NEW YORK – New research suggests that combined next-generation sequencing (NGS) on DNA and RNA from advanced non-small cell lung cancer (NSCLC) cases can pick up targetable structural variants (SVs) that might otherwise be missed or delayed.
The National Comprehensive Cancer Network (NCCN) guidelines for non-small cell lung cancer suggest that RNA next-generation sequencing may improve the detection of fusions and splicing variants compared with only DNA NGS, co-corresponding authors Halla Nimeiri and Justin Guinney, with Tempus AI, and their colleagues noted in JAMA Network Open on Monday. However, they wrote, "there is limited adoption of RNA-NGS in routine oncology clinical care today."
For their retrospective analysis, Nimeiri, Guinney, and colleagues from Tempus, Northwestern University, and elsewhere considered data generated using RNA and DNA profiling assays applied to solid tumor samples from 5,570 de-identified individuals between the ages of 61.3 and 75.4 years old who were treated for stage IIIb to stage IV lung adenocarcinoma from February 2021 to October 2023.
"Our findings suggest that RNA-NGS has a robust clinical sensitivity, enhances SV detection when used in conjunction with DNA-NGS for both existing and emerging actionable structural variants, and should be routinely offered with DNA-NGS in the clinic to maximize SV detection in patients with advanced adenocarcinoma NSCLC," the authors reported.
The team focused on SVs recommended as being actionable under NCCN guidelines, comparing the number of cases marked by actionable SVs (aSVs) that could be picked up using DNA-NGS or RNA-NGS data.
All told, the investigators identified 491 NSCLC cases involving aSVs, including 426 aSVs that could be detected using DNA profiles. They estimated that the inclusion of RNA profiles through concurrent RNA-NGS led to the identification of 15.3 percent more targetable SVs than DNA-NGS alone, particularly when it came to finding 376 cases marked by actionable fusions.
"[A]s our study shows, 13.2 percent of patients who had an aSV would have experienced a meaningful delay of several weeks or more in the detection of a matched therapy if RNA-NGS and DNA-NGS had been performed sequentially rather than concurrently," the authors reported, noting that "clinical benefits of targeted therapy adoption via NGS results (whether DNA or RNA) have not yet been fully realized."
When it came to advanced lung adenocarcinoma cases involving exon 14 skipping in the MET gene, for example, the team tracked down 115 cases with combined RNA and DNA profiling, but just 97 cases based on the DNA-NGS data.
"[T]hese findings support a possible evaluation of upfront dual variation targeted treatment to mitigate this resistance mechanism," the authors reported, adding that "[f]urther prospective clinical studies are needed to validate these findings, and incorporation of RNA-NGS as a companion diagnostic test in future registrational studies should be considered."
The team noted that the proportion of SVs found with transcriptomic data ticked up further when it came to targeted treatment markers known as "emerging SVs" (eSVs) that are not included in existing clinical guidelines. In the lung cancer cohort considered, DNA-NGS identified just shy of 48 percent of the 40 eSVs found overall, including eSV fusions involving the BRAF, EGFR, NRG1, and FGFR2/3 genes.
The investigators did not see significant assay-associated differences in clinical outcomes or in the proportion of the advanced lung adenocarcinoma patients receiving targeted treatment. Even so, they noted that an analysis focused on targeted therapy adoption "demonstrated that about 1 in 5 patients did not receive NCCN-recommended first-line targeted therapies, highlighting the ongoing need for education about implementing NGS results in clinical practice."