Prognostic and predictive values of PD-L1 expression in patients with digestive system cancer: a meta-analysis

Figures & data

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

Abbreviation: ELISA, enzyme-linked immunoabsorbent assay.

Table 1 Characteristics of included studies for meta-analyses

First author	Year	Patient source	No of patients	Tumor types	Specimen	Method	PD-L1 expression (%)	Median (range) follow-up (months)	Outcome	M/U	HR (95% CI)	NOS score
Dunne et al^Citation22	2016	UK	424	CRC	Tissue	IHC	19.8	–	RFS	M	0.76 (0.39–1.45)	7
Wang et al^Citation20	2016	China	262	CRC	Tissue	IHC	20.6	43.5 (21–68)	OS	M	1.90 (0.88–4.14)	7
Yuan et al^Citation18	2016	China	165	GC	Tissue	IHC	33.9	63.1	OS	U	1.15 (0.80–1.67)	6
Dong et al^Citation23	2016	China	547	GC	Tissue	IHC	84.8	–	OS	U	0.74 (0.49–1.10)	7
Böger et al^Citation26	2016	Germany	465	GC	Tissue	IHC	23.9	20.7 (0.2–109)	OS	M	0.75 (0.58–0.97)	9
Wang et al^Citation19	2016	China	105	GC	Tissue	IHC	49.5	42	OS	U	1.93 (1.12–3.32)	8
Chen et al^Citation25	2016	China	536	EC	Tissue	IHC	41.4	32.7 (1.0–88.7)	OS; DFS	M	0.83 (0.59–1.18); 0.80 (0.55–1.17)	9
Chen et al^Citation24	2016	China	162	EC	Tissue	IHC	45	–	OS	U	3.90 (2.51–6.05)	8
Leng et al^Citation21	2016	China	106	EC	Tissue	IHC	53.8	55	OS	U	1.39 (0.65–2.99)	7
Lim et al^Citation31	2015	Korea	83	Bile duct cancer	Tissue	IHC	68	27–69	DFS	M	0.55 (0.27–1.12)	7
Lim et al^Citation32	2015	Korea	73	EC	Tissue	IHC	56.2	–	OS; DFS	M	2.29 (1.12–4.69); 1.46 (0.75–2.84)	7
Tamura et al^Citation29	2015	Japan	431	GC	Tissue	IHC	29.7	34	OS	M	1.50 (1.02–2.19)	6
Zhang et al^Citation27	2015	China	132	GC	Tissue	IHC	50.8	66.0 (3.0–153.0)	OS	M	2.70 (1.47–4.95)	8
Qing et al^Citation30	2015	China	107	GC	Tissue	IHC	50.5	42	OS	U	2.01 (1.09–3.70)	7
Eto et al^Citation35	2015	Japan	105	GC	Tissue	IHC	24.8	34 (7–87)	OS; DFS	U	2.26 (0.61–8.33); 1.88 (0.95–3.71)	7
Geng et al^Citation34	2015	China	100	GC	Tissue	IHC	65	>60	OS	M	2.12 (1.59–2.34)	8
Kan and Dong^Citation33	2015	China	128	HC	Tissue	IHC	82.03	10	OS	U	2.12 (1.32–3.38)	7
Umemoto et al^Citation28	2015	Japan	80	HC	Tissue	IHC	46.3	80	OS; RFS	U	1.27 (0.54–3.01); 1.45 (0.80–2.63)	8
Kim et al^Citation37	2014	Korea	243	GC	Tissue	IHC	56.4	74 (0–123)	OS; DFS	M	0.65 (0.42–1.02); 0.58 (0.37–0.91)	9
Hou et al^Citation38	2014	China	111	GC	Tissue	IHC	63.1	7–48	OS	U	1.47 (0.60–3.57)	9
Liang et al^Citation36	2014	China	185	CRC	Tissue	IHC	55.1	60	OS; DFS	U	0.58 (0.37–0.84); 0.55 (0.36–0.82)	8
Song et al^Citation39	2013	China	347	CRC	Tissue	IHC	–	32.4 (1.2–109.2)	OS	M	1.17 (0.70–1.98)	7
Droeser et al^Citation41	2013	Switzerland	1,420	CRC	Tissue	IHC	37	–	OS	M	0.92 (0.88–0.96)	6
Shi et al^Citation40	2013	China	143	CRC	Tissue	IHC	44.8	–	OS	U	2.61 (1.01–3.58)	8
Loos et al^Citation43	2011	Germany	101	Barrett carcinoma	Tissue	IHC	36.6	75 (7–209)	OS; DFS	U	2.92 (1.50–5.66); 2.99 (1.61–5.64)	8
Zeng et al^Citation42	2011	China	141	HC	Tissue	IHC	51.8	23 (6–36)	OS	M	0.37 (0.19–0.77)	7
Wang et al^Citation44	2010	China	81	PC	Tissue	IHC	49.4	24 (8–39)	OS	U	2.56 (1.44–4.56)	6
Gao et al^Citation45	2009	China	240	HC	Tissue	IHC	25	–	OS; DFS	U	0.62 (0.40–0.96); 0.56 (0.37–0.85)	8
Chen et al^Citation46	2009	China	40	PC	Tissue	IHC	45	58.5 (5–122)	OS; RFS	M	3.23 (1.34–7.80); 4.33 (1.53–12.28)	7
Nomi et al^Citation48	2007	Japan	51	PC	Tissue	IHC	39.2	22 (3–91)	OS	U	2.44 (1.22–4.89)	6
Sun et al^Citation47	2007	China	92	GC	Tissue	IHC	46.7	6–31	OS	U	2.10 (1.09–4.05)	7
Wu et al^Citation49	2006	China	102	GC	Tissue	IHC	42.2	42	OS	U	2.06 (0.99–4.28)	6

Abbreviations: CI, confidence interval; CRC, colorectal cancer; DFS, disease-free survival; EC, esophageal carcinoma; GC, gastric cancer; HC, hepatocellular carcinoma; HR, hazard ratio; IHC, immunohistochemistry; M, multivariate; NOS, Newcastle–Ottawa Scale; OS, overall survival; PC, pancreatic carcinoma; RFS, recurrence-free survival; U, univariate.

Figure 2 Forest plot of HR for the association of PD-L1 overexpression and OS.

Note: Weights are from random-effects analysis.
Abbreviations: CI, confidence interval; HR, hazard ratio; OS, overall survival.

Table 2 Main meta-analysis results for OS

Analysis	No of studies	No of patients	Model	HR (95% CI)	P-value	Heterogeneity
						I^2 (%)	P-value
OS	30	6,801	Random	1.44 (1.18–1.76)	0.000	87.8	0.000
Ethnicity
Asian	27	4,815	Random	1.50 (1.19–1.89)	0.001	82.0	0.000
Non-Asian	3	1,98	Random	1.07 (0.72–1.58)	0.740	85.7	0.001
Tumor types
CRC	5	2,357	Random	1.15 (0.76–1.72)	0.511	79.7	0.001
GC	13	2,705	Random	1.43 (1.05–1.94)	0.021	83.6	0.000
EC	5	978	Random	1.96 (0.97–3.97)	0.061	88.1	0.000
HC	4	589	Random	0.89 (0.40–1.97)	0.776	86.5	0.000
PC	3	172	Fixed	2.64 (1.78–3.93)	0.00	0.0	0.878
HR estimate
Multivariate analysis	12	4,190	Random	1.22 (0.92–1.63)	0.171	90.5	0.000
Univariate analysis	18	2,611	Random	1.64 (1.21–2.23)	0.001	80.4	0.000

Note: Bold means that there was significant association between PD-L1 expression and the items of “Analysis”.

Abbreviations: CI, confidence interval; CRC, colorectal cancer; EC, esophageal carcinoma; GC, gastric cancer; HC, hepatocellular carcinoma; HR, hazard ratio; OS, overall survival; PC, pancreatic carcinoma.

Figure 3 Forest plot of HR for the association of PD-L1 overexpression and RFS.

Note: Weights are from random-effects analysis.
Abbreviations: CI, confidence interval; HR, hazard ratio; RFS, recurrence-free survival.

Figure 4 Forest plot of HR for the association of PD-L1 overexpression and DFS.

Note: Weights are from random-effects analysis.
Abbreviations: CI, confidence interval; DFS, disease-free survival; HR, hazard ratio.

Table 3 Main meta-analysis results for DFS

Analysis	No of studies	No of patients	Model	HR (95% CI)	P-value	Heterogeneity
						I^2 (%)	P-value
DFS	8	1,566	Random	0.91 (0.61–1.37)	0.657	80.1	0.000
Ethnicity
Asian	7	1,465	Random	0.76 (0.56–1.05)	0.094	64.2	0.010
Non-Asian	1	101	–	0.97 (0.62–1.52)	0.001	–	–
Tumor types
GC	2	348	Random	1.01 (0.32–3.21)	0.981	87.5	0.005
EC	3	710	Random	1.47 (0.66–3.30)	0.346	84.5	0.002
HR estimate
Multivariate analysis	4	935	Fixed	0.75 (0.59–0.97)	0.026	49.5	0.115
Univariate analysis	4	631	Random	1.11 (0.50–2.46)	0.805	89.6	0.000

Note: Bold means that there was significant association between PD-L1 expression and the items of “Analysis”.

Abbreviations: CI, confidence interval; DFS, disease-free survival; EC, esophageal carcinoma; GC, gastric cancer; HR, hazard ratio.

Figure 5 Sensitivity analysis of pooled HRs on the association between PD-L1 expression and OS.

Abbreviations: CI, confidence interval; HR, hazard ratio; OS, overall survival.

Table 4 Meta-regression analyses of potential source of heterogeneity

Heterogeneity factors	Coefficient	SE	Z	P-value	95% CI
					LL	UL
Publication year	−0.024	0.038	−0.63	0.536	−0.102	0.054
Ethnicity	−0.246	0.351	−0.70	0.489	−0.966	0.473
Number of patients	−0.001	0.000	−2.33	0.028	−0.002	−0.000
Tumor types	0.089	0.094	0.94	0.353	−1.039	0.282
PD-L1 expression	0.001	0.008	0.08	0.938	−0.015	0.016

Abbreviations: CI, confidence interval; LL, lower limit; SE, standard error; UL, upper limit.

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

Abbreviations: HR, hazard ratio; OS, overall survival; SE, standard error.

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