Lack of cytoplasmic expression of a new marker programmed cell death ligand-1 in tumor cells is significant

Table 1 Characteristics of patients with breast cancer

Breast cancer characteristics	n (%)
Т stage
Тin situ	4 (2.7)
Т1в	11 (7.5)
Т1с	89 (60.1)
Т2	44 (29.7)
N stage
N0	81 (54.7)
N1	47 (31.8)
N2	16 (10.8)
N3	4 (2.7)
Clinical stage
0	4 (2.7)
I (IA)	53 (35.8)
IIA	55 (37.2)
IIB	17 (11.5)
IIIA	15 (10.1)
IIIB	4 (2.7)
Histology
Intraductal	4 (2.7)
Ductal	134 (90.5)
Lobular	2 (1.4)
Others	8 (5.4)
Tumor grade (G)
G1	16 (10.8)
G2	89 (60.1)
G3	43 (29.1)
Estrogen receptor status
negative	16 (10.8)
positive	132 (89.2)
Progesterone receptor status
Negative	41 (27.7)
Positive	107 (72.3)
HER2 status
Negative	128 (85.5)
Positive	20 (14.5)
Breast cancer molecular biological subtype
Luminal A	56 (37.8)
Luminal B HER2-	66 (44.6)
Luminal B HER2+	10 (6.8)
Nonluminal HER2+	10 (6.8)
Triple negative breast cancer	6 (4.0)

HER2: Human epidermal growth factor receptor 2.

Table 2 The severity of cytoplasmic programmed cell death protein 1 ligand 1 expression in tumor cells according to the clinical and pathological characteristics of breast cancer

Breast cancer characteristics	Severity of cPDCD1 LG1 expression in the tumor cells	Р value
T stage
Тin situ	8.0 ± 2.8	0.86
Т1в	8.4 ± 2.4
Т1с	8.5 ± 2.3
Т2	8.2 ± 2.2
N stage
N0	8.7 ± 2.2	0.67
N1	8.3 ± 1.9
N2	6.9 ± 2.5
N3	9.1 ± 3.3
Clinical stage
0	8.0 ± 2.8	0.906
I (IA)	8.7 ± 2.3
IIA	8.5 ± 1.9
IIB	8.1 ± 1.9
IIIA	6.8 ± 2.6
IIIB	9.1 ± 3.2
Tumor grade
G1	9.4 ± 2.2	0.003a
G2	8.6 ± 2.5
G3	7.6 ± 1.9
Lymphovascular invasion
Absent	8.6 ± 2.2	0.27
Present	8.1 ± 2.2
Perineural invasion
Absent	8.7 ± 2.2	0.12
Present	7.7 ± 2.3
Intraductal component
Absent	8.5 ± 2.1	0.44
Present	8.0 ± 2.4
Estrogen receptor status
Negative	8.3 ± 1.2	0.87
Positive	8.4 ± 2.3
Progesterone receptor status
Negative	7.4 ± 2.1	0.0009a
Positive	8.7 ± 2.2
HER2 status
HER2 -	8.7 ± 2.4	0.15
HER2 1+	8.1 ± 1.3
HER2 2+	7.4 ± 2.8
HER2 3+	8.1 ± 1.3
Breast cancer molecular biological subtype
Luminal A	8.3 ± 2.5	0.41
Luminal B HER2-	8.4 ± 2.2
Luminal B HER2+	8.8 ± 2.1
Nonluminal HER2+	8.3 ± 1.2
TNBC	8.5 ± 1.2

^aP < 0.05 was considered statistically significant.

Statistical tests: Mann-Whitney U test - for two groups; Median test - for three or more groups. TNBC: Triple negative breast cancer; HER2: Human epidermal growth factor receptor 2; cPDCD1 LG1: Cytoplasmic programmed cell death protein 1 ligand 1.

Table 3 Distribution of patients according to the lack of cytoplasmic programmed cell death protein 1 ligand 1 expression and the clinical and pathological characteristics of breast cancer patients

	The lack of cPDCD1 LG1 in < 20% of the TCs		The lack of cPDCD1 LG1 in ≥ 20% of the TCs		P value
	n	%	n	%
T stage
Тin situ	4	100	0	0	0.0052a
Т1в	9	81.8	2	18.2
Т1с	51	57.3	38	42.7
Т2	16	36.4	28	63.6
N stage
N0	42	51.9	39	48.1	0.24
N1	24	51.1	23	48.9
N2-3	14	62.5	6	37.5
Clinical stage
0	4	100	0	0	0.059
I (IA)	30	56.6	23	43.4
IIA	24	43.6	31	56.4
IIB	8	47.1	9	52.9
IIIA	10	66.7	5	33.3
IIIB	4	100	0	0
Tumor grade
G1	14	87.5	2	12.5	0.0000a
G2	55	63.2	32	36.8
G3	11	24.4	34	75.6
Lymphovascular invasion
Absent	48	57.1	36	42.9	0.39
Present	32	50.0	32	5.0
Perineural invasion
Absent	64	55.7	51	44.3	0.47
Present	16	48.5	17	51.5
Intraductal component
Absent	57	53.3	50	46.7	0.76
Present	23	56.1	18	43.9
Estrogen receptor status
Negative	5	31.3	11	68.7	0.052
Positive	75	56.8	57	43.2
Progesterone receptor status
Negative	21	51.2	20	48.8	0.67
Positive	59	55.1	48	44.9
HER2 status
Negative	73	57.0	55	43.0	0.070
Positive	7	35.0	13	65.0
Molecular biological subtype
Luminal A	42	75.0	14	25.0	0.0011a
Luminal B HER2-	28	42.4	38	57.6
Luminal B HER2+	5	50.0	5	50.0
Nonluminal HER2+	2	20.0	8	80.0
TNBC	3	50.0	3	50.0

^aP < 0.05 was considered statistically significant.

Statistical test: χ². HER2: Human epidermal growth factor receptor 2; TNBC: Triple negative breast cancer; cPDCD1 LG1: Cytoplasmic programmed cell death protein 1 ligand 1; TCs: Tumor cells.

Table 4 Distribution of patients according to cytoplasmic programmed cell death protein 1 ligand 1 + immune cell score and the clinical and pathological characteristics of patients with breast cancer

Breast cancer characteristics	PDCD1 LG1+ IC score						Р value
	< 10%		≥ 10% and < 30%		≥ 30%
	n	%	n	%	n	%
T stage
Тin situ	2	50.0	2	50.0	0	0	0.035a
Т1в	4	36.4	5	45.4	2	18.2
Т1с	59	66.3	18	20.2	12	13.5
Т2	36	81.8	3	6.8	5	11.4
N stage
N0	58	71.6	11	13.6	12	14.8	0.488
N1	31	66.0	11	24.4	5	10.6
N2-3	12	60.0	6	30.0	2	10.0
Clinical stage
0	2	50.0	2	50.0	0	0	0.158
I (IA)	38	71.7	6	11.3	9	17.0
IIA	35	63.6	14	25.4	6	10.9
IIB	15	88.2	0	0	2	11.8
IIIA	9	60.0	4	26.7	2	13.3
IIIB	2	50.0	2	50.0	0	0
Tumor grade
G1	10	62.5	6	37.5	0	0	0.018a
G2	64	73.6	15	17.2	8	9.2
G3	27	60.0	7	15.6	11	24.4
Lymphovascular invasion
Absent	60	71.4	15	17.9	9	10.7	0.581
Present	41	64.1	13	20.3	10	15.6
Perineural invasion
Absent	79	68.7	24	20.9	12	10.4	0.185
Present	22	66.7	4	12.1	7	21.2
Intraductal component
Absent	73	68.2	21	19.6	13	12.2	0.885
Present	28	68.3	7	17.1	6	14.6
Estrogen receptor status
Negative	5	31.25	5	31.25	6	37.5	0.0012a
Positive	96	72.7	23	17.4	13	9.9
Progesterone receptor status
Negative	25	61.0	7	17.1	9	21.9	0.122
Positive	76	71.0	21	19.6	10	9.4
HER2 status
Negative	99	77.3	23	18.0	6	4.7	0.0000a
Positive	2	10.0	5	25.0	13	65.0
Breast cancer subtypes
Luminal A	42	75.0	8	14.3	6	10.7	0.0000a
Luminal B HER2-	54	81.8	12	18.2	0	0
Luminal B HER2+	0	0	3	30	7	70
Nonluminal HER2+	2	20.0	2	20.0	6	60.0
TNBC	3	50.0	3	50.0	0	0

^aP < 0.05 was considered statistically significant.

Statistical test: χ². ER: Estrogen receptor; HER2: Human epidermal growth factor receptor 2; PR: Progesterone receptor; TNBC: Triple negative breast cancer; cPDCD1 LG1: Cytoplasmic programmed cell death protein 1 ligand 1; IC: Immune cells.

Table 5 Results of the correlation analysis

Breast cancer characteristics	Correlation coefficient	P value
Т stage1	-0.103	0.40932
N stage1	-0.385	0.00302a
Clinical stage1	-0.079	0.15234
Tumor grade1	0.874	0.00000a
Estrogen receptor status1	-0.988	0.00000a
Progesterone receptor status1	-0.540	0.00004a
HER2 status1	0.978	0.00000a
Ki67 index2	0.861	0.00000a
Lymphovascular invasion1	0.094	0.51440
Perineural invasion1	-0.515	0.00199a
Intraductal component1	0.114	0.54373
сPDCD1 LG1 expression in TCs1	0.081	0.42558
Lack of cPDCD1 LG1 in TCs1	0.432	0.00000a
PDCD1 LG1+ IC score1	0.454	0.00000a

¹Kendall rank correlations.

²Spearman Rank Order Correlations.

^aP < 0.05 was considered statistically significant.

ER: Estrogen receptors; HER2: Human epidermal growth factor receptor 2; ICs: Immune cells; TCs: Tumor cells; TNBC: Triple negative breast cancer; cPDCD1 LG1: Cytoplasmic programmed cell death protein 1 ligand 1.

Table 6 Results of the univariate and multivariate analyses

Breast cancer characteristics	Univariate analysis		Multivariate analysis
	OR (95%CI)	P value	OR (95%CI)	P value
N stage		0.017a
N0	-		-
N1	1.62 (0.75-3.48)	0.217	1.64 (0.63-35.39)	0.303
N2-3	6.18 (1.34-28.47)	0.019a	5.45 (0.83-35.73)	0.077
Tumor grade		< 0.0000a
G3	-		-
G1-2	12.62 (5.40-29.56)	< 0.0000a	4.54 (1.59-12.95)	0.0057a
Estrogen receptor status		0.0001a
≤ 80%	-
> 80%	7.52 (2.71-20.82)	< 0.0000a	2.57 (0.69-9.62)	0.16
Progesterone receptor status		0.0000a
< 30%	-
≥ 30%	6.67 (3.11-14.28)	< 0.0000a	5.77 (2.09-15.97)	0.001a
HER2 status		< 0.0000a
HER2 0 and +	-		-
HER2 ++ and +++	8.54 (3.61-20.21)	< 0.0000a	3.51 (1.17-10.47)	0.024
PNI		0.044a
No	-
Yes	2.69 (1.03-7.03)	0.032a	2.41 (0.73-7.89)	0.14
Lack of cPDCD1 LG1 in TCs		< 0.0000a
≥ 20%	-		-
< 20%	12.52 (5.50-28.50)	< 0.0000a
PDCD1 LG1 IC score
≥ 10%	-
< 10%	1.50 (0.59-3.84)	0.03977
Combination of PDCD1 LG1+ IC score and lack of cPDCD1 LG1 in TCs		0.0001a
Lack of cPDCD1 LG1 in ≥ 20% of the TCs and PDCD1 LG1 IC scores ≥ 10%	-		-
Lack of cPDCD1 LG1 in ≥ 20% of the TCs and PDCD1 LG1 IC scores < 10%	3.11 (0.94-10.25)	0.06a	1.51 (0.30-7.49)	0.616
Lack of cPDCD1 LG1 in < 20% of the TCs and PDCD1 LG1 IC scores ≥ 10%	2.49 (0.87-0.09)	0.09a	1.82 (0.45-7.37)	0.399
Lack of cPDCD1 LG1 in < 20% of the TCs and PDCD1 LG1 IC scores < 10%	12.00 (3.70-38.90)	< 0.0000a	7.59 (1.63-4.24)	0.01a

^aP < 0.05 was considered statistically significant.

ICs: Immune cells; PNI: Perineural invasion; TCs: Tumor cells; cPDCD1 LG1: Cytoplasmic programmed cell death protein 1 ligand 1.

Table 7 Distribution of patients in groups 1 and 2 depending on the combination of the lack of cytoplasmic programmed cell death protein 1 ligand 1 tumor cells and cytoplasmic programmed cell death protein 1 ligand 1 immune cell scores

The combination of the lack of cPDCD1 LG1 in TCs and PDCD1 LG1 IC scores	1 group (luminal A BC)	2 group (BC with Ki67 ≥ 40%)	P value (χ2 test)
BC with the lack of cPDCD1 LG1 in < 20% of the TCs and PDCD1 LG1 IC scores < 10%	28 (87.5)	4 (12.5)	< 0.0000
BC with the lack of cPDCD1 LG1 in ≥ 20% of the TCs and PDCD1 LG1 IC scores < 10%	14 (58.3)	10 (41.7)
BC with the lack of cPDCD1 LG1 in < 20% of the TCs and PDCD1 LG1 IC scores ≥ 10%	10 (55.6)	8 (44.4)
BC with the lack of cPDCD1 LG1 in ≥ 20% of the TCs and PDCD1 LG1 IC scores ≥ 10%	4 (15.4)	22 (84.6)

BC: Breast cancer; cPDCD1 LG1: Cytoplasmic programmed cell death protein 1 ligand 1; ICs: Immune cells; TCs: Tumor cells.

Table 8 The levels of estrogen receptors, progesterone receptors and Ki67 proliferation index according to the breast cancer immune profile

	The combination of the lack of cPDCD1 LG1 in TCs and PDCD1 LG1 IC scores				P value (χ2 test)
	BC with the lack of cPDCD1 LG1 in < 20% of the TCs and PDCD1 LG1 IC scores < 10% (group 1)	BC with the lack of cPDCD1 LG1 in ≥ 20% of the TCs and PDCD1 LG1 IC scores < 10% (group 2)	BC with the lack of cPDCD1 LG1 in < 20% of the TCs and PDCD1 LG1 IC scores ≥ 10% (group 3)	BC with the lack of cPDCD1 LG1 in ≥ 20% of the TCs and PDCD1 LG1 IC scores ≥ 10% (group 4)
Estrogen receptors (%)	89.4 ± 24.91	91.9 ± 25.22	81.4 ± 30.23	42.1 ± 48.94	0.0071,4; 0.0042,4; 0.0053,4
Progesterone receptors (%)	53.4 ± 44.71	53.7 ± 44.32	55.1 ± 40.13	25.4 ± 40.94	0.0411,4; 0.0112,4; 0.0123,4
Ki67 proliferation index (%)	17.2 ± 14.91	29.0 ± 17.82	31.8 ± 27.33	66.2 ± 28.24	0.0141,2; 0.0031,3; < 0.000011,4; 0.000122,4; 0.0033,4

¹Levels of markers in group 1.

²Levels of markers in group 2.

³Levels of markers in group 3.

⁴Levels of markers in group 4.

BC: Breast cancer; cPDCD1 LG1: Cytoplasmic programmed cell death protein 1 ligand 1; ICs: Immune cells; TCs: Tumor cells.

Table 9 Results of the studies of the prognostic and predictive significance of programmed cell death-ligand 1 expression in tumor cells

Ref.	No. of patients BC subtype	Clone of anti-PD-L1 antibody	Staining type; cutoff point; n (%) with expression	Association of PD-L1 expression in TCs with BC characteristics
Mori et al[16], 2017	248, all	Clone E1 L3N (monoclonal rabbit antibody, Cell Signaling Technology, Beverly, MA, United States)	NS; ≥ 1%; three scoring intervals: < 1% - negative (58.5); 1%-49% - weak-positive (26.2); ≥ 50% - strong-positive (15.3)	With tumor G3 (Р = 0.0015), a high Ki67 (Р < 0.0001), a high TILs (Р < 0.0001); Correlations with RFS and OS were absent
Oner et al[17], 2023	50, TNBC	Clone SP263 (rabbit monoclonal antibody, Ventana Clone kit)	Membrane; ≥ 1%; four scoring intervals: ≥ 1% and < 5%; ≥ 5% and < 10%; ≥ 10% and < 20%; ≥ 20%; 25 (50)	With G3 (Р < 0.0001) TCs+ score ≥ 20% were associated with a better DFS and DSS
Shang et al[18], 2022	155, HER2+	Clone SP142 (rabbit monoclonal antibody, Ventana, Shanghai Roche Diagnostic Products Limited Company, Shanghai, China)	Membrane or cytoplasmic; ≥ 1%; continuous scale with 5% step; 62 (40)	No correlation
Çetin et al[19], 2024	85, HER2+	Clone 73-10 (monoclonal antibody, Leica Biosystems, Newcastle, United Kingdom)	Membrane; ≥ 1%; 36 (42.4)	No correlation
Hoffmann et al[20], 2022	127, all	Clone ZR3 (rabbit monoclonal antibody, Cell Marque – Sigma-Aldrich, MO, United States)	Membrane or cytoplasmic; ≥ 1%; 40 (31.5)	with a high TILLs (Р = 0.02) and pCR (Р = 0.02)
Kitano et al[21], 2022	166, all (II-III stage)	antihuman PD-L1 polyclonal antibody (ProScience, Poway, California, United States)	Membrane or cytoplasmic; > 0%; All 62 (34); HR+HER2- (20); HR-HER2+ (32); TNBC (49)	With tumor G3 (Р < 0.0001), TNBC (Р < 0.0001), a high TILs (Р < 0.0001), p53 (Р = 0.0074) and pCR for TNBC (Р = 0.05). Correlations with RFS and OS were absent
Qin et al[22], 2015	870, all	Rabbit primary anti-PD-L1 antibody (Cell Signaling Technology, Beverly, MA, United States)	Membrane; ≥ 5%; All 189 (21.7); Luminal A (11.5); HR+HER2+ (7.7); HR+HER2 (8.6); TNBC (55.9)	With tumor size > 20 mm (Р = 0.002), tumor G3 (Р = 0.013), presence of LVI (Р = 0.015), ER-negative status (Р < 0.001) and PR-negative status (Р < 0.001), TNBC (Р < 0.001) and decreased DFS (Р = 0.012) and OS (Р < 0.001)
Muenst et al[23], 2014	650, all	Rabbit-anti-human PD-L1 polyclonal antibody (Abcam, Cambridge, United Kingdom)	Membrane or cytoplasmic; H-score 0-300 (0–99 - negative/Low expression, and 100–300 - positive expression); All 152 (23.4); Luminal A (12.1); HR+HER2+ (28.8); HR+HER2- (20.4); HR-HER2+ (33.9); TNBC (30.7)	With T3-T4 stages (Р < 0.0001), N2 stage (Р < 0.0001), tumor G3 (Р = 0.0007), ER-negative status (Р = 0.002), HER2-positive status (Р = 0.0237), a high Ki67 (Р = 0.043) and decreased OS (Р < 0.0001)
Li et al[24], 2016	501, all	Clone ab58810 (primary polyclonal anti-PD-L1 antibody, Abcam, Cambridge, United Kingdom)	Membrane or cytoplasmic; H-score 0-300 (0–99 - negative/Low expression, and 100–300 - positive expression); All 231 (46.1); Luminal A (37.0); HR+HER2- (45.8); HR+HER2+ (48.5); HR-HER2+ (57.5); TNBC (58.2)	With tumor G3 (Р = 0.0008), N2-N3 stages (Р = 0.005), ER-negative status (Р = 0.006) and PR-negative status (Р < 0.001), and decreased DFS (Р < 0.001) and OS (Р = 0.002)
Wang et al[25], 2017	443, all	Clone SP142 (Pleasanton, CA, United States)	NS; H-score 0-300; All 73 (16.5); Luminal A (12); Luminal B (21); HR-HER2+ (9); TNBC (31)	With tumor G3 (Р = 0.001), ER-negative status (Р = 0.005) and PR-negative status (Р = 0.002), a high TILs (Р < 0.05). Correlations with RFS and OS were absent (Р > 0.05)
Parvathareddy et al[26], 2021	1003, TNBC	Clone E1 L3N (Cell Signaling Technology, Danvers, MA, United States)	Membrane and cytoplasmic but only membrane was assessed; ≥ 5%; 329 (32.8)	With younger age (Р = 0.0432), tumor G3 (Р = 0.0025), ER-negative status (Р < 0.0001), PR-negative status (Р = 0.0001), TNBC (Р = 0.0062) and a high Ki67 (Р < 0.0001). Correlations with RFS and OS were absent (Р > 0.05)
Guo et al[27], 2020	341, all	Clone 22C3 (Dako North America Inc., Carpinteria, CA, United States)	Membrane; ≥ 1%; All 24 (10); HR+ (9); HER2+ (16); TNBC (10)	with tumor G3 (Р < 0.0001), PR-negative status (Р = 0.0125), a high TILs (Р < 0.0001)
Chu et al[28], 2022	132, TNBC	Clone SP142 (Ventana Medical Systems)	Membrane; ≥ 1%; All 36 (27.3); ≥ 10% (2.3)	Correlations with RFS and OS were absent
Ni et al[29], 2022	1752, all	Clone SP142 (rabbit monoclonal primary antibody, Ventana Medical Systems Inc.)	Membrane; ≥ 1%; 173 (10.1)	With ER-negative status, PR-negative status, HER-positive status, TNBC, a high Ki67, a high TILs and PD-L1-positive ICs; Correlations with DSS, RFS and OS were absent

BC: Breast cancer; DSS: Disease-specific survival; ER: Estrogen receptor; HER2: Human epidermal growth factor receptor 2; HR: Hormone receptor; H-score: Histo-score; LVI: Lymphovascular invasion; NS: Not specified; OS: Overall survival; pCR: Pathologic complete response; PD-L1: Programmed cell death ligand 1; PR: Progesterone receptor; RFS: Relapse-free survival; TCs: Tumor calls; TILs: Tumor infiltrating lymphocytes; TNBC: Triple negative breast cancer.

Table 10 Results of the studies of the prognostic and predictive significance of programmed cell death ligand 1 expression in immune cells

Ref.	No. of patients BC subtype	Clone of anti-PD-L1 antibody	Staining type, cutoff point, n (%)	Association of PD-L1 expression in ICs with BC characteristics
Oner et al[17], 2021	50, TNBC	Clone SP263 (rabbit monoclonal antibody, Ventana)	NS; ≥ 1%; four scoring intervals: ≥ 1%; ≥ 5%; ≥ 10% and ≥ 20%; 23 (46)	ICs+ score ≥ 1% was associated with tumor G3 (Р = 0.0001) and pCR (Р = 0.064). ICs+ score ≥ 20% was associated with better DFS (Р = 0.041) and OS (Р = 0.049)
Shang et al[18], 2022	155, HER2+	Clone SP142 (rabbit monoclonal antibody, Ventana, Shanghai Roche Diagnostic Products Limited Company, Shanghai, China)	Membrane or cytoplasmic; ≥ 1%; continuous scale with 5% step; 108 (69.7)	With ER-negative status (Р < 0.05), PR-negative status (Р < 0.05), and pCR
Çetin et al[19], 2024	85, HER2+	Clone 73–10 (monoclonal antibody, Leica Biosystems, Newcastle, United Kingdom)	Membrane or cytoplasmic; ≥ 1%; 32 (37.6)	With tumor G3 (Р = 0.002), a high Ki67, a high TILs and pCR
Stanowska et al[32], 2022	93, TNBC, G3	Clone SP142 (rabbit monoclonal antibody, Roche Diagnostics, Basel, Switzerland)	NS; ≥ 1%; 53 (57)	With a high TILs (Р < 0.001) and pCR (Р < 0.01)
Hoffmann et al[20], 2022	127, all	Clone ZR3 (rabbit monoclonal antibody, Cell Marque – Sigma-Aldrich, MO, United States)	Membrane or cytoplasmic; ≥ 1%; All 70 (55.1); HR+HER2- (46.2); HR+HER2+ (61.5); HR-HER2+ (50.0); TNBC (87.5)	With a high TILs (Р = 0.01)
Bae et al[33], 2016	465, all	Clone E1 L3 (rabbit monoclonal antibody, Cell Signaling Technology, Beverly, United States)	Membrane or cytoplasmic; H-score 0-300 (0–99 - negative/Low expression, and 100–300 - positive expression); All 63 (13.5); Luminal A (2.5); HR+HER2- (17.1); HR+HER2+ (18.9); HR-HER2+ (28.9); TNBC (29.6)	With tumor G3 (Р < 0.001), N0 stage (Р = 0.011), early stages (Р = 0.025), ER-negative status (Р < 0.001) and PR-negative status (Р = 0.002), HER2-positive status (Р = 0.003), a high Ki67, a high TILs (Р < 0.001), with better DFS and OS in patients with HR+HER2+, HR-HER2+ and TNBC (Р < 0.05)
Mori et al[16], 2017	248, all	Clone E1 L3N (monoclonal rabbit antibody, Cell Signaling Technology, Beverly, MA, United States)	NS; ≥ 5%; 129 (52.0)	Correlations with RFS and OS were absent
Hoda et al[34], 2020	156, TNBC	Clone SP142 (Ventana Medical Systems, United States)	NS; ≥ 1%; 74 (47.4)	With a high TILs (Р < 0.001); PD-L1 expression in ICs was more frequently detected in primary tumors than in metastatic tumors
Sigurjonsdottir et al[31], 2024	237, early-stage TNBC	Clone SP142 (Ventana Medical Systems, Inc., AZ, United States)	NS; ≥ 1%; 120 (50.6)	With better DFS (Р = 0.017), OS (Р = 0.032) and distant relapse-free interval (Р = 0.027) but only in patients who received neo-A-ChT
Cha et al[35], 2021	316, all	Clone SP142 (Ventana Medical System)	Membrane and cytoplasmic; ≥ 1%; All 43 (14.3); HR+HER2- (1.4); HR+HER2+ (11.9); HR-HER2+ (11.9); TNBC (20.7)	With tumor G3 (Р < 0.001), early stages (Р = 0.042), ER-negative status (Р < 0.001) and PR-negative status (Р < 0.001), a high Ki67 (Р < 0.001) and TNBC (Р < 0.001). Correlations of markers with RFS and OS were absent (Р > 0.05)
Cha et al[35], 2021	316, all	Clone SP263 (Ventana Medical System)	Membrane and cytoplasmic; ≥ 1%; All 115 (38.5); HR+HER2- (9.9); HR+HER2+ (37.3); HR-HER2+ (37.3); TNBC (54.8)	With tumor G3 (Р < 0.001), ER-negative status (Р = 0.008) and PR-negative status (Р = 0.003), a high Ki67 (Р = 0.002) and TNBC (Р < 0.001). Correlations of markers with RFS and OS were absent (Р > 0.05)
Guo et al[27], 2020	341, all	Clone 22C3 (Dako North America Inc., Carpinteria, CA, United States)	Membrane and cytoplasmic; ≥ 1%; All 58 (17.1); HR+ (13); HER2+ (29); TNBC (31)	With tumor G3 (Р < 0.0001), ER-negative status (Р = 0.0011), PR-negative status (Р < 0.0001), TNBC (P = 0.0069), a high TILs (Р < 0.0001) and decreased OS in patients with HAChT (Р = 0.021)
Chu et al[28], 2022	132, TNBC	Clone SP142 (Ventana Medical Systems)	Membrane and cytoplasmic; ≥ 1%; All 46 (34.8); ≥ 10% (20.5)	ICs+ score ≥ 10% with pT1 (Р = 0.03), fewer lymph node metastases (Р = 0.002), the absence of LVI (Р = 0.024) and better DFS (Р = 0.038)
Ni et al[29], 2022	1752, all	Clone SP142 (rabbit monoclonal primary antibody, Ventana Medical Systems Inc.)	Membrane and cytoplasmic; ≥ 1%; 600 (34.2)	With ER-negative status, PR-negative status, HER-positive status, TNBC, a high Ki67, a high TILs and PD-L1-positive TCs. Correlations with DSS, RFS and OS were absent

BC: Breast cancer; DSS: Disease-specific survival; ER: Estrogen receptor; HER2: Human epidermal growth factor receptor 2; HR: Hormone receptor; H-score: Histo-score; ICs: Immune cells; LVI: Lymphovascular invasion; NS: Not specified; OS: Overall survival; pCR: Pathologic complete response; PD-L1: Programmed cell death ligand 1; PR: Progesterone receptor; RFS: Relapse-free survival; TCs: Tumor calls; TILs: Tumor infiltrating lymphocytes; TNBC: Triple negative breast cancer.