High hypoxia inducible factor-1α expression is associated with reduced survival in patients with breast cancer: A meta-analysis

Table 1 Characteristics of included studies on prognostic impact of hypoxia-inducible factor 1α on survival in breast carcinoma patients

Ref.	Recruitment period	Study design	Sample size	Age median mean year (range)	Histological grading, and TNM staging	Percentage of grading and staging	Molecular typing	N of HIFα positive (%), cut-off, and antibody	Survival endpoint (months)	Hazard ratio, 95%CI and P value	HR estimation	Follow-up months (range)
El-Guindy et al[17], 2023, Egypt	June 2019-June 2022	Prospective	60	47.5	G2: 24, G3: 36; NA	G1/G2: 40%; I/II: NA	TNBC	28 (46.6); ≥ 10%; EP1215Y	OS	(M) 7.56 (1.21-47.24), 0.03	Reported	24
Jögi et al[26], 2019, Sweden	1977-2007	NA	634 of 688 (BC2)	NA	NA; I: 273, II: 1 59, III: 83, Unknow: 119	G1/G2: NA; I/II: 82.6%	NA	111 (17.3); ≥ 1%; BD610959	OS	(U) 1.6 (1.2-2.2), 0.001	Reported	NA
										(M) 1.6 (1.0-2.5), 0.03
Laurinaviciu et al[31], 2015, Lithuania	1977-2007	NA	107	NA	G1: 25, G2: 51, G3: 31	G1/G2: 71%; I/II: NA	Luminal A: 60, luminal B: 29, HER2 +: 28	NA; score 14; EP1215Y	OS	(M) 0.23 (0.08-0.62), 0.002	Reported	84
Li et al[48], 2016, China	2005-2009	NA	156	50	G1: 32, G2: 78, G3: 46; I: 23, II: 60, III: 48, IV: 25	G1/G2: 70%; I/II: 53%	NA	83 (53.3); score 6; ab82832	OS	(U) 2.07 (1.58-2.71), < 0.001	(U) Survival curve (M) reported	60
										(M) 2.37 (1.09-5.15), 0.029
Zhuang et al[22], 2024, China	May 2014-August 2016	NA	197	NA	G1-G2: 130, G3: 57; I-II: 147, III- IV: 50	G1/G2: 69%; I/II: 75%	Luminal A: 37, luminal B: 133, HER2 +: 13, TNBC: 14	121 (61.4); score 3; ab51608	OS	(U) 5.36 (2.02-14.22), 0.001	Reported	NA
										(M) 4.94 (1.86-13.14), 0.001
Rajković-Molek et al[38], 2014, Croatia	2000-2004	Retrospective	208	65	G1: 46, G2: 113, G3: 49; I: 67, II: 68, III: 60, IV: 3, Unknown: 10	G1/G2: 76%; I/II: 68%	Luminal A: 111, luminal B: 46, HER2 +: 19, TNBC: 32	82 (39.4); ≥ 10 %; NB100-131	OS	(U) 1.63 (1.03-2.60), 0.0369	Reported	NA
Malfettone et al[39], 2012, Italy	NA	NA	187	50	G1: 31, G2: 87, G3: 69; NA	G1/G2: 63%; I/II: NA	NA	58 (31.0); ≥ 1%; H206	OS	(U) 1.52 (1.10-2.11), 0.011	Estimate	NA
Ni et al[42], 2013, China	January 2005-October 2006	NA	85 of 95	NA	G1: 16, G2: 35, G3: 24; I-II: 38, III: 37	G1/G2: 68%; I/II: 51%	NA	52 (61.2); score ≥ 1; NA	OS	(U) 1.56 (1.01-2.42), 0.045; (M) 2.25 [1.38-6.45], 0.037	U: Survival curve M: Reported	60
Peurala et al[54], 2012, Finland	2002-2005	NA	102	59	G1: 30, G2: 35, G3: 37; NA	G1/G2: 63%; I/II: NA	NA	27 (26.4); score ≥ 2; NA	BCSS	(U) 2.4 (0.75-7.5), 0.126	Reported	NA
Kornegoor et al[13], 2012, Netherlands	1986-2010	NA	MBC; 126	66	G1-G2: 81, G3: 44; NA	G1/G2: 50%; I/II: NA	NA	51 (40.5); ≥ 5%; NA	OS	(M) 2.50 (1.1-5.6), 0.029	Reported	NA
Deb et al[12], 2014, Australia	1990-2007	Retrospective	MBC; 286	70	NA	NA; NA	NA	68 (23.8); score 6; NA	OS	(U) 3.8 (1.5-9.8), 0.006	Reported	96
Dales et al[34], 2005, France	1986-1995	Retrospective	745	56.1	NA	NA; NA	NA	543 (72.9); > 10 %; H206	OS; DFS	OS: (U) 1.21 (1.03-1.43), 0.019	U: Survival curve	162
										(M) 1.20 (1.02-1.41), 0.03	M: Estimate
										DFS: (M) 1.12 (0.96-1.32), 0.158
Kronblad et al[37], 2006, Sweden	1984-1991	Prospective	377	NA	G1: 41, G2: 142, G3: 183, Unknow: 12; NA	NA; NA	NA	91 (24.1); > 2%; NB100-123H2	OS; RFS	OS: (U) 1.21 (0.95-1.53), 0.11; RFS: (U) 1.27 (1.00-1.61), 0.048	Survival curve	166.8
										LN-: 1.17 (0.66-2.09), 0.59
										LN+: 1.69 [1.11-2.57], 0.014
Bos et al[32], 2003, Netherlands	1985-1993	NA	150	60	G1: 35, G2: 49, G3: 66; NA	G1/G2: 56%; I/II: NA	NA	51 (34.0); > 5%; H1α67	OS; DFS	LN+: (M) OS: 6.37 (1.32-30.67), 0.021; (U) 1.21 (1.05-1.39), 0.008; DFS: (M) 4.19 (1.56-12.08), 0.008; (U) 1.38 (1.11-1.72), 0.004	M: Reported	106
										LN-: (M) OS: 2.16 (0.95-4.89), 0.067; DFS: 1.67 (0.88-3.17), 0.115	U: Survival curve
Gruber et al[29], 2004, Switzerland	August 1988-June 1998	NA	77	57	Moderate/G2: 43, poor/G3: 32; NA	G1/G2: 57%; I/II: NA	NA	43 (55.8); score 1; H1α67	OS; DFS	(U) OS: 1.34 (0.85-2.11), 0.21	M: Reported	36
										DFS: 1.61 (1.02-2.55), 0.04	U: Estimate
										(M) OS: 2.66 (0.83–8.51), 0.09; DFS: 1.68 (0.62–4.47), 0.30
Giatromanolaki et al[27], 2022, Greece	2003-2009	Prospective	175	61	NA	NA; NA	Luminal A: 88, luminal B: 47, HER2 +: 24, TNBC: 16	39 (22.3); ≥ 50%; ESEE122	OS, DFS	(U) OS: 2.26 (1.06-4.82), 0.035	Survival curve	130
										DFS: 1.96 (1.01-3.80), 0.004
Ong et al[19], 2022, Singapore	2003-2013	Retrospective	307	55	G1/2: 48, G3: 288; NA	G1/G2: 14%; I/II: NA	TNBC	141 (45.9); score ≥ 1; NA	OS, DFS	(U) OS: 1.06 (0.65-1.75), 0.807	Estimate	NA
										DFS: 1.40 (0.90-2.17), 0.137
Schindl et al[33], 2002, Austria	NA	Prospective	206	52.3	NA	NA; NA	NA	48 (23.3); score 3; H1α67	OS, DFS	OS: (U) 1.89 (1.01-3.53), 0.045; (M) 1.41 (1.12-1.77), 0.003	M: Reported	87
										DFS: (U) 2.83 (1.54-5.19), 0.0008; (M) 1.40 (1.14-1.72), 0.001	U: Survival curve
Yamamoto et al[43], 2008, Japan	1993-2001	NA	171	NA	G1: 56, G2: 83, G3: 32	G1/G2: 81%; I/II: 90%	NA	63 (36.8); > 5%; H1α67	OS, DFS	OS: (U) 1.39 (1.17-1.65), 0.0002; (M) 2.15 (1.15-5.76), 0.016	M: Reported	60
					I: 45, II: 109, III: 17					DFS: (U) 1.7 (1.67-1.70), < 0.0001	U: Survival curve
										1.59 (1.05-2.43), 0.017
Lu et al[18], 2022, China	2017-2019	NA	189	52.0	NA; I-II: 91, III- IV: 98	G1/G2: NA; I/II: 48%	Luminal A: 61, luminal B: 43, HER2 +: 56, TNBC: 29	122 (64.6); score ≥ 2; ab51608	OS; DFS	(M) OS: 1.024 (0.85-1.23), 0.788; DFS: 1.07 (0.88-1.29), 0.506	Reported	60
Choi et al[52], 2013, South Korea	January 2000-December 2001	NA	276	49.0	G1: 33, G2: 147, G3: 96	G1/G2: 65%; I/II: NA	Luminal A: 121, luminal B: 33, HER2 +: 25, TNBC: 97	13 (4.7); > 10%; EP1215Y	OS; DFS	OS: (U) 1.95 (1.49-2.54), < 0.001; (M) 4.54 (1.46-14.11), 0.009; DFS: (M) 5.21 (1.84-14.78), 0.002	M: Reported	67
					NA						U: Estimate
Dong et al[53], 2013, China	April 1999-October 2008	NA	378	48.5	G1: 15, G2: 127, G3: 56, Unknown: 178; NA	G1/G2: 72%; I/II: NA	NA	195 (50.1); score 4; MAB5382	OS; DFS	(U) OS: 1.05 (0.81-1.36), 0.714	Estimate	73.8
										DFS: 1.01 (0.81-1.25), 0.963
Huang et al, [46], 2014, Taiwan	1991-2001	NA	96	46.5	NA	NA; NA	NA	29 (30.2); score ≥ 3; NA	OS; DFS	(M): OS: 1.61 (0.63-4.13), 0.322	Reported	NA
										DFS: 2.18 (0.93-5.11), 0.073
Koo and Jung[49], 2010, South Korea	January 2000-December 2001	NA	182 of 224	48.8	NA; I: 32, II: 123, III: 69	G1/G2: NA; I/II: 69%	Luminal A: 115, luminal B: 20, HER2 +: 29, TNBC: 60	33 (18.1); ≥ 1%; EP1215Y	OS; RFS	(U): OS: 2.94 (1.98-4.37), < 0.0001	Survival curve	89.6
										RFS: 2.78 (1.42-5.46), 0.003
Ramírez-Tortosa et al [20], 2022, Spain	NA	Prospective	88 of 95	20	G1: 20, G2: 37, G3: 34, unknown: 4	G1/G2: 63%; I/II: 68%	Luminal A: 31, luminal B: 28, HER2 +: 20, TNBC: 13, Missing: 3	35 (39.8); ≥ 5%; NA	OS; DFS	OS: (M) 1.31 (0.81-2.13), 0.295; DFS: (U) 1.70 (1.12-2.57), 0.013; (M) 2.5 (1.0-6.2), 0.047	DFS: U: Survival curve OS: Estimate	88.8
					Stage: II: 63, III: 29, unknown: 3
Sato-Tadano et al[15], 2013, China	2004-2008	NA	118	57	NA; I: 68, II: 31, III: 19	G1/G2: NA; I/II: 84%	Luminal A: 23, luminal B: 15, HER2 +: 4, TNBC: 10	62 (52.5); score ≥ 3; NA	BCSS; DFS	(U) BCSS: 1.12 (0.78-1.61), 0.54; DFS: 1.07 (0.74-1.53), 0.72	Estimate	57
Trastour et al[30], 2007, France	1993	Retrospective	132	62	G1: 57, G2: 44, G3: 10	G1/G2: 91%; I/II: NA	NA	59 (44.7); > 1%	OS, DFS	(U) OS: 1.84 (1.31-2.5), 0.0005; DFS: 1.64 (1.28-2.1), 0.0001	U: Estimate	138
										(M) OS: 1.25 (0.89-1.76), 0.2	M: DFS reported
					NA			Antiserum 2087		DFS: 4.2 [2.1-8.5], < 0.001	M: OS estimate
Schoppmann et al[40], 2006, Austria	NA	Prospective	119	50.9	G1: 9, G2: 54, G3: 56	G1/G2: 53%; I/II: NA	NA	30 (25.2); score 3; H1α67	OS; DFS	OS: (U) 1.60 (1.05-2.41), 0.027; DFS: (U) 1.59 (1.05-2.40), 0.029; (M) 1.61 (1.06-2.43), 0.025	Estimate	110
					NA
Yan et al[36], 2009, Australia	NA	NA	125	NA	G1: 7, G2: 30, G3: 67, Unknow: 19; NA	G1/G2: 36%; I/II: NA	Luminal: 49, HER2 +: 6, TNBC: 37	55 (44.0); score 1; NA	DFS	(U) 3.25 (1.01-10.51), 0.049;	Survival curve	64
Nie et al[51], 2018, China	January 2013-December 2014	NA	220	46	NA; II: 54, III: 166	G1/G2: NA; I/II: 25%	Luminal A: 8, luminal B: 127, HER2 +: 50, TNBC: 35	150 (68.2); score ≥ 1; NA	DFS	(M) 4.17 (1.01–17.17), 0.048	Reported	220
Chen et al[47], 2007, Taiwan	1988-2002	Retrospective	104	NA	G1: 33, G2: 43, G3: 28; NA	G1/G2: 73%; I/II: NA	NA	47 (45.2); score 3; H1α67	DFS	(U): 3.82 (2.14-6.84), < 0.0001	Reported	> 120
Cui and Jiang[45], 2019, China	January 2012-December 2015	Retrospective	87 of 126	50.4	G1: 5, G2: 48, G3: 34	G1/G2: 70%; I/II: 84%	TNBC	36 (41.4); score ≥ 1; ab51608	DFS	(U): 2.03 (1.36–3.51), < 0.001; (M): 2.22 (1.47–3.77), < 0.001	Reported	24
					I: 19, II: 54, III: 14
Generali et al[35], 2006, Italy	January 1997-December 2001	Prospective	187	NA	G2: 95; G3: 135; missing: 3	G1/G2: 41%; I/II: NA	NA	138 (73.8); score ≥ 1; ESEE122	DFS	(U) 1.83 (1.10-3.04), 0.02	Survival curve	53
					NA					ER +: 1.39 (1.00-1.92), 0.05
Jin et al[44], 2016, South Korea	2003-2006	NA	270	NA	G2: 59, G3: 211; NA	G1/G2: 22%; I/II: NA	TNBC	39 (14.4); ≥ 1%; NA	DFS	(U) 1.26 (1.04-1.52), 0.017	U: Survival curve M: Reported	NA
										(M) 2.62 (1.33-5.15), 0.05
Kuijper et al[14], 2005, Netherlands	NA	NA	37	NA	NA	NA; NA	NA	15 (40.5); ≥ 1%; NA	DFS	(U) 4.39 (1.14-16.99), 0.032	Survival curve	NA
Vleugel et al[28], 2005, Netherlands	NA	NA	200	NA	G1: 61, G2: 78, G3: 61; NA	G1/G2: 70%; I/II: NA	NA	88 (44.0); ≥ 1%; NA	RFS	(M) 2.23 (1.18-4.21), 0.01	Reported	105
Shi et al[50], 2017, China	September 2004-September 2008	Retrospective	60	53	NA; I: 20, II: 28, III: 12	G1/G2: NA; I/II: 80%	NA	20 (33.3); ≥ 5%; ab85886	DFS	(U): 4.76 (2.17, 10.44), < 0.001	Survival curve	60
Tan et al[16], 2007, United Kingdom	NA	NA	295	57	G1: 37, G2: 66, G3: 50; NA	G1/G2: 67%; I/II: NA	NA	125 (42.4); score ≥ 2; ESEE122	DFS	(U) 1.60 (1.02-2.42), 0.04	Reported	105
Shamis et al[21], 2022, United Kingdom	1995-1998	NA	Cohort I: 289 of 373	NA	NA,	NA; NA	ER +	39 (13.5); NA; H1α67	DFS	(U) 1.52 (1.08-2.13), 0.015	Survival curve	> 12
Marton et al[38], 2012, Croatia	2001-2005	NA	31	61.7	G1: 7, G2: 19, G3: 5; NA	G1/G2: 84%; I/II: NA	NA	7 (22.6); score ≥ 1; NA	DFS	(U) 2.20 (0.95-5.11), 0.066	Estimate	144
										(M) 2.74 (1.18-6.36), 0.019

TNM: Tumor-node-metastasis; HIFα: Hypoxia-inducible factor 1α; NA: Not available; TNBC: Triple-negative breast cancer; OS: Overall survival; RFS: Recurrence-free survival; DMSF: Distant metastasis-free survival; DFS: Disease-free survival; DSS/SS: Disease-specific survival; HER2 +: HER2 enrich; MBC: Male breast cancer; BDC: Breast ductal cancer; RCS: Randomized controlled study; BCSS: Breast cancer-specific survival; U: Univariate; M: Multivariate; HR: Hazard ratio; CI: confidence interval.

Table 2 Meta-analysis results and sensitivity analysis

Analysis	Number of studies	Pooled HR ratio (95%CI)	I2 statistic (%)	χ2 P value for heterogeneity	Analytical model	P value for overall effect
Primary analyses
OS	28	1.47 (1.29-1.69)	65	< 0.00001	REM	< 0.00001
DFS	29	1.82 (1.56-2.12)	71	< 0.00001	REM	< 0.00001
Sensitivity analyses
OS
Exclusion of study with the largest effect size[42]	27	1.51 (1.31-1.74)	62	< 0.0001	REM	< 0.00001
Sample size ≥ 200[12,19,26,33,34,37,38,52,53]	9	1.20 (1.06-1.36)	48	0.05	FEM	0.004
NOS scoring ≥ 7[12,13,19,20,32,37,53]	7	1.46 (1.08-1.97)	62	0.02	REM	0.02
DFS
Exclusion of study with the largest effect size[34]	28	1.88 (1.60-2.22)	69	< 0.00001	REM	< 0.00001
Sample size ≥ 200[16,19,21,28,33,34,37,44,51-53]	11	1.44 (1.21-1.71)	63	0.003	REM	< 0.0001
NOS scoring ≥ 7[16,19-21,32,36,37,45,53]	9	1.57 (1.24-1.99)	63	0.005	REM	0.0002

HR: Hazard ratio; CI: Confidence interval; NOS: Newcastle-ottawa scale; OS: Overall survival; DFS: Disease-free survival; FEM: Fixed-effects model; REM: Random-effects model.

Table 3 Subgroup analysis of hypoxia-inducible factor 1α and overall survival in breast cancer patients.

Stratified analysis	Number of studies	Pooled HR ratio (95%CI)	I2 statistic (%)	χ2 P value for heterogeneity	Analytical model	χ2 P value for subgroup differences
Age (median)
< 53[17,18,20,33,39,40,46,48,49,52,53]	11	1.35 (1.21-1.51)	76	< 0.00001	REM	-
≥ 53[12,13,15,19,27,29,30,32,34,38,54]	11	1.52 (1.33-1.74)	45	0.05	FEM	0.18
Location
Asia[15,18,19,22,42,43,46,48,49,52,53]	11	1.55 (1.39-1.73)	31	0.11	FEM	-
Europe[12,13,20,26,27,29-34,37-40,54]	16	1.58 (1.39-1.79)	29	0.14	FEM
Africa[17]	1	1.20 (1.02-1.41)	NA	-	-	0.002
Antibody
H1α67[29,32,33,40,43]	5	1.52 (1.26-1.83)	27	0.24	FEM	-
EP1215Y[17,31,49,52]	4	1.42 (1.22-1.64)	87	< 0.0001	REM	-
ab51608[18,22]	2	2.23 (1.37-3.64)	0	0.85	FEM	-
H206[34,39]	2	1.65 (1.21-2.25)	70	0.07	REM	-
NB100- 123H2[37]	1	1.21 (0.95-1.54)	NA	-	-	-
NB100- 131[38]	1	1.63 (1.03-2.58)	NA	-	-	-
BD610959[26]	1	1.61 (0.63-4.11)	NA	-	-	-
Ab82832[48]	1	0.23 (0.08-0.66)	NA	-	-	-
Antiserum 2087[30]	1	1.41 (1.12-1.77)	NA	-	-	-
MAB5382[53]	1	1.05 (0.81-1.36)	NA	-	-	-
ESEE122[27]	1	2.26 (1.06-4.82)	NA	-	-	0.16
Cut-off value
Percentage ≥ 1%[26,30,37,39,49]	5	1.49 (1.30-1.71)	72	0.006	REM	-
Percentage ≥ 5%[13,17,20,27,32,34,38,43,52]	9	1.36 (1.20-1.55)	59	0.01	REM	-
Scoring ≥ 1 [18,19,29,31,42,54]	6	1.21 (1.05-1.39)	69	0.007	REM	-
Scoring ≥ 3[12,15,22,33,40,46,48,53]	8	1.25 (1.06-1.47)	70	0.002	REM	0.71
Study design
Retrospective[12,19,30,34,38]	5	1.48 (1.23-1.77)	59	0.04	REM	-
Prospective[17,20,27,33,37,40]	6	1.27 (1.13-1.44)	26	0.24	FEM	0.18
Publish date
Before 2013[13,15,29,30,32-34,37,39,40,42,43,49,52-54]	16	1.32 (1.22-1.44)	68	< 0.0001	REM	-
After 2013[12,17-20,22,26,27,31,38,46,48]	12	1.35 (1.19-1.54)	64	0.001	REM	0.53
Grading
G1/G2 < 65%[13,17,19,20,29,32,37,39,40,54]	10	1.35 (1.21-1.50)	40	0.09	FEM	-
G1/G2 ≥ 65%[22,30,31,38,42,43,48,52,53]	9	1.19 (1.07-1.33)	71	0.0005	REM	0.54
Staging
I/II < 70%[18,20,38,42,48,49]	6	1.26 (1.09-1.45)	87	< 0.0001	REM	-
I/II ≥ 70%[15,22,26,43]	4	1.32 (1.03-1.69)	11	0.34	REM	0.69
Molecular typing
TNBC[17,19]	2	1.18 (1.01-1.38)	0	0.62	FEM	-
Gender
Male[12,13]	2	1.85 (1.25-2.72)	62	0.1	REM	-
Female[15,17-20,22,26,27,29-34,37-40,42,43,46,48,49,52-54]	26	1.29 (1.21-1.38)	65	< 0.00001	REM	0.08

HR: Hazard ratio; CI: Confidence interval; FEM: Fixed-effects model; REM: Random-effects model; TNBC: Triple negative breast cancer.

Table 4 Subgroup analysis of hypoxia-inducible factor 1α and disease-free survival in breast cancer patients

Stratified analysis	Number of studies	Pooled HR ratio (95%CI)	I2 statistic (%)	χ2 P value for heterogeneity	Analytical model	χ2 P value for subgroup differences
Age median
≤ 53[18,20,33,40,45,46,49,51-53]	10	1.32 (1.18-1.47)	74	< 0.001	REM	-
>53[15,16,19,27,29,30,32,34,41,50]	10	1.35 (1.20-1.53)	76	< 0.001	REM	0.74
Location
Asia[15,18,19,43-47,49-53]	13	1.37 (1.23-1.53)	80	< 0.001	REM	-
Europe[14,16,20,21,27-30,32-37,40,41]	16	1.73 (1.45-2.07)	60	0.001	REM	0.51
Antibody
H1α67[29,32,33,40,43,47]	6	1.61 (1.38-1.87)	63	0.02	REM	-
EP1215Y[49,52]	2	3.34 (1.90-5.90)	0	0.32	FEM	-
ESEE122[16,27,35]	3	1.79 (1.36-2.34)	0	0.82	FEM	-
ab51608[18,45]	2	1.23 (1.03-1.47)	90	0.002	REM	-
H206[34]	1	1.12 (0.96-1.31)	NA	-	-	-
MAB5382[53]	1	1.01 (0.81-1.26)	NA	-	-	-
NB100- 123H2[37]	1	1.27 (1.00-1.61)	NA	-	-	-
ab85886[50]	1	4.76 (2.17-10.44)	NA	-	-	-
Antiserum 2087[30]	1	4.20 (2.10-8.40)	NA	-	-	0.0004
Cut-off value
Percentage ≥ 1%[14,28,30,37,44,49]	6	1.70 (1.40-2.05)	73	0.002	REM	-
Percentage ≥ 5%[20,27,32,34,43,50,52]	7	1.36 (1.19-1.55)	81	< 0.001	REM	-
Scoring ≥ 1[16,18,19,29,35,36,41,45,51]	9	1.40 (1.21-1.61)	60	0.01	REM	-
Scoring ≥ 3[15,33,40,46,47,53]	6	1.31 (1.15-1.48)	78	0.0005	REM	0.25
Study design
Retrospective[19,30,34,45,47,50]	6	1.42 (1.25-1.62)	88	< 0.01	REM	-
Prospective[20,27,33,35,37,40]	6	1.46 (1.28-1.66)	8	0.37	FEM	0.79
Recruitment period
Before 2013[14-16,21,28-30,32-37,40,41,43,47,49,52,53]	19	1.37 (1.26-1.48)	73	< 0.001	REM	-
After 2013[18-21,27,44-46,50,51]	10	1.29 (1.15-1.44)	71	0.0003	REM	0.63
Grading
G1/G2 < 65%[19,20,29,32,35-37,40,44,45]	10	1.63 (1.40-1.89)	37	0.12	FEM	-
G1/G2 ≥ 65%[16,28,30,41,43,47,52,53]	8	2.25 (1.47-3.45)	82	< 0.001	REM	0.35
Staging
I/II < 70%[18,20,49,51]	4	1.22 (1.01-1.47)	76	0.005	REM	-
I/II ≥ 70%[15,43,45,50]	4	1.65 (1.33-2.05)	79	0.003	REM	0.85
Molecular typing
TNBC[19,44,45]	3	1.79 (1.03-3.11)	72	0.03	REM	-

HR: Hazard ratio; CI: Confidence interval; TNBC: Triple negative breast cancer; FEM: Fixed-effects model; REM: Random-effects model.