Concordance of tissue and plasma NGS in early-stage non–small cell lung cancer

Background
Comprehensive molecular profiling is standard of care for patients with advanced non-small cell lung cancer (NSCLC), and plasma-based next generation sequencing (NGS) demonstrates high concordance with tissue testing in metastatic disease. However, the performance of liquid biopsy in early-stage NSCLC remains poorly defined. In early stage, tissue-based NGS may be limited by inadequate sample quantity, low tumor cellularity, or DNA degradation. We evaluated the concordance of tissue and plasma NGS in patients with stage I to III NSCLC to determine whether liquid biopsy can reliably complement tissue-testing in this setting.

 

Methods
We conducted a retrospective analysis of patients diagnosed with stage I to III NSCLC from 2021 to 2025 at the University of Illinois Cancer Center. Clinical and demographic data were abstracted through chart review. Paired NGS results were obtained from the Tempus Hub, including tissue-based sequencing (Tempus xT) and plasma-based sequencing (Tempus xF+). Actionable genomic alterations were assessed for concordance using 2x2 contingency tables, with calculation of overall concordance and positive percentage agreement (PPA).

 

Results
A total of 71 patients with early-stage NSCLC were identified. The cohort was 52% male and 48% female; 61% Black, 23% White, 14% Asian and 3% other; 9% Hispanic and 88% non-Hispanic. 52% were 65 years or older at diagnosis. Disease stage included stage I (20%), stage II (10.6%), stage III (41%), with stage unknown 29%. No NTRK2/3, ROS1, RET, and MET alterations were detected on liquid or tissue. PPA for actionable mutations was low overall: BRAF V600E 66.7%, KRAS G12C 40%, EGFR 16.7%, HER2 0%, and EML4-ALK 0%. Despite low PPA, overall concordance exceeded 80% for all genes, driven by high negative percent agreement.

 

Conclusions
In early-stage NSCLC, plasma-based NGS demonstrates limited sensitivity for detecting actionable driver alterations, despite high overall concordance driven by negative agreement. Reliance on liquid biopsy alone may miss clinically meaningful oncogenic drivers, even in potentially curable disease. While plasma NGS may be useful as a complementary or rule-out tool when tissue is inadequate, tissue-based molecular profiling remains essential for accurate genomic characterization in early-stage NSCLC.

 

Concordance and PPA analysis.

	Concordance	PPA
BRAF V600E	91.2%	66.7%
EGFR	86.0%	16.7%
HER2	98.6%	0%
KRAS G12C	84.5%	40%
EML4-ALK	98.6%	0%