Baseline Cell-Free DNA Can Predict Malignancy of Nodules Observed in the ITALUNG Screening Trial

Abstract

The role of total plasma cell-free DNA (cfDNA) in lung cancer (LC) screening with low-dose computed tomography (LDCT) is uncertain. We hypothesized that cfDNA could support differentiation between malignant and benign nodules observed in LDCT. The baseline cfDNA was measured in 137 subjects of the ITALUNG trial, including 29 subjects with screen-detected LC (17 prevalent and 12 incident) and 108 subjects with benign nodules. The predictive capability of baseline cfDNA to differentiate malignant and benign nodules was compared to that of Lung-RADS classification and Brock score at initial LDCT (iLDCT). Subjects with prevalent LC showed both well-discriminating radiological characteristics of the malignant nodule (16 of 17 were classified as Lung-RADS 4) and markedly increased cfDNA (mean 18.8 ng/mL). The mean diameters and Brock scores of malignant nodules at iLDCT in subjects who were diagnosed with incident LC were not different from those of benign nodules. However, 75% (9/12) of subjects with incident LC showed a baseline cfDNA ≥ 3.15 ng/mL, compared to 34% (37/108) of subjects with benign nodules (p = 0.006). Moreover, baseline cfDNA was correlated (p = 0.001) with tumor growth, measured with volume doubling time. In conclusion, increased baseline cfDNA may help to differentiate subjects with malignant and benign nodules at LDCT.

Keywords: biomarkers; cell-free DNA; low-dose CT; lung cancer; prediction; screening.

Figure 1

Increased baseline cfDNA in two subjects with prevalent (A) and incident (B) screen-detected lung cancer appearing as Lung-RADS 2 (<6 mm in diameter) solid nodules at iLDCT. (A) Prevalent adenosquamous LC in a subject with baseline plasma cfDNA of 18.9 ng DNA/mL appearing at iLDCT as a solid nodule of 5.9 mm in diameter in the anterior right lobe (arrow left panel); the nodule showed remarkable growth at 3 months follow-up LDCT (right panel). The Brock score at iLDCT was 0.1%. (B) Incident adenocarcinoma in a subject with baseline plasma cfDNA of 3.3 ng DNA/mL appearing at iLDCT as a solid nodule of 4.6 mm in diameter within a scar in the right apex (arrow left panel); the nodule showed growth in a follow-up LDCT obtained 14 months later (right panel). The Brock score was 0.4% at the iLDCT and 6.9% at the last LDCT.

Figure 2

Correlation between cfDNA and tumor volume doubling time. The natural logarithm of baseline cfDNA (ng/mL) (x-axis) and tumor volume doubling time (days) (y-axis) shows an inverse significant correlation (ρ = −0.77; 95% CI: −0.92 to −0.40) in 14 subjects with screen-detected (4 prevalent and 10 incident LC) (○ = adenocarcinomas; + = others lung cancers, including 2 squamous carcinomas, 1 adeno-squamous carcinoma, 1 pleomorphic carcinoma, and 1 small cell carcinoma).