Updated NCCN Guidelines on RNA Sequencing

NCCN Stresses the Importance of RNA Sequencing in Updated NSCLC Guidelines

Translocations and gene fusions represent approximately 20% of cancer mortality globally, however the detection and targeting of these events demonstrates a revolution in personalized medicine1. Precise identification of both common and rare fusion events are critical to providing appropriate targeted therapy and improving outcomes in patients with a targetable fusion1.

Recently, the National Comprehensive Cancer Network® (NCCN) published updated Clinical Practice Guidelines in Oncology for Non-Small Cell Lung Cancer (NSCLC) version 1.2020.  As part of this update, NCCN stressed the importance of using RNA-based sequencing to maximize the detection of fusion events2.

The updated guideline states:
“It is recommended at this time that when feasible, testing be performed via a broad, panel-based approach, most typically performed by NGS.  For patients who, in broad panel testing don’t have an identifiable driver oncogene (especially in never smokers), consider RNA-based NGS if not already performed, to maximize detection of fusion events
2.”

 

Furthermore, the update mentioned several limitations of using DNA-based NGS for the detection of fusion events including: the potential for DNA-based NGS to under detect ROS1 fusions that have rare or novel fusion partners, and the potential for DNA-based NGS to under detect NTRK1 and NTRK3 fusions due to numerous fusion partners2.

The use of RNA sequencing to maximize the number of fusion events detected is also found in literature. For example, a recent study of 2,522 NSCLC cases, of which 232 lacked an oncogenic driver and were subsequently sequenced via targeted RNA sequencing3. After targeted RNA sequencing, 36 (15.5%) were found to have an oncogenic driver, and importantly the DNA sequencing methods did not detect any fusions in NTRK 2/33While this data is significant, the authors noted it was limited by the use of targeted RNA sequencing and that whole transcriptome sequencing (WTS) may detect even more fusion events3.

Caris Molecular Intelligence® comprehensive tumor profiling includes MI Transcriptome™, Whole Transcriptome Sequencing, via RNA next-generation sequencing for all orders (MI Profile™ or MI Tumor Seek™), in addition to DNA and protein testing. MI Transcriptome provides unbiased detection of fusion events independent of the breakpoints in DNA and, therefore, has the ability to detect rare, novel fusion events better than DNA-based methods.  Additionally, by providing broad exon coverage and capturing essentially all possible fusion partners, MI Transcriptome can reliably detect different types of expressed gene fusions, while reducing false positives caused by non-expressed rearrangements.

 

1.    Latysheva, N.S. and Babu, M.M. Discovering and understanding oncogenic gene fusions through data intensive computational approaches. Nucleic Acids Res 2016;44(10):4487–4503
2.    National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology. Non-Small Cell Lung Cancer Version 1.2020. 2019 Nov 6; National Comprehensive Cancer Network.
3.    Benayed R, Offin M, Mullaney K. et al. High yield of RNA sequencing for targetable kinase fusions in lung adenocarcinomas with no driver alteration detected by DNA sequencing and low tumor mutation burden. Clin Cancer Res 2019; 25(15): 4712–4722.