Genomic profiling of NSCLC tumors with the TruSight Oncology 500 assay provides broad coverage of clinically actionable genomic alterations and detection of known and novel associations between genomic alterations, TMB, and PD-L1

Wallen ZD, Ko H, Nesline MK, Tierno M, Roos A, Schnettler E, Husain H, Sathyan P, Caveney B, Eisenberg M, Severson EA, Ramkissoon SH. Genomic profiling of NSCLC tumors with the TruSight Oncology 500 assay provides broad coverage of clinically actionable genomic alterations and detection of known and novel associations between genomic. Front Oncol. 2024 Nov 5;14:1473327. doi: 10.3389/fonc.2024.1473327.

ABSTRACT

Introduction: Matching patients to an effective targeted therapy or immunotherapy is a challenge for 
advanced and metastatic non-small cell lung cancer (NSCLC), especially when relying on assays that test one 
marker at a time. Unlike traditional single marker tests, comprehensive genomic profiling (CGP) can 
simultaneously assess NSCLC tumors for hundreds of genomic biomarkers and markers for immunotherapy 
response, leading to quicker and more precise matches to therapeutics. Methods: In this study, we performed 
CGP on 7,606 patients with advanced or metastatic NSCLC using the Illumina TruSight Oncology 500 (TSO 
500) CGP assay to show its coverage and utility in detecting known and novel features of NSCLC. Results: 
Testing revealed distinct genomic profiles of lung adenocarcinoma and squamous cell carcinomas and 
detected variants with a current targeted therapy or clinical trial in >72% of patient tumors. Known associations 
between genomic alterations and immunotherapy markers were observed including significantly lower TMB 
levels in tumors with therapy-associated alterations and significantly higher PD-L1 levels in tumors with ALK, 
MET, BRAF, or ROS1 driver mutations. Co-occurrence analysis followed by network analysis with gene 
module detection revealed known and novel co-occurrences between genomic alterations. Further, certain 
modules of genes with co-occurring genomic alterations had dose-dependent relationships with histology and 
increasing or decreasing levels of PD-L1 and TMB, suggesting a complex relationship between PD-L1, TMB, 
and genomic alterations in these gene modules. Discussion: This study is the largest clinical study to date 
utilizing the TSO 500. It provides an opportunity to further characterize the landscape of NSCLC using this 
newer technology and show its clinical utility in detecting known and novel facets of NSCLC to inform treatment 
decision-making.

DATA AVAILABILITY

The data and code presented in the study are deposited in this Zenodo repository, accession number 
13137232 (https://zenodo.org/record/13137232). Raw sequencing data were derived from routine clinical testing of real-world patients and cannot be shared publicly. Further data inquiries can be directed to the corresponding 
author.