Clinicopathologic, genomic and protein expression characterization of 356 ROS1 fusion driven solid tumors cases
Richard S P Huang1, James Haberberger1, Ethan Sokol2
1Foundation Medicine, Inc., Morrisville, North Carolina, USA.
Abstract:
Based on the approvals of crizotinib and entrectinib by the Food and Drug Administration for the treatment of ROS1 positive nonsmall cell lung cancer (NSCLC), we sought to examine the mutational profile of a variety of solid tumors (excluding sarcomas) with ROS1 fusions that underwent comprehensive genomic profiling. A review of our database was performed to extract all nonsarcoma patients with ROS1 fusions that were discovered by the hybrid capture-based DNA only sequencing assays. We examined the coalterations representing potentially targetable biomarkers, resistance alterations and other alterations in these cases. In addition, we examined the histologic characteristics and protein expression with immunohistochemistry (IHC). From a series of clinically advanced nonsarcoma solid tumors, 356 unique cases with ROS1 fusions included 275 (77.2%) NSCLC and 81 (22.8%) non-NSCLC. Ten novel ROS1 fusions were discovered. Importantly, the NSCLC ROS1 fusionpos tumors had a higher PD-L1 IHC expression positivity when compared to the NSCLC ROS1 fusionneg population (P = .012, Chi-squared). The frequency of known and likely anti-ROS1 targeted therapy resistance genomic alterations in NSCLC was 7.3% (20/275) and in non-NSCLC was 4.9% (4/81). Overall, the coalteration profile of ROS1 fusionpos NSCLC and non-NSCLC was similar with only three genes altered significantly more frequently in non-NSCLC vs NSCLC: TERT, PTEN, APC. In our study, we characterized a large cohort of ROS1 fusionpos NSCLC and non-NSCLC solid tumors and discovered 10 novel ROS1 fusions.
Insights
This study analyzed solid tumors with ROS1 fusions, finding higher PD-L1 expression in non-small cell lung cancer (NSCLC) and discovering ten new ROS1 fusions. The findings aid in understanding treatment resistance and identifying new therapeutic targets.
Area of Science:
- Oncology
- Genomics
- Molecular Diagnostics
Background:
- Crizotinib and entrectinib are approved for ROS1-positive non-small cell lung cancer (NSCLC).
- Comprehensive genomic profiling (CGP) is crucial for identifying actionable targets in solid tumors.
- Understanding the mutational landscape of ROS1 fusions beyond NSCLC is essential for expanding therapeutic strategies.
Purpose of the Study:
- To investigate the mutational profile and co-alterations in a diverse cohort of solid tumors harboring ROS1 fusions.
- To compare characteristics of ROS1 fusion-positive (ROS1pos) versus ROS1 fusion-negative (ROS1neg) NSCLC, including PD-L1 expression.
- To identify novel ROS1 fusions and potential resistance mechanisms in non-small cell lung cancer and other solid tumors.
Main Methods:
- Retrospective database review of patients with ROS1 fusions identified via hybrid capture-based DNA sequencing.
- Analysis of co-occurring genomic alterations, including potential biomarkers and resistance mutations.
- Histologic evaluation and immunohistochemistry (IHC) for protein expression, particularly PD-L1.
Main Results:
- A total of 356 unique non-sarcoma solid tumors with ROS1 fusions were analyzed, comprising 275 (77.2%) NSCLC and 81 (22.8%) non-NSCLC cases.
- Ten novel ROS1 fusions were identified.
- ROS1pos NSCLC exhibited significantly higher PD-L1 IHC expression compared to ROS1neg NSCLC (P = .012).
- The frequency of known resistance alterations was 7.3% in NSCLC and 4.9% in non-NSCLC.
- Co-alteration profiles were similar between ROS1pos NSCLC and non-NSCLC, with TERT, PTEN, and APC being more frequent in non-NSCLC.
Conclusions:
- This study characterizes a large cohort of ROS1 fusion-positive solid tumors, revealing distinct features in NSCLC.
- Higher PD-L1 expression in ROS1-positive NSCLC may have implications for immunotherapy.
- The identification of novel ROS1 fusions and co-alterations provides insights into potential therapeutic targets and resistance mechanisms in a broader range of solid tumors.
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