A screening method that incorporates assessment of cell-free DNA (cfDNA) can identify lung cancers with 94% sensitivity and 80% specificity, according to a study published in Nature Communications.

The method involves DELFI (DNA evaluation of fragments for early interception), an approach that can detect many abnormalities in cfDNA through genome-wide analysis of fragmentation patterns.

“This approach provides a view of cfDNA ‘fragmentomes,’ permitting evaluation in any individual of the size, distribution, and frequency of millions of naturally occurring cfDNA fragments across the genome,” the researchers explained. “As a cfDNA fragmentome can comprehensively represent both genomic and chromatin characteristics, it has the potential to identify a large number of tumor-derived changes in the circulation.”

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The researchers first tested the utility of DELFI to detect lung cancer using blood samples from 365 patients enrolled in a prospective, observational trial in Denmark. Most patients (90%) in this cohort were symptomatic. Asymptomatic patients had chest x-rays or CT scans showing suspicious findings for lung malignancy.

Ultimately, 129 patients were diagnosed with lung cancer, 87 had benign nodules, and 149 were not biopsied due to “low clinical and radiographic suspicion for cancer,” according to the researchers.

The researchers found that cfDNA fragmentomes were “remarkably consistent” in the patients without cancer, including those with non-malignant lung nodules. However, the cfDNA fragmentomes of cancer patients showed “widespread genome-wide variation.”

The median DELFI scores were significantly higher for patients with cancer than for those without cancer (P <.01), and DELFI scores increased with cancer stage. The median DELFI score was 0.16 for noncancer patients without a biopsy, 0.21 for those with benign lesions, 0.35 for those with stage I lung cancer, 0.75 for stage II, 0.90 for stage III, and 0.99 for patients with stage IV lung cancer.

The researchers validated these findings in an independent cohort of 385 noncancer individuals and 46 lung cancer patients. The results were similar to results from the initial cohort.

Finally, the researchers combined DELFI with other characteristics — age, carcinoembryonic antigen levels, smoking history, and presence of chronic obstructive pulmonary disease — in a multimodal model.

The model was able to detect lung cancer with 94% sensitivity and 80% specificity. The sensitivity was 87% for stage I, 100% for stage II, 97% for stage III, and 96% for stage IV lung cancer.

Based on these results, the researchers proposed that “facile and scalable analyses of cfDNA fragmentomes could be used to prescreen high-risk populations for lung cancer to increase the accessibility of lung cancer detection and decrease unnecessary follow-up imaging procedures and invasive biopsies.”

Disclosures: Some study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of disclosures.


Mathios D, Johansen JS, Cristiano S, et al. Detection and characterization of lung cancer using cell-free DNA fragmentomes. Nat Commun. Published online August 20, 2021. doi:10.1038/s41467-021-24994-w