Preoperative circulating FPR and CCF score are promising biomarkers for predicting clinical outcome of stage II–III colorectal cancer patients

Figures & data

Table 1 Correlations of preoperative circulating Fib, Alb, pre-Alb, AFR, and FPR with clinicopathologic characteristics in 702 CRC patients

Characteristics		Patients grouped by FPR level (n=555)		p-value*	Patients grouped by AFR level (n=680)		p-value*	Patients grouped by Fib level (n=682)		p-value*	Patients grouped by Alb level (n=700)		p-value*	Patients grouped by pre-Alb level (n=566)		p-value*
		>18.3	≤18.3		>9.2	≤9.2		>3.8 mg/L	≤3.8 mg/L		>33.3 g/L	≤33.3 g/L		>187.4 mg/L	≤187.4 mg/L
Gender	Male	141	209	0.477	345	81	0.144	108	319	0.092	398	41	0.304	202	156	0.001
	Female	89	116		217	37		50	205		230	31		86	122
Age (years)	≤60	148	173	<0.001	270	39	0.003	59	250	0.023	299	14	<0.001	150	107	0.001
	>60	82	152		292	79		99	274		329	58		138	171
Smoking	Yes	39	63	0.505	90	28	0.060	30	88	0.549	112	8	0.187	62	41	0.039
	No	191	262		472	90		128	436		516	64		226	237
Drinking	Yes	25	34	0.890	47	15	0.158	18	44	0.269	60	3	0.189	34	26	0.413
	No	205	291		515	103		140	480		568	69		254	252
Hypertension	Yes	41	60	0.911	117	20	0.379	32	106	1.000	123	19	0.215	59	46	0.236
	No	189	265		445	98		126	418		505	53		229	232
Diabetes	Yes	19	15	0.105	34	12	0.109	17	30	0.047	41	10	0.031	15	22	0.234
	No	211	310		528	106		141	494		587	62		273	256
Chemotherapy	Yes	152	214	1.000	366	87	0.085	118	335	0.012	421	43	0.237	190	182	0.930
	No	78	111		196	31		40	189		207	29		98	96
Tumor grade	G1–G2	209	286	0.332	500	109	0.323	141	470	0.882	101	66	0.687	254	250	0.591
	G3–G4	21	39		62	9		17	54		527	6		34	28
Tumor stage	I	15	60	<0.001	83	7	0.013	10	80	0.007	86	5	0.232	54	21	<0.001
	II	102	142		247	49		68	229		272	36		122	130
	III	113	123		232	62		80	215		270	31		112	127
Depth of invasion	T1–T2	15	73	<0.001	99	7	0.001	10	96	<0.001	101	6	0.086	63	25	<0.001
	T3–T4	215	252		463	111		148	428		527	66		225	253
Lymph node status	N0	117	202	0.009	330	56	0.032	78	309	<0.001	358	41	1.000	176	151	0.107
	N1–N2	113	123		232	62		80	215		270	31		112	127
Tumor size (cm)	≤5	111	251	<0.001	391	40	<0.001	61	371	<0.001	411	30	<0.001	219	148	<0.001
	>5	119	74		171	78		97	153		217	42		69	130
CA199 (U/mL)	≤37	174	270	0.006	443	88	0.592	120	411	0.761	495	43	<0.001	243	207	0.009
	>37	40	37		73	18		24	68		83	10		28	50
	NA	16	18		46	12		14	45		50	19		17	21
CEA (ng/mL)	≤5	128	228	0.002	355	62	0.002	87	330	0.182	393	31	<0.001	206	155	<0.001
	>5	86	81		163	44		57	151		187	22		67	102
	NA	16	16		44	12		14	43		48	19		15	21
OS	Alive	176	290	<0.001	477	87	0.005	118	448	0.002	526	51	0.009	258	217	<0.001
	Dead	54	35		85	31		40	76		102	21		30	61

Notes:

* Difference between groups was tested by chi-square test. p-value <0.05 shown in bold.

Abbreviations: AFR, albumin-to-fibrinogen ratio; Alb, albumin; CA199, carbohydrate antigen 19-9; CEA, carcinoembryonic antigen; CRC, colorectal cancer; Fib, fibrinogen; FPR, fibrinogen-to-pre-albumin ratio; NA, not available; OS, overall survival.

Figure 1 The optimal cutoff value of preoperative circulating FPR in 702 CRC patients using X-tile software.

Notes: The data are represented graphically in a right-triangular grid where the point represents the data from a given set of divisions (A). The plots showed the χ² log-rank values produced, dividing them into three groups by the cutoff points 18.3 and 30.2. The optimal cutoff point, 18.3, was determined by locating the brightest pixel on the X-tile plot. The distribution of number of patients is shown on the histogram (B) and the corresponding populations are displayed on the Kaplan–Meier curve (C). Larger low population= larger population with low FPR level; larger high population= larger population with high FPR level.

Abbreviations: CRC, colorectal cancer; FPR, fibrinogen-to-pre-albumin ratio.

Figure 2 The correlation of FPR with clinical characteristics and comparison of FPR in nonrelapse and recurrent CRC patients.

Notes: (A) FPR with depth of invasion; (B) FPR with lymph node; (C) FPR with tumor grade; (D) FPR with tumor size; (E) FPR with tumor stage; (F) comparison of FPR in nonrelapse and recurrent CRC patients. *p<0.05, **p<0.01, ***p<0.001.

Abbreviations: CRC, colorectal cancer; FPR, fibrinogen-to-pre-albumin ratio; NS, no significance.

Table 2 Univariate and multivariate analyses of prognostic factors for 3-year overall survival by Cox regression model

Variables	Overall survival
	Univariate cox regression		Multivariate cox regression
	Crude HR (95% CI)	p-value	Adjusted HR (95% CI)	p-value
Sex (female)	0.880 (0.606–1.277)	0.501	–	–
Age (>60 years)	1.223 (0.851–2.805)	0.277	–	–
Alcohol (yes)	1.186 (0.654–2.152)	0.575	–	–
Tobacco (yes)	0.995 (0.622–1.591)	0.982	–	–
Hypertension (yes)	0.878 (0.558–1.382)	0.575	–	–
Diabetes (yes)	1.115 (0.584–2.130)	0.741	–	–
Chemotherapy (yes)	0.882 (0.611–1.274)	0.504	–	–
Tumor grade (G3–G4)	1.867 (1.145–3.046)	0.012	1.718 (1.052–2.805)	0.030
Tumor stage (III)	3.834 (1.567–9.381)	0.003	3.368 (1.370–8.280)	0.008
Depth of invasion (T3-T4)	3.792 (1.669–8.614)	0.001	2.792 (1.208–6.452)	0.016
lymph node (N1–N3)	1.934 (1.354–2.762)	<0.001	1.888 (1.322–2.698)	<0.001
Tumor size (>5 cm)	1.979 (1.389–2.819)	<0.001	1.905 (1.336–2.715)	0.001
CEA (>5 ng/mL)	2.961 (2.019–4.342)	<0.001	2.719 (1.850–3.996)	<0.001
CA199 (>37 U/mL)	2.916 (1.934–4.398)	<0.001	2.605 (1.683–4.033)	<0.001
Fib (>3.8 mg/dL)	1.913 (1.304–2.806)	0.001	1.450 (0.961–2.188)	0.077
Alb (>33.3 g/L)	0.504 (0.315–0.806)	0.004	0.564 (0.349–0.912)	0.020
pre-Alb (>187.4 mg/L)	0.444 (0.287–0.687)	<0.001	0.520 (0.329–0.823)	0.005
AFR (>9.2)	0.531 (0.352–0.801)	0.003	0.709 (0.455–1.107)	0.130
FPR (>18.3)	2.398 (1.567–3.669)	<0.001	1.940 (1.236–3.046)	0.004

Notes: Adjusted HR (95%) was adjusted by sex, age, alcohol, tobacco, hypertension, diabetes, chemotherapy, tumor size, tumor grade, and tumor stage. The endash represent that these variables were not included in the multivariate cox regression. p-value <0.05 shown in bold.

Abbreviations: AFR, albumin/fibrinogen ratio; Alb, albumin; pre-Alb, pre-albumin; CA199, carbohydrate antigen 19-9; CEA, carcinoembryonic antigen; Fib, fibrinogen; FPR, fibrinogen-to-pre-albumin ratio; HR, hazard ratio.

Figure 3 Kaplan–Meier curves of FPR, AFR, Fib, Alb, and pre-Alb for 3 years’ OS in 702 CRC patients.

Notes: (A) Alb; (B) pre-Alb; (C) Fib; (D) AFR; (E) FPR; (F) CCI; (G) CFI; (H) CCF. Time-dependent receiver operating characteristic analysis of preoperative circulating FPR, Alb, pre-Alb, CA199, and CEA for clinical outcome of 702 CRC patients (I).

Abbreviations: AFR, albumin-to-fibrinogen ratio; Alb, albumin; pre-Alb, pre-albumin; CA199, carbohydrate antigen 19-9; CCF, CEA-CA199-FPR; CCI, CEA-CA199; CEA, carcinoembryonic antigen; CFI, CEA-FPR; CRC, colorectal cancer; Fib, fibrinogen; FPR, fibrinogen-to-pre-albumin ratio; HR, hazard ratio; OS, overall survival.

Figure 4 The HRs of CCI, CFI, and CCF scores in CRC patients.

Notes: (A) The crude and adjusted HRs of CCI and CFI score; (B) The crude and adjusted HRs of CCF score.

Abbreviations: CCF, CEA-CA199-FPR; CCI, CEA-CA199; CA199, carbohydrate antigen 19-9; CEA, carcinoembryonic antigen; CFI, CEA-FPR; CRC, colorectal cancer; HR, hazard ratio; FPR, fibrinogen-to-pre-albumin ratio.

Figure 5 Kaplan–Meier curves of stage II–III CRC patients with or without treatment of chemotherapy in each subgroup stratified by FPR, CFI, and CCF.

Notes: (A) FPR≤18.3; (B) FPR>18.3; (C) CFI=0; (D) CFI≥1; (E) CCF=0; (F) CCF≥1.

Abbreviations: CCF, CEA-CA199-FPR; CFI, CEA-FPR; CRC, colorectal cancer; FPR, fibrinogen-to-pre-albumin ratio; OS, overall survival.

Figure 6 Prognostic nomograms with or without CCF score for predicting 3-year OS in CRC patients.

Notes: (A) Nomogram without CCF; (B) Nomogram including CCF.

Abbreviations: CCF, CEA-CA199-FPR; CRC, colorectal cancer; FPR, fibrinogen-to-pre-albumin ratio; OS, overall survival.