Early Detection and Recurrence of Colorectal Adenomas by Combination of Eight Cancer-Associated Biomarkers in Plasma

Figures & data

Table 1 Characteristics and Current Knowledge in Association with CRC and HRA of AFP, CA19-9, CEA, CyFra21-1, Ferritin, Galectin-3, Hs-CRP and TIMP-1

Marker		References
AFP	Tumor marker in hepatocellular carcinoma and embryonal testicular tumors. Increased levels in the circulation are associated with cancer deriving from several organs (stomach, pancreas, lung, renal, ovary and colorectal cancer).	[^Citation32,Citation33]
CA19-9	Increased levels in the circulation are associated with CRC.	[^Citation33^–^Citation37]
CEA	Clinically approved for detection of metastatic disease or recurrence and monitoring response to treatment of CRC. Limited sensitivity for screening in asymptomatic individuals.	[^Citation34^–^Citation38]
CyFra21-1	Diagnostic value in differentiating individuals with advanced colorectal adenomas from individuals with no colorectal adenomas or CRC. Indicator of the neoplastic burden induced by carcinogenesis. Increased levels in the circulation are associated with CRC.	[^Citation27,Citation39,Citation40]
Ferritin	Increased levels in the circulation are associated with CRC. Complex interactions; levels in the circulation are positive correlated to cancer-specific processes which could be antagonized by iron-deficiency anemia caused by chronic gastrointestinal bleeding.	[^Citation26,Citation27,Citation37,Citation41,Citation42]
Galectin-3	Increased expression in tumor tissue of CRC and associated with advanced CRC.	[^Citation43]
hs-CRP	Associated with CRC and carcinogenesis in general.	[^Citation27]
TIMP-1	Increased levels in the circulation are associated with CRC.	[^Citation44^–^Citation46]

Abbreviations: AFP, alpha-feto protein; CA19-9, cancer antigen 19–9; CEA, carcino embryogenic antigen; CRC, colorectal cancer; CyFra21-1, cytokeratin fragment 21–1; HRA, high risk adenoma; hs-CRP, high sensitivity C-reactive protein; TIMP-1, tissue inhibitor of metalloproteinases-1.

Table 2 Inclusion and Findings at Colonoscopy in the Endoscopy II Study

	Men	Women	Total	Median Age
Included individuals in Endoscopy II	2243	2455	4698	64 (18–96)
Individuals with CRC	306	206	512
Stage I–II CRC	156	108	264
Stage III–IV CRC	150	97	247
No stage available	–	1	1
Individuals with colorectal adenoma	384	305	689
LRA	168	122	290
● No recurrence at follow-up			249
● Recurrence at follow-up			41
● CRC at follow-up^a			2
HRA	216	183	399
● No recurrence at follow-up			300
● Recurrence at follow-up			99
● CRC at follow-up^a			9

Notes: ^aNumbers of individuals with CRC at follow-up are included in numbers of individuals with recurrence at follow-up.

Abbreviations: CRC, colorectal cancer, LRA, low-risk colorectal adenoma, HRA, high-risk colorectal adenoma.

Figure 1 (A) Sensitivities at specificity=0.90 in univariate analyses of Endpoint 1–3 (including 3a and b) and secondary Endpoint. (B) AUC_ROC in univariate analyses of Endpoint 1–3 (including 3a and 3b) and secondary Endpoint.

Notes: Red: Endpoint 1, Turquise: Endpoint 2, Black: Endpoint 3, Magenta: Endpoint 3a, Green: Endpoint 3b, Blue: Secondary Endpoint.

Abbreviations: AFP, alpha-feto protein; CA19-9, cancer antigen 19–9; CEA, carcino embryogenic antigen; CyFra21-1, cytokeratin fragment 21–1; Hs-CRP, high sensitivity C-reactive protein; TIMP-1, tissue inhibitor of metalloproteinases-1.

Table 3 Results of Multivariate Analyses of Endpoint 1–3 and Secondary Endpoint

	Odds Ratio	Lower CI	Upper CI	p-value	AUCROC	Sensitivity at 70% Specificity	Sensitivity at 80% Specificity	Sensitivity at 90% Specificity
Endpoint 1
CEA	1.17	1.05	1.31	0.003	0.63	0.49	0.33	0.19
Hs-CRP	1.07	1.01	1.13	0.020
Endpoint 2
Ferritin	0.85	0.76	0.94	0.003	0.61	0.41	0.33	0.13
TIMP-1	1.60	1.11	2.32	0.012
Endpoint 3
CA19-9	0.89	0.80	1.00	0.048	0.78	0.70	0.56	0.34
CEA	0.70	0.61	0.80	˂0.001
CyFra21-1	0.60	0.50	0.73	˂0.001
Ferritin	1.34	1.22	1.48	˂0.001
Hs-CRP	0.82	0.75	0.89	˂0.001
TIMP-1	1.94	1.30	2.90	0.001
Endpoint 3a
CEA	0.71	0.61	0.83	˂0.001	0.74	0.64	0.48	0.28
CyFra21-1	0.73	0.59	0.90	0.003
Ferritin	1.43	1.28	1.59	˂0.001
Hs-CRP	0.86	0.78	0.95	0.002
Endpoint 3b
CA19-9	0.78	0.68	0.89	˂0.001	0.80	0.67	0.58	0.39
CEA	0.71	0.60	0.83	˂0.001
CyFra21-1	0.55	0.44	0.67	˂0.001
Secondary Endpoint
AFP	1.10	1.00	1.21	0.048	0.63	0.50	0.37	0.17
CEA	1.20	1.10	1.31	˂0.001
CyFra21-1	0.88	0.80	0.98	0.018
Hs-CRP	1.05	1.01	1.10	0.024

Abbreviations: AFP, alpha-feto protein; CA19-9, cancer antigen 19–9; CEA, carcino embryogenic antigen; CyFra21-1, cytokeratin fragment 21–1; Hs-CRP, high sensitivity C-reactive Protein; TIMP-1, tissue inhibitor of metalloproteinases-1.

Figure 2 Hazard ratios for individual plasma levels of AFP, CA19-9, CEA, CyFra21-1, Ferritin, Galectin-3, hs-CRP and TIMP-1 and adenoma recurrence.

Abbreviations: AFP, alpha-feto protein; CA19-9, cancer antigen 19–9; CEA, carcino embryogenic antigen; CyFra21-1, cytokeratin fragment 21–1; Hs-CRP, high sensitivity C-reactive protein; TIMP-1, tissue inhibitor of metalloproteinases-1.

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