Table 2.
Characteristics and Performance of Liquid Biopsies (CTCs, ctDNA, and Methylated DNA) Predicting Malignancy in Pulmonary Nodules
| Publication | Population | Technique | Performance | Comments |
|---|---|---|---|---|
| Marquette et al, 29 2020 | AIR prospective cohort (high-risk individuals, n = 614; lung cancers, n = 19) | Blood-based CTC detection via isolation by size of epithelial tumor cell technique | Sens 26%, Spec 96% | LDCT imaging detected 178 pulmonary nodules with Sens 83%, Spec 71% |
| Li et al,30 2019 | Single-center case-control (patients with lung cancer, n = 174; healthy control subjects, n = 90) | Blood-based CTC detection via negative enrichment/fluorescence in situ hybridization | AUC 0.85 (Sens 68%, Spec 100%) Among patients with early-stage (I-II) lung cancer, Sens 64% |
Combination of CTCs and tumor markers (CEA, CA125, CYFRA 21-1, and SCC) improved diagnosis for all patients (Sens 83%) and in those with early-stage disease (Sens 79%) |
| Mathios et al,31 2021 | Training: LUCAS prospective cohort (patients with lung cancer, n = 129; high-risk individuals, n = 236) Validation: multinational cohort (healthy control subjects, n = 385; patients with early-stage lung cancer, n = 46) |
Blood-based cell-free DNA fragment detection and machine learning model | Training: AUC = 0.90, with greater AUCs for stages II, III, and IV (0.89, 0.92, and 0.92) vs stage I disease (0.76) Independent validation: comparable range of Sens and Spec across various stages and histologic subtypes |
Multimodal model of fragmentation profiles with CEA, age, tobacco use history, and presence of COPD increased AUC to 0.93 Use of multimodal model as a prescreen to stratify patients requiring LDCT imaging yielded improved performance with Sens 94% and Spec 80% |
| Leung et al,32 2020 | Single-center prospective cohort (patients with known or suspected early primary or secondary lung cancer, n = 192) | Blood-based ctDNA detection via qRT-PCR | Sens 75%, Spec 89% | Detected mutations in ctDNA and corresponding tissue biopsy results showed concordance of 83% and kappa statistic of 0.63 (P < .001) |
| Kneip et al,33 2011 | Training: single-center case-control (patients with stage IV lung cancer, n = 20; healthy control subjects, n = 20) Validation: two-center case-control (patients with suspected lung cancer, n = 343; healthy control subjects, n = 150) |
Blood-based methylation-specific qRT-PCR for SHOX2 | Training: Sens 75%, 95% Testing: AUC 0.78 (Sens 60%, Spec 90%) |
Small cell lung cancer and squamous cell carcinoma were detected more readily than adenocarcinomas (Sens 80% and 63% vs 39%), likely reflecting underlying differences in tumor biology |
| Hulbert et al,34 2017 | Single-center case-control (stage I or IIA lung cancer, n = 150; control with suspicious pulmonary nodule, n = 60) | Blood and sputum-based methylation-specific qRT-PCR for 6 cancer-specific methylated genes | Three-gene panel (TAC1, HOXA17, and SOX17) yielded Sens 93%, Spec 62% with blood and Sens 98%, Spec 71% and with sputum | Combination of blood-based methylated DNA and age, pack-y, COPD status, and FVC values using blinded random forest prediction models improved AUC to 0.89 (Sens 93%, Spec 67%) |
| Ooki et al,35 2017 | NYU LCBC case-control (patients with stage IA adenocarcinoma, n = 43; patients with stage IA SCC, n = 40; healthy control subjects, n = 42) | Blood-based promoter methylation-specific qRT-PCR for 30 cancer-specific methylated genes | Six-gene panel (CDO1, HOXA9, AJAP1, PTGDR, UNCX, and MARCH11) yielded Sens 72% and 60% for stage IA adenocarcinoma and SCC, respectively; Spec 71% | Risk stratification based on differential methylation significantly stratified prognosis, with 5-y OS of 100.0% for low risk, 96.0% for moderate risk, and 55.6% for high risk (P = .015) |
AIR = AIR Project Study Group; AUC = area under the curve; CTC = circulating tumor cell; ctDNA = circulating tumor DNA; CA-125 = cancer antigen 125; CEA = carcinoembryonic antigen; CYFRA 21-1 = cytokeratin 19 fragment; LDCT = low-dose CT scan; LUCAS = Longitudinal Urban Cohort Aging Study; qRT-PCR = quantitative reverse transcription polymerase chain reaction; NYU LCBC = New York University Lung Cancer Biomarker Center; OS = overall survival; SCC = squamous cell carcinoma; SCCA = squamous cell carcinoma antigen; Sens = sensitivity; Spec = specificity.