Table 1.

Plasma cfDNA methylation-based diagnostic biomarkers in clinical use or development.

Application	Cancer	Test/Assay/Target	Study Size (N)	Sensitivity	Specificity	Comments	References
Diagnosis	Colon	Epi proColon®/methylation specific PCR/SEPT9	245	67% (95% CI: 56–77%)	89% (95% CI: 83–93%)	Obtained FDA approval in 2016	[77]
Diagnosis	Lung	Epi proLung®/methylation specific PCR/SHOX2 and PTGER4	172	AUROC = 0.88; at specificity = 90%, sensitivity = 67%; at sensitivity = 90%, specificity = 73%.		Obtained CE-IVD mark in 2017	[79]
Diagnosis	Colon	EarlyTect® Colon/methylation-specific PCR/SCD2	256	87.0% (95% CI: 80.0–92.3%)	95.2% (95% CI: 89.8–98.2%)	--	[80]
Diagnosis	Lung	EarlyTect® Lung Cancer/methylation-specific PCR/PCDHGA12	--	75.0% (95% CI: 61.8–81.8%)	78.9% (95% CI: 62.2–89.8%)	In development for use with bronchial washings or blood	[90]
Diagnosis (MCED)	Pan-cancer	GRAIL(Galleri™)/NGS and custom classifier/ methylation panel covering 1.1 × 106 CpGs	4077	51.5% (95% CI: 49.6–53.3%)	99.5% (95% CI: 99.0–99.8%)	Data based on CCGA trial (NCT02889978)	[91]
MRD	Pan-cancer	Guardant Reveal™/NGS and custom classifier/500 genes and 4Mb of DMRs	CRC cohort = 84; Breast cancer cohort = 20	CRC cohort: 55.6% (95% CI: 35.3–74.5) Breast cancer cohort: sensitivity = 85% 1	CRC cohort: 100% (95% CI: 90.5–100) Breast cancer cohort: specificity = 100% 1	--	[92,93]
Diagnosis (MCED)/Prognosis/MRD	Pan-cancer	ADELA/cfMeDIP-seq/whole genome	MCED = 4322 Prognosis: HNSCC cohort = 93; RCC cohort = 151	MCED: Multi-cancer cohort—Cancer cases discriminated from controls with an AUROC of 0.94 (95% CI: 0.93, 0.96). In low cfDNA shedding tumors, AUROC was 0.92 (95% CI: 0.91, 0.94). Prognosis: HNSCC—Likelihood of recurrence or progression (HR 3.51, 95% CI: 1.1–11.19, p = 0.034); RCC—Likelihood of recurrence or progression (HR 13.28, 95% CI: 5.47–32.26, p < 0.001)		MRD assay currently in development	[88,94,95]

¹ 95% CI: not reported.