensive NGS DNA and RNA panel. Positive ROS1-fusion was defined as those samples positive in at least two of the three methods (IHC, FISH, NGS).
Results:
Fifty cases were IHC positive. Of these, three samples were both NGS and FISH-positive and considered positive for ROS1 fusion. Two more samples were FISH positive only, and whilst IHC and NGS were negative. These were also negative with Reverse Transcription quantitative real time Polymerase Chain Reaction (RT-qPCR). The prevalence of ROS1 fusion in adenocarcinomas was 0.6%. All cases with ROS1 fusion had TP53 mutations. IHC-positivity was associated with adenocarcinoma. Among SP384-IHC positive cases we also found an association with never smoking status. There was no association between positive IHC and overall survival, time to relapse, age, stage, sex or pack-year of smoking.
Conclusions:
ROS1 seems to be less frequent in early-stage disease than in advanced stages. IHC is a sensitive, but less specific method and the results need to be confirmed with another method like FISH or NGS.
Insights
ROS1 fusions are less common in early-stage lung cancer than advanced stages. Immunohistochemistry (IHC) is sensitive but requires confirmation with FISH or NGS for accurate ROS1 fusion detection.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- ROS1 fusions are a targetable biomarker in metastatic non-small cell lung cancer (NSCLC), occurring in 1-3% of patients.
- Early-stage lung cancer may also benefit from ROS1-targeted therapies, necessitating investigation into fusion prevalence.
- This study examines ROS1 fusion prevalence in a Norwegian early-stage lung cancer cohort and its clinical associations.
Purpose of the Study:
- To determine the prevalence of ROS1 fusions in early-stage lung cancer.
- To explore associations between ROS1 fusion status, mutations, clinical characteristics, and patient outcomes.
- To evaluate the utility of immunohistochemistry (IHC) in detecting ROS1 fusions.
Main Methods:
- Utilized biobank samples from 921 early-stage lung cancer patients, including 542 with adenocarcinoma.
- Screened samples using ROS1 IHC (two clones), followed by FISH and comprehensive NGS (DNA/RNA) for IHC-positive and selected negative cases.
- Defined ROS1 fusion positivity based on concordance across at least two methods (IHC, FISH, NGS).
Main Results:
- Identified a ROS1 fusion prevalence of 0.6% in adenocarcinomas.
- All ROS1 fusion-positive cases harbored TP53 mutations.
- IHC positivity correlated with adenocarcinoma, and SP384-IHC positivity with never-smoking status; no survival associations were found.
Conclusions:
- ROS1 fusions appear less frequent in early-stage lung cancer compared to advanced disease.
- Immunohistochemistry (IHC) is a sensitive but not fully specific method for ROS1 fusion detection.
- Confirmation of IHC results with methods like FISH or NGS is crucial for accurate diagnosis.
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