Role of Serum CYFRA 21-1 in Diagnosis and Prognostic in Colorectal Liver Metastases

Figures & data

Figure 1 Study design and workflow diagram.

Table 1 Basic Characteristics of CRC Patients with Stage I–III and CRLM

Parameters	All CRC Patients	CRC Patients with Stage I–III	CRLM Patients	p-value(I–III VS CRLM)
Sex(n)
Female	96	81	15
Male	150	115	35	0.14
Age(years)	60(51, 67)	60(52, 67)	57.5(47.75, 68)	0.34
Location of primary tumor(n)
Colon	114	86	28
Rectum	128	108	20
Rectum&colon	4	2	2	0.075
CEA (ng/mL)	4.36(2.19, 15.40)	3.80(2.03, 11.54)	19.54(5.00, 291.68)	<0.001
CA19-9 (U/mL)	7.15(3.18, 26.25)	6.25(2.83, 14.20)	57.15(8.33, 404.73)	<0.001
HSP90α (ng/mL)	46.60(30.79, 70.53)	43.90(29.36, 61.85)	60.35(34.82, 125.25)	0.002
AFP (ng/mL)	2.57(1.90, 3.38)	2.60(1.87, 3.37)	2.51(1.97, 3.45)	0.579
CYFRA 21-1 (ng/mL)	2.47(1.77, 4.07)	2.29(1.66, 3.08)	5.85(3.95, 19.50)	<0.001
Lymphatic invasion(n)
Ly 0	97	92	5
Ly1, 2, 3	149	104	45	<0.001
Stage(n)
I	23	23	0
II	62	62	0
III	111	111	0
IV	50	0	50	-

Notes: The Mann–Whitney U-test or Student’s t-test was used to compare continuous variables between CRC patients with stage I–III and CRLM patients. The Chi square test was used to compare categorical variable between the two groups.

Figure 2 The distribution of serum CYFRA 21-1 and CA19-9, CEA, HSP90α, AFP levels in CRC patients with stages I–III and CRLM. (A) CYFRA 21-1 levels (p <0.001); (B) CA19-9 levels (p <0.001); (C) CEA levels (p <0.001); (D) HSP90α levels (p <0.001); (E) AFP levels (p =0.279).

Table 2 Association of Pre-Treatment CYFRA21-1 Levels with Clinicopathological Features in CRC Patients and Their Subgroups

Parameters	All CRC Patients			CRC Patients with Stage I–III			CRLM Patients
	Median	r	p	Median	r	p	Median	r	p
Sex
Female	2.29(1.62, 3.74)			2.05(1.58, 2.93)			6.88(4.27, 19.86)
Male	2.59(1.99, 4.17)	−0.112	0.08	2.35(1.83, 3.29)	−0.115	0.108	4.99(3.70, 19.38)	0.071	0.624
Age
≤60	2.45(1.60, 4.35)			2.06(1.51, 3.22)			6.95(3.51, 24.34)
>60	2.51(2.02, 3.80)	0.062	0.331	2.33(1.99, 3.03)	0.128	0.074	5.15(4.09, 13.77)	−0.125	0.388
Tumor locations
Colon	2.70(1.87, 4.99)			2.32(1.61, 3.29)			6.47(4.09, 19.68)
Rectum	2.31(1.71, 3.51)			2.25(1.67, 2.86)			4.70(2.61, 10.08)
Colon&Rectum	15.85(2.71, 63.52)	0.144	0.024	2.80(2.62,-)	0.047	0.515	51.93(28.73,-)	0.282	0.047
Lymphatic invasion
Ly 0	2.24(1.67, 3.16)			2.22(1.65, 2.99)			7.63(2.11, 17.30)
Ly 1,2,3	2.77(1.89, 4.83)	0.162	0.011	2.31(1.66, 3.18)	0.011	0.875	5.65(4.10, 19.73)	0.039	0.787
Stage
I–III	2.29(1.66, 3.08)			2.29(1.66, 3.08)			-
IV	5.85(3.95, 19.50)	0.369	<0.001	-	-	-	5.85(3.95, 19.50)	-	-

Notes: Pearson correlation analysis was used to analyze two continuous variables, and Spearman correlation analysis was used if one of them was a categorical variable. Bold values indicate statistical significance (p<0.05).

Table 3 Association of Pre-Treatment CYFRA21-1 Levels with Other Markers in CRC Patients and Their Subgroups

Parameters	All CRC Patients		CRC Patients with Stage I–III		CRLM Patients
	r	p	r	p	r	p
Pre-treatment CEA	0.366	<0.001	−0.009	0.905	0.259	0.069
Pre-treatment CA19-9	0.452	<0.001	0.015	0.83	0.404	0.004
Pre-treatment HSP90α	0.620	<0.001	−0.068	0.349	0.722	<0.001
Pre-treatment AFP	0.106	0.099	0.032	0.663	0.147	0.307

Notes: Pearson correlation analysis was used to analyze two continuous variables, and Spearman correlation analysis was used if one of them was a categorical variable. Bold values indicate statistical significance (p<0.05).

Figure 3 Receiver operating characteristic (ROC) curves of CYFRA 21-1, CA19-9, CEA, HSP90α, AFP and combined indexes detection (CYFRA 21-1+ CA19-9+ CEA) showed their discriminative power between patients with stage I–III and CRLM.

Figure 4 Kaplan–Meier survival curves of overall survival(OS) and progression-free survival(PFS) according to serum CYFRA 21-1 level in different groups. (A) All CRC patients’ overall survival(OS); (B) All CRC patients’ progression-free survival (PFS); (C) The overall survival(OS) of CRC patients with stage I–III; (D) The progression-free survival(PFS) of CRC patients with stage I–III; (E) The overall survival(OS) of CRC patients with CRLM; (F) The progression-free survival(PFS) of CRC patients with CRLM.

Figure 5 Receiver operating characteristic (ROC) curves were used to analyze overall patient survival(OS) at the 12-, 24-, 36-, and 48-month follow-up periods. The areas under the ROC curve (AUCs) assessed the discriminative ability of serum CYFRA 21-1 in all CRC patients (A), in stage I–III colorectal cancer patients (B), and in colorectal liver metastasis (CRLM) patients (C).

Figure 6 Receiver operating characteristic (ROC) curves were used to analyze patient progression-free survival (PFS) at the 12-, 24-, 36-, and 48-month follow-up periods. The areas under the ROC curve (AUCs) assessed the discriminative ability of serum CYFRA 21-1 in all CRC patients (A), in stage I–III colorectal cancer patients (B), and in colorectal liver metastasis (CRLM) patients (C).

Table 4 The Correlations between OS, PFS, and various Clinicopathological Factors in CRLM Patients

	Univariate Analysis				Multivariate Analysis
	OS		PFS		OS		PFS
	HR (95% CI)	p-value	HR (95% CI)	p-value	HR (95% CI)	p-value	HR (95% CI)	p-value
Sex(female vs male)	1.217(0.613–2.415)	0.575	1.111(0.574–2.147)	0.755
Age (≤60 vs >60)	2.744(1.409–5.345)	0.003	1.923(1.026–3.605)	0.041	3.304(1.653–6.605)	0.001	2.154(1.134–4.093)	0.019
Location of the primary tumor (colon vs rectum vs rectumandcolon)	1.095(0.957–1.254)	0.187	1.038(0.907–1.188)	0.588
Lymphatic invasion (ly 0 vs ly1, 2, 3)	1.585(0.486–5.161)	0.445	1.492(0.528–4.213)	0.450
Pre-treatment CEA (≤5 ng/mL vs >5 ng/mL)	1.094(0.501–2.389)	0.822	0.897(0.439–1.833)	0.766
Pretreatment CA19-9 (≤37 U/mL vs >37 U/mL)	1.727(0. 0.891–3.347)	0.106	1.466(0.782–2.751)	0.233
Pretreatment HSP90α(≤82ng/mL vs >82 ng/mL)	0.930(0.475–1.822)	0.832	1.104(0.584–2.088)	0.760
Pretreatment AFP (≤8.78ng/mL vs >8.78 ng/mL)	0.045(0–62.998)	0.402	0.045(0–34.785)	0.361
Pretreatment CYFRA 21-1 (≤7.63ng/mL vs >7.63 ng/mL)	2.128(1.108–4.088)	0.023	1.786(0.952–3.350)	0.071	2.701(1.361–5.362)	0.004	2.038(1.069–3.883)	0.031

Note: Bold values indicate statistical significance (p<0.05).

Table 5 The Correlations between OS, PFS, and various Clinicopathological Factors in Stage I–III CRC Patients

	Univariate Analysis				Multivariate Analysis
	OS		PFS		OS		PFS
	HR (95% CI)	p-value	HR (95% CI)	p-value	HR (95% CI)	p-value	HR (95% CI)	p-value
Sex(female vs male)	0.560(0.217–1.443)	0.230	0.794(0.402–1.569)	0.507
Age (≤60 vs >60)	1.123(0.477–2.646)	0.790	0.908(0.472–1.747)	0.772
Location of the primary tumor (colon vs rectum vs rectumandcolon)	1.023(0.735–1.424)	0.893	0.909(0.612–1.348)	0.634
Lymphatic invasion (ly 0 vs ly1, 2, 3)	1.872(0.755–4.642)	0.176	2.167(1.066–4.406)	0.033			1.399(0.364–5.369)	0.625
Pre-treatment CEA (≤5 ng/mL vs >5 ng/mL)	4.338(1.681–11.193)	0.002	2.245(1.163–4.335)	0.016	3.660(1.363–9.825)	0.010	2.066(1.053–4.055)	0.035
Pretreatment CA19-9 (≤37 U/mL vs >37 U/mL)	3.434(1.331–8.858)	0.011	1.842(0.765–4.433)	0.173	2.137(0.797–5.734)	0.131
Pretreatment HSP90α(≤82ng/mL vs >82 ng/mL)	1.133(0.334–3.847)	0.841	1.072(0.417–2.758)	0.886
Pretreatment AFP (≤8.78ng/mL vs >8.78 ng/mL)	0.049(0–2.195E+10)	0.826	0.049(0–20833779.62)	0.766
Pretreatment CYFRA 21-1 (OS:≤2.14ng/mL vs >2.14 ng/mL, PFS: ≤2.56ng/mL vs >2.56 ng/mL)	1.925(0.747–4.961)	0.175	1.797(0.653–4.947)	0.022			2.167(1.121–4.188)	0.021
Stage (I, II vs III)	1.561(0.630–3.869)	0.336	2.072(0.999–4.298)	0.050			1.366(0.348–5.358)	0.655

Note: Bold values indicate statistical significance (p<0.05).

Figure 7 Nomograms of CRC prognosis. (A) The prognostic nomogram for overall survival (OS) based on the prognostic scores of CYFRA 21-1, lymphatic invasion(LYM) and CA19-9 in all CRC patients. (B) The prognostic nomogram for progression-free survival (PFS) based on the prognostic scores of CYFRA 21-1, lymphatic invasion(LYM) and CA19-9 in all CRC patients. (C) The prognostic nomogram for overall survival (OS) based on the prognostic scores of CYFRA 21-1 and CEA in the stage I–III CRC cohort. (D) The prognostic nomogram for progression-free survival (PFS) based on the prognostic scores of CYFRA 21-1 and age in the stage I–III CRC cohort. (E) The prognostic nomogram for overall survival (OS) based on the prognostic scores of CYFRA 21-1 and age in the CRLM cohort. (F) The prognostic nomogram for progression-free survival (PFS) based on the prognostic scores of CYFRA 21-1 and age in the CRLM cohort.

Data Sharing Statement

The original contributions involved in this study are included in the article/Supplementary Material. Further enquiries can be directed to the corresponding authors.