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Updated: Jul 2, 2025
Author Spotlight: Advancements in Molecular Biomarker Testing for Non-Squamous Non-Small Cell Lung Cancer
Published on: September 8, 2023
Real-World Clinical Performance of a DNA-Based Comprehensive Genomic Profiling Assay for Detecting Targetable Fusions
Philip C Mack1, Rachel B Keller-Evans2, Gerald Li2
1Center for Thoracic Oncology, Tisch Cancer Institute, Icahn School of Medicine, Mount Sinai, New York, NY, USA.
Background:
Genomic fusions are potent oncogenic drivers across cancer types and many are targetable. We demonstrate the clinical performance of DNA-based comprehensive genomic profiling (CGP) for detecting targetable fusions.
Materials And Methods:
We analyzed targetable fusion genes in >450 000 tissue specimens profiled using DNA CGP (FoundationOne CDx, FoundationOne). Using a de-identified nationwide (US-based) non-small cell lung cancer (NSCLC) clinico-genomic database, we assessed outcomes in patients with nonsquamous NSCLC (NonSqNSCLC) who received matched therapy based on a fusion identified using DNA CGP. Lastly, we modeled the added value of RNA CGP for fusion detection in NonSqNSCLC.
Results:
We observed a broad diversity of fusion partners detected with DNA CGP in conjunction with targetable fusion genes (ALK, BRAF, FGFR2, FGFR3, NTRK1/2/3, RET, and ROS1). In NonSqNSCLC with oncogenic ALK, NTRK, RET, and ROS1 fusions detected by DNA CGP, patients treated with a matched tyrosine kinase inhibitor had better real-world progression-free survival than those receiving alternative treatment regimens and benefit was observed regardless of the results of orthogonal fusion testing. An estimated 1.3% of patients with NonSqNSCLC were predicted to have an oncogenic driver fusion identified by RNA, but not DNA CGP, according to a model that accounts for multiple real-world factors.
Conclusion:
A well-designed DNA CGP assay is capable of robust fusion detection and these fusion calls are reliable for informing clinical decision-making. While DNA CGP detects most driver fusions, the clinical impact of fusion detection is substantial for individual patients and exhaustive efforts, inclusive of additional RNA-based testing, should be considered when an oncogenic driver is not clearly identified.
Insights
Comprehensive genomic profiling (CGP) using DNA effectively detects targetable gene fusions in cancer. DNA CGP identifies most driver fusions, improving patient outcomes with targeted therapies, though RNA testing may be needed for comprehensive detection.
Area of Science:
- Oncology
- Genomics
- Molecular Diagnostics
Background:
- Genomic fusions are key drivers of cancer and often actionable targets.
- DNA-based comprehensive genomic profiling (CGP) is a clinical tool for detecting these fusions.
Purpose of the Study:
- To evaluate the clinical performance of DNA CGP in detecting targetable genomic fusions.
- To assess real-world outcomes for non-small cell lung cancer (NSCLC) patients treated based on DNA CGP findings.
- To model the added value of RNA CGP for fusion detection in NSCLC.
Main Methods:
- Analysis of over 450,000 tissue specimens using DNA CGP.
- Assessment of outcomes in a US-based non-squamous NSCLC (NonSqNSCLC) cohort treated with matched therapies.
- Modeling of RNA CGP's utility for detecting fusions missed by DNA CGP.
Main Results:
- DNA CGP identified diverse fusion partners across targetable genes (e.g., ALK, NTRK, RET, ROS1).
- Patients with NonSqNSCLC and ALK, NTRK, RET, or ROS1 fusions treated with matched tyrosine kinase inhibitors showed improved progression-free survival.
- An estimated 1.3% of NonSqNSCLC patients may have driver fusions detectable by RNA but not DNA CGP.
Conclusions:
- DNA CGP assays reliably detect driver fusions for clinical decision-making.
- While DNA CGP is effective, RNA-based testing can complement detection for a more comprehensive analysis.
- Fusion detection significantly impacts individual patient treatment and outcomes.
