Research Spotlight: Real-World Clinical Performance of a DNA-Based Comprehensive Genomic Profiling Assay for Detecting Targetable Fusions in Nonsquamous NSCLC

Mack, P., et al. Real-World Clinical Performance of a DNA-Based Comprehensive Genomic Profiling Assay for Detecting Targetable Fusions in Nonsquamous NSCLC. Oncologist. 2024 Feb 24. doi: 10.1093/oncolo/oyae028.

Background:

Genomic fusions are potent oncogenic drivers across cancer types, and many are targetable. The current realities of comprehensive genomic profiling (CGP) testing necessitate that many patients still rely on DNA-based CGP for fusion detection, and it is thus critical that DNA-based assays are optimally designed to identify these important driver events which can significantly influence treatment decisions and patient outcomes. Moreover, it is of value to identify the clinical scenarios in which patients are most likely to benefit from additional RNA-based testing.

Study details:

In this study, researchers demonstrate that robust detection of fusions is possible using carefully designed DNA-based sequencing methodologies and that fusions detected using high-quality DNA CGP assays are associated with clinical benefit from matched targeted agents. Using a de-identified nationwide (US-based) clinico-genomic database, researchers assessed clinical outcomes in patients with non-squamous NSCLC (NonSqNSCLC) who underwent tissue-based DNA CGP using Foundation Medicine DNA CGP (FoundationOne®CDx, FoundationOne®) which identified a targetable fusion and who received matched therapy. Lastly, they used a mathematical model to estimate the added value of RNA CGP for fusion detection in NonSqNSCLC.

Researchers observed a broad diversity of fusion partners detected across all clinically actionable fusion genes analyzed, as well as comparable or higher fusion prevalence in select cancer types compared to a large public database. In NonSqNSCLC in which oncogenic ALK, NTRK, RET, and ROS1 fusions were detected, patients treated with a matched tyrosine kinase inhibitor (TKI) had better real-world progression-free survival than those receiving alternative treatment regimens and benefit was observed regardless of the results of other non-Foundation Medicine fusion testing methods. An estimated 1.3% of patients with NonSqNSCLC were predicted to have an oncogenic driver fusion identified by RNA CGP, but not DNA CGP, according to a model that accounts for multiple real-world factors.

Why this matters:

A well-designed DNA CGP assay is capable of robust fusion detection and these fusion calls can be reliably used to inform clinical decision-making. While DNA CGP is capable of detecting a large majority of driver fusions, the clinical impact of identifying an actionable fusion is substantial for individual patients. Exhaustive efforts, inclusive of additional RNA-based testing, should be considered for patients in whom an oncogenic driver is not clearly identified on DNA CGP.

View the full publication in Oncologist.