The genomic subtype of a tumor may contribute to the level of circulating tumor DNA (ctDNA) shedding in patients with advanced non–small cell lung cancer (NSCLC), according to the results of a retrospective study reported in the Journal of Thoracic Oncology that could have implications for the clinical utility of ctDNA testing in early detection and disease monitoring.

The analysis included 144 patients with advanced NSCLC who had ctDNA testing performed at The University of Texas MD Anderson Cancer Center in Houston between November 2015 and July 2017. All patients had a computed tomography scan and brain magnetic resonance imaging to measure tumor burden within 30 days of ctDNA sampling. Genomic subtypes seen in the study population included TP53 mutation (53.5%), KRAS mutation (22.9%), EGFR mutation (39.6%), and ALK fusion (2.8%). 

The analysis showed that ctDNA variant allele frequency (VAF) was significantly associated with tumor burden, as determined by CT volume (rho=0.34; P ≤0.0001) and metabolic tumor volume (rho=0.36; P =0.003).

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“While positive, the modest correlation observed between VAF and tumor burden in our cohort suggests that other factors also significantly impact ctDNA shedding,” the study authors wrote.

All genomic subtypes assessed were found to have an association between ctDNA VAF and tumor burden. This association varied by genomic subtype. For example, tumors with KRAS mutations had the strongest association (rho=0.56; P ≤0.001) while tumors with EGFR mutations had the weakest (rho=0.24; P =0.077).

A multivariate analysis revealed that TP53 mutations (HR, 1.45; 95% CI, 1.16-1.80; P =0.001) and EGFR mutations (HR, 1.36; 95% CI, 1.08-1.71; P =0.009) were both independent predictors of elevated ctDNA shedding.

Among tumors with EGFR mutations, those that had EGFR copy number gain had a significantly higher ctDNA VAF compared with tumors without EGFR copy number gain (P ≤0.00001).

Visceral metastasis (hepatic, adrenal, renal, or splenic) was also an independent predictor of elevated ctDNA shedding (HR, 1.48; 95% CI, 1.16-1.91; P =0.002), as was tumor burden (HR, 1.00; 95% CI, 1.00-1.00; P <0.001), according to a multivariate analysis.

“Our findings strongly suggest that ctDNA shedding is not only impacted by tumor burden but also by anatomic location and genomic subtype,” the study authors concluded.

Disclosures: Some of the study authors disclosed financial relationships with the pharmaceutical industry and/or the medical device industry. For a full list of disclosures, please refer to the original study.


Lam VK, Zhang J, Wu CC, et al. Genotype-specific differences in circulating tumor DNA levels in advanced NSCLC. J Thorac Oncol. Published online December 31, 2020. doi:10.1016/j.jtho.2020.12.011