Prognostic values of HE4 expression in patients with cancer: a meta-analysis

Figures & data

Figure 1 Flowchart of the selection of the studies in the meta-analysis.

Table 1 Main characteristics of all studies included in the meta-analysis

Study	Year	Patient source	Number of patients	Tumor types	Method	Sample	Cutoff	Outcome	M/U	HR (95% CI)	Quality
Stiekema et al^Citation7	2017	Netherlands	88	EC	ECLIA	Blood	60 pmol/L for women <40 years, 75 pmol/L for patients between 40 and 60 years of age, and 90 pmol/L for patients >60 years of age	OS	M	7.37 (2.16–25.1)	9
Orsaria et al^Citation14	2016	Italy	105	OC	IHC	Tissue	H-score value >1	OS	M	1.82 (0.81–4)	8
Aarenstrup Karlsen et al^Citation8	2016	Denmark	198	OC	IHC	Tissue	–	OS	U	1.44 (1.01–2.0)	8
								PFS		1.49 (1.06–2.11)
Lan et al^Citation15	2015	People’s Republic of China	218	LC	EIA	Blood	20.5 ng/mL	OS	M	3.78 (2.23–7.34)	8
Deng et al^Citation16	2015	People’s Republic of China	65	EC	IHC	Tissue	–	OS	U	2.51 (0.66–9.53)	7
Li et al^Citation17	2015	People’s Republic of China	102	EC	IHC	Tissue	H-score value >2	OS	U	1.85 (0.37–9.28)	6
Lee et al^Citation18	2015	United States of America	53	OC	–	Tissue	–	OS	U	1.72 (0.87–3.46)	6
Lamy et al^Citation9	2015	France	346	LC	EIA	Blood	140 pm	OS	U	1.96 (1.53–2.53)	8
Guo et al^Citation19	2015	United States of America	243	GC	IHC	Tissue	H-score value >1	OS	U	1.62 (1.00–2.62)	7
Lou et al^Citation20	2014	United States of America	153	LC	EIA	Blood	65–83 pm	OS	U	1.08 (0.87–1.36)	6
								PFS		0.95 (0.78–1.17)
Jiang et al^Citation21	2014	People’s Republic of China	100	LC	EIA	Blood	7.26 ng/mL	OS	M	3.65 (2.75–11.98)	7
Brennan et al^Citation22	2014	Australia	373	EC	CMIA	Blood	H-score >75%	DFS	M	2.40 (1.19–4.38)	9
Zhang et al^Citation23	2014	People’s Republic of China	191	LC	EIA	Blood	91.63 pmol/L	OS	M	2.15 (1.49–3.12)	7
Braicu et al^Citation24	2014	Germany	73	OC	ECLIA	Blood	250 pm	OS	U	3.33 (1.03–10.7)	6
Zheng et al^Citation25	2013	People’s Republic of China	112	OC	EIA	Blood	415.5 pmol/L	OS	U	2.17 (1.11–4.23)	8
Liu et al^Citation26	2013	People’s Republic of China	169	LC	EIA	Blood	83.90 pm	OS	M	2.2 (0.8–5.9)	7
Zanotti et al^Citation27	2012	Italy	190	EC	CMIA	Blood	51 pm	OS	M	2.78 (1.16–6.63)	9
								DFS		2.49 (1.13–5.49)
								PFS		2.66 (1.10–6.45)
Yamashita et al^Citation28	2012	Japan	74	LC	EIA	Blood	50.3 pm	DFS	U	3.28 (0.57–18.84)	7
Trudel et al^Citation29	2012	Canada	136	OC	CMIA	Blood	394 pmol/L	OS	M	1.67 (1.08–2.59)	9
								PFS		1.32 (0.87–1.99)
Mutz-Dehbalaie et al^Citation30	2012	Austria	183	EC	CMIA	Blood	81 pmol/L	OS	M	2.41 (1.17–4.97)	8
								DFS		1.59 (0.82–3.08)
Kong et al^Citation31	2012	Korea	80	OC	EIA	Blood	98.7 pm	PFS	M	1.47 (1.02–2.1)	8
Kalapotharakos et al^Citation32	2012	Sweden	312	OC	EIA	Blood	405 pm	OS	M	2.02 (1.1–3.8)	9
Hu et al^Citation33	2012	People’s Republic of China	76	OC	EIA	Blood	208 pmol/L	PFS	U	1.72 (0.92–3.21)	6
Steffensen et al^Citation34	2011	Denmark	139	OC	EIA	Blood	140 pm	OS	M	3.17 (1.41–7.10)	9
								PFS		1.77 (1.03–3.04)
Yamashita et al^Citation35	2011	Japan	137	LC	IHC	Tissue	H-score >75%	OS	M	5.5 (1.8–17.2)	8
								DFS		3.7 (1.7–8.4)
Paek et al^Citation36	2011	Korea	45	OC	EIA	Blood	70 pm	PFS	M	2.24 (1.14–6.84)	8
Han et al^Citation37	2011	United States of America	23	OC	EIA	Blood	74 pm	PFS	U	1.97 (0.61–6.39)	7
Bignotti et al^Citation38	2011	Italy	153	EC	EIA	Blood	–	OS	U	3.74 (0.43–32.45)	8
								PFS		1.78 (0.30–10.44)
								DFS		2.43 (0.87–6.77)
Bandiera et al^Citation39	2011	Italy	98	OC	CMIA	Blood	43.8 pm	OS	M	3.98 (1.35–11.75)	8
								DFS		2.46 (1.09–5.56)
								PFS		2.77 (1.12–6.85)

Abbreviations: M, multivariate analysis; U, univariate analysis; HR, hazard ratio; EC, endometrial cancer; OC, ovarian cancer; LC, lung cancer; GC, gastric cancer; ECLIA, electrochemiluminescence immunoassay assay; IHC, immunohistochemistry; EIA, enzyme immunoassay assay; CMIA, chemiluminescent microparticle immunoassay; OS, overall survival; DFS, disease-free survival; PFS, progression-free survival.

Table 2 Main meta-analysis results for OS

Analysis	Number of studies	Number of patients	Model	HR (95% CI)	P-value	Heterogeneity
						I^2 (%)	P-value
OS	23	3,564	Random	2.15 (1.77–2.62)	0.000	55.6	0.001
Race
White	15	2,470	Random	1.92 (1.53–2.39)	0.000	55.9	0.004
Asian	8	1,094	Fixed	2.62 (2.06–3.35)	0.000	0.0	0.587
Tumor types
EC	6	781	Fixed	2.91 (1.86–4.53)	0.000	0.0	0.719
OC	9	1,226	Fixed	1.82 (1.50–2.22)	0.000	0.0	0.515
LC	7	1,314	Random	2.31 (1.54–3.47)	0.000	82.4	0.000
GC	1	243	–	1.62 (1.00–2.62)	–	–	–
Sample
Blood	16	2,661	Random	2.34 (1.82–3.02)	0.000	65.7	0.000
Tissue	7	903	Fixed	1.67 (1.32–2.11)	0.000	0.0	0.488
Method
ECLIA	2	161	Fixed	4.86 (2.09–11.34)	0.000	0.0	0.358
IHC	6	850	Fixed	1.66 (1.30–2.13)	0.000	8.1	0.365
EIA	10	1,893	Random	2.20 (1.61–3.01)	0.000	73.1	0.000
CMIA	4	607	Fixed	2.10 (1.51–2.91)	0.000	0.0	0.402
HR estimate
Multivariate analysis	13	2,066	Fixed	2.47 (2.05–2.97)	0.000	13.4	0.310
Univariate analysis	10	1,498	Fixed	1.50 (1.31–1.71)	0.000	47.8	0.045

Abbreviations: HR, hazard ratio; OS, overall survival; EC, endometrial cancer; OC, ovarian cancer; LC, lung cancer; GC, gastric cancer; ECLIA, electrochemiluminescence immunoassay assay; IHC, immunohistochemistry; EIA, enzyme immunoassay assay; CMIA, chemiluminescent microparticle immunoassay.

Figure 2 Forest plot of hazard ratio for the association of HE4 expression and overall survival.

Figure 3 Sensitivity analysis of pooled HRs on the association between HE4 expression and overall survival.

Figure 4 Forest plot of hazard ratio for the association of HE4 expression and disease-free survival.

Figure 5 Forest plot of hazard ratio for the association of HE4 expression and progression-free survival.

Figure 6 Funnel plots of publication bias for all of the included studies reported with overall survival.

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