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In advanced non-small cell lung cancer (NSCLC), RNA next-generation sequencing (RNA-NGS) identifies more actionable structural variants (aSVs) than DNA-NGS alone, according to the largest study to reinforce National Comprehensive Cancer Network (NCCN) guidelines. Guidelines already call for concurrent use of DNA-NGS and RNA-NGS in NSCLC. 

DNA-NGS is commonly used to detect structural variants, such as gene fusions, in patients with advanced NSCLC. However, identifying these variants is challenging when rearrangements or other variants occur in areas where adequate sensitivity, particularly for rare variants, is difficult to achieve.^2,3 Several studies have indicated that use of DNA-NGS risks under-detection of clinically actionable variants because of this issue. For example, an evaluation of more than 7000 samples found that exonic-breakpoint fusions are unreliable, underscoring the need for RNA-NGS to validate exonic-breakpoint fusion cases.⁴

Despite previous studies demonstrating that RNA-NGS provides greater detection of actionable variants in advanced NSCLC and guidelines that recommend using both methods to guide therapy, RNA-NGS is not employed uniformly, according to the authors of this study, which employed the deidentified Tempus multimodal database to compare RNA-NGS plus DNA-NGS with RNA-NGS alone. Leveraging the database, which accrues information from a large array of oncology practices, including those in the community and in academic centers, permitted analysis of the value of RNA-NGS across diverse settings. 

The evaluable cohort was 5570 NSCLC patients with stage IIIB- IV metastatic NSCLC. They had undergone tissue-based DNA-NGS and whole-transcriptome RNA-NGS between February 2021 and October 2023 following diagnosis. The goal was to look for actionable mutations with recommended targeted therapies, as documented in NCCN guidelines. These included ALK, RET, ROS1, and NTRK1/2/3 fusions and MET exon 14 skipping variants. 

Overall, an aSV with a known targeted therapy was found in 491 (8.8%) of the 5570 participants whose information was drawn from the database. The most common fusion was ALK, which was found in 4.5%. The least common was NTRK1/2/3, which was found in 0.1%. The MET exon 14 skipping fusion was identified in 2.1%. 

In total, the addition of RNA-NGS identified 15.3% more patients with aSVs relative to DNA-NGS alone. The rate of additional detection with RNA-NGS varied modestly by type of aSV, but RNA-NGS identified 14.3% more patients with actionable fusions and 18.6% more patients with MET exon 14 skipping alterations. 

Fusion partners, the most common of which were ALK-EML, RET-KIF5B, and ROSI-CD74, were more likely to be detected by RNA-NGS than by DNA-NGS. With RNA-NGS, 93.2% of ALK fusions had EML4 as a dominant partner. In contrast, the rate was only 82.1% with DNA-NGS. 

Because the number of US Food and Drug Administration-approved therapies for SVs is expanding, the authors also compared the relative rates at which RNA-NGS and DNA-NGS detected emerging structural variants (eSVs) such as BRAF, EGFR, and NRG1 fusions. Although the rate of eSVs in the dataset was low, concurrent RNA-NGS plus DNA-NGS more than doubled the eSV detection rate relative to DNA-NGS alone. 

The guidelines do not specify the relative timing of DNA-NGS and RNA-NGS. At many centers, RNA-NGS is offered if no aSVs are detected on DNA-NGS, but the new data argue against this approach, according to the authors, who were led by Dwight H. Owen, MD, a medical oncologist at Ohio State University School of Medicine, Columbus, Ohio. 

Based on this study, more than 13% of patients with advanced NSCLC and an aSV 鈥渨ould have experienced a meaningful delay of several weeks or more鈥� in identification of an appropriate targeted therapy 鈥渋f RNA-NGS and DNA-NGS had been performed sequentially rather than concurrently,鈥� Dr. Owen reported.

Published: December 30, 2024