Predictive value of tumor-infiltrating lymphocytes for neoadjuvant therapy response in triple-negative breast cancer: A systematic review and meta-analysis

Table 1 Characteristics of the impact of tumor-infiltrating lymphocytes on the response to neoadjuvant therapy in triple-negative breast cancer patients included in the meta-analysis

Ref.	Data collection	Recruitment period	Sample size	Age in yr, median/mean (range)	TNM stage	Neoadjuvant regimen	Number of high/middle TILs as %, cut-off, and method	End point and pCR standard	Number of overall pCR as %	pCR rates as high TILs vs low TILs	OR or RR
Cerbelli et al[36], Germany	Retrospective consecutive cohort	2011.6-2017.6	61	50 (28-74)	T1: 8; T2: 46; T3: 3; T4: 4; N0: 32; N1-N3: 29	AC×4 (Q3W) →T×12 (QW)	49 (17/32) (80.3), (50%) 10%, HE	pCR, ypT0	23 (37.7)	18 (36.7) vs 5 (41.7)	OR: [U] 0.41 (0.17-0.95), 0.037; [M] 2.39 (0.96-5.96), 0.062
Galvez et al[17], Peru	Retrospective cohort	2003.1-2014.12	435	49 (24-84)	II: 72, III: 363;	AC×4 (Q3W) →T×12 (QW)	181 (41.6), 50%, HE	pCR, ypT0	46 (11.0)	26 (14.4) vs 20 (7.9)	NR
Abdelrahman et al[39], Egypt	Prospective cohort	2017.1-2019.5	50	45 (22-72)	T1: 20; T2: 30; N0: 18; N1-N3: 32	AC→T	14 (28.0), 50%, HE	pCR, ypT0	20 (40.0)	10 (71.4) vs 10 (27.8)	NR
Jung et al[53], Korea	Retrospective cohort	2009.1-2014.12	143	NR	T1-T2: 91; T3: 52; N0: 64; N1-N3: 79	AC→T	74 (51.7), 30%, HE	pCR, ypT0	66 (46.2)	43 (58.1) vs 23 (33.3)	OR: [U] 2.774 (1.404-5.481), 0.003; [M] 3.484 (1.407-8.627), 0.007
Russo et al[47], Venezuela	Retrospective cohort	2008-2013	41	NR	II: 80, III: 107;	AC→T	14 (34.1), 30%, HE	pCR, ypT0	15 (36.6)	11 (78.6) vs 4 (14.8)	OR: [U] 8.85 (3.62-21.66), 0.001
Vicent et al[48], Spain	Retrospective cohort	1998-2015	164	49 (29-81)	II: 63, III: 37	AC×4 (Q3W) →T×12 (QW)	58 (35.4), 40%, HE	pCR, ypT0/is, ypN0	61 (37.2)	51 (88.0) vs 10 (9.0)	NR
Ochi et al[32], Japan	Retrospective consecutive cohort	2001-2009	80	52 (27-75)	NR	AC→T	55 (19/36) (68.8), (50%) 10%, HE	pCR, ypT0	25 (31.3)	24 (43.6) vs 1 (4.0)	NR
Bockstal et al[49], Belgium	Retrospective consecutive cohort	2015.1-2020.3	35	55.8 ± 13.3	NR	AC→T	10 (28.6), 40%, HE	pCR, ypT0	13 (37.1)	8 (80.0) vs 5 (20.0)	NR
Rangan et al[43], India	NR	NR	75	NR	T1-T3: 49; T4: 26; N0: 36; N1-N3: 39	NR	57 (76.0), 50%, HE	pCR, ypT0	27 (36.0)	25 (43.9) vs 2 (11.1)	OR: [U] 6.25 (1.312-29.763), 0.025
Pang et al[18], ChiNR	Retrospective cohort	2010.1-2018.12	310	NR	T1-2: 298; T3-4: 97	AC→T	177 (85/92) (57.1), (20%) 10%, HE	pCR, ypT0	88 (28.4)	53 (31.1) vs 33 (34.5)	NR
Zhang et al[52], America	Retrospective cohort	2005-2016	58	46 (24-64)	T1: 7; T2-T4: 51; N0: 30; N1-N3: 28	AC×4 (Q3W) →T×12 (QW)	17 (29.3), 60%, HE	pCR, ypT0	26 (44.8)	12 (70.6) vs 14 (34.1)	NR
Zhao et al[50], ChiNR	Retrospective cohort	2017-2018	126	50.1 ± 11.2	T1: 78; T2-T3: 48; N0: 74; N1-N3: 52	AC→T	42 (33.3), 40%, HE	pCR, ypT0	76 (60.3)	38 (90.5) vs 38 (45.2)	NR
Cerbelli et al[40], Italy	Retrospective consecutive cohort	2011.1-2016.12	54	50 (28-75)	T1: 7; T2-T4: 47; N0: 24; N1-N3: 30	AC×4 (Q3W) →T×12 (QW)	22 (40.7), 50%, HE	pCR, ypT0/is, N0	19 (35.2)	11 (50.0) vs 8 (25.0)	OR: [U] 1.61 (0.40-6.52), 0.025
Rao et al[30], ChiNR	Retrospective consecutive cohort	2009.7-2014.6	52	46.9 (23-67)	II: 34, III: 16;	TAC	21 (40.4), CD8: ≥ 0.15, HE	pCR, ypT0 DFS OS	14 (26.9)	CD8: 10 (47.6) vs 4 (12.9)	CD8 OR: [U] 6.14 (1.6-23.8), 0.010
Lusho et al[28], Japan	Retrospective consecutive cohort	2008-2019	120	56 (28-86)	NR	TAC	18 (15.0), 30%, HE	pCR, ypT0/Tis ypN0	34 (28.3)	10 (55.6) vs 24 (23.5)	NR
Hida et al[37], Japan	Retrospective cohort	2007-2014	48	56 (22-79)	T1: 93; T2: 59; T3: 2; N0: 98; N1-N3: 56	AC×4 (Q3W) →T×12 (QW)	31 (11/20) (64.6), (50%) 10%, HE	pCR, ypT0/is, ypN0	21 (43.8)	18 (58.0) vs 3 (17.6)	NR
Hida et al[27], Japan	Retrospective consecutive cohort	2007-2014	80	NR	N0: 56; N1-N3: 24	TAC	23 (28.8), 50%, HE	pCR, ypT0/is, N0	28 (35.0)	12 (52.2) vs 16 (28.1)	NR
Kolberg et al[51], Germany	Retrospective cohort	NR	311	NR	NR	AC→T	59 (19.0), 60%, HE	pCR, ypT0	110 (35.4)	35 (59.3) vs 75 (29.8)	OR: [U] 3.44 (1.92-6.18), 0.001
Foldi et al[38], America	II RCT	2015.12-2018.11	54	NR	I: 12, II: 33, III: 14;	T→ddAC- Durvalumab (3 and 10 mg/kg)	26 (16/10) (48.1), (30%) 10%, HE	pCR, ypT0/Tis ypN0	23 (42.6)	15 (57.7) vs 8 (28.6)	NR
Abuhadra et al[16], America	Prospective cohort	2015.10-2019.11	318	52.5 (24-77)	I: 38, II: 210, III: 70;	ddAC→T+ (Atezolizumab/ Panitumumab/ Bevacizumab)	106 (33.3), 20%, HE	pCR, ypT0	130 (40.9)	68 (64.2) vs 62 (29.2)	NR
Denkert et al[33], Germany	RCT IPD pooled analysis	2010.1-2016.12	906	NR	NR	T+ Bevacizumab	646 (273/373) (71.3), (60%) 10%, HE	pCR, ypT0	333 (36.8)	253 (39.2) vs 80 (30.8)	NR
Yuan et al[34], America	II RCT	2012.1-2018.8	63	52 (28-79)	II: 55, III: 12;	TCb	28 (6/22) (45.9), (60%) 10%, HE	pCR, ypT0	30 (47.6)	17 (60.7) vs 13 (39.3)	Medium vs low1: OR: [U] 2.23 (0.74- 6.69), 0.16; high vs low1: OR: [U] 3.06 (0.49-9.30), 0.23
Sharma et al[46], America	II RCT	2015.7-2018.5	100	51 (29–70)	T1: 19; T2: 70; T3-T4: 11; N0: 70; N1-N3: 30	Arm-A: CbP + AC; Arm-B: CbD	39 (43.3), 20%, HE	pCR ypT0/is, ypN0	51 (56.7)	26 (66.7) vs 25 (49.0)	OR: [U] 2.08 (0.88-4.93), 0.096
Pons et al[45], Spain	NR	2016-2022	67	NR	T1-T2: 59; T3: 10; N0: 43; N1-N3: 26	TCb + ddAC	24 (35.8), 20%, HE	pCR, ypT0/is, ypN0	36 (53.7)	14 (58.3) vs 22 (51.2)	NR
Abuhadra et al[15], America	NR	2015.10-2020.10	408	51 (23–77)	I: 41, II: 284, III: 83	AC→TCb	143 (35.0), 20%, HE	pCR, ypT0/is, N0	166 (40.7)	85 (59.4) vs 81 (30.6)	NR
Asano et al[31], Japan	Retrospective cohort	2007-2013	61	NR	T1: 24; T2-T4: 153; N0: 41; N1-N3: 136	FEC→T	48 (78.7), 10%, HE	pCR, ypT0	28 (45.9)	26 (54.2) vs 2 (15.4)	NR
Ono et al[54], Japan	NR	1999-2007	92	52 (23-76)	II: 23, III: 36;	AC→T CEF	67 (72.8)1, high: (3-5), HE	pCR, ypT0	29 (31.5)	25 (37.3) vs 4 (16.0)	NR
Wang et al[35], America	NR	2007-2014	72	NR	T1: 5; T2: 48; T3: 15; T4: 5; N0: 38; N1-N3: 34	NR	53 (1/52) (73.6), (50%) 10%, HE	pCR, ypT0	38 (52.8)	35 (66.0) vs 3 (15.8)	NR
Dong et al[29], ChiNR	Retrospective cohort	2010.1-2014.12	170	NR	T1-2: 110; T3-4: 60	TAC	122 (74/48) (71.8), (20%) 10%, HE	pCR, ypT0 DFS OS	48 (28.2)	38 (31.1) vs 10 (24.8)	NR
Würfel et al [44], Germany	NR	2015.5-2017.4	146	NR	T1: 59; T2-T4: 90	NR	24 (16.4), 50%, HE	pCR ypT0 ypN0	56 (38.4)	16 (66.7) vs 40 (32.8)	NR
Hamy et al[42], France	NR	2015.1-2017.3	717	NR	T1-T2: 529; T3: 189; N0: 282; N1-N3: 435	NR	81 (11.3), 50%, HE	pCR, ypT0	202 (28.2)	48 (59.2) vs 154 (24.2)	OR: [U] 5.02 (4.27-5.77), 0.001
Cerbelli et al[41], Italy	Retrospective consecutive cohort	NR	59	49 (28-74)	II: 36, III: 24	NR	17 (28.8), 50%, HE	pCR, ypT0	22 (37.3)	13 (76.5) vs 9 (21.4)	NR

¹High: Tumor-infiltrating lymphocyte proportion > 10% (2 points) combined with mild (1 point) or marked (2 points) intensity.

DFS: Disease-free survival; HE: Hematoxylin eosin staining; IPD: Individual patient data; M: Multivariate analysis; NR: Not reported; OR: Odds ratio; OS: Overall survival; pCR: Pathological complete response; RCT: Randomized controlled trial; RR: Risk ratio; TIL: Tumor-infiltrating lymphocyte; U: Univariate analysis.

Table 2 Subgroup analysis examining heterogeneity among the included studies

Analysis	No. of studies	Risk ratio (95%CI)	I2 statistic (%)	P value for heterogeneity	Analytical model	P value for subgroup differences
Study design
RCT	5	1.42 (1.23-1.64)	41	0.15	FEM
Prospective cohort	2	2.24 (1.77-2.83)	0	0.64	FEM
Retrospective cohort	18	2.27 (1.84-2.80)	58	0.01	REM
Not reported	7	2.05 (1.77-2.36)	45	0.09	FEM	0.02
Cut-off
60%	2	2.01 (1.57-2.58)	0	0.90	FEM
50%	8	2.31 (1.95-2.74)	0	0.71	FEM
40%	3	3.06 (1.60-5.84)	78	0.01	REM
30%	3	2.33 (1.61-3.37)	46	0.16	FEM
20%	4	1.68 (1.29-2.20)	67	0.03	REM
10%	10	1.63 (1.24-2.15)	49	0.04	REM
Locations
Asia	12	1.90 (1.62-2.24)	46	0.04	FEM
Europe	11	2.07 (1.58-2.71)	77	0.01	REM
Americas	9	2.01 (1.76-2.30)	34	0.14	FEM	0.35
Sample size
n ≤ 80	16	2.62 (2.14-3.20)	35	0.08	FEM
n > 80	16	1.82 (1.56-2.12)	69	0.01	REM	0.04
NAT regimens
AC-T	14	2.13 (1.72-2.63)	56	0.01	REM
TAC	4	1.99 (1.43-2.75)	0	0.44	FEM
AC-T + targeted therapy	3	1.73 (1.12-2.67)	82	0.01	REM
AC-TCb	4	1.57 (1.31-1.90)	43	0.15	FEM
AC-T + Fu	2	2.75 (1.28-5.92)	0	0.61	FEM	0.02

AC: Anthracycline combined with cyclophosphamide; AC-T: Anthracycline combined with cyclophosphamide followed by paclitaxel or docetaxel; AC-T + Fu: Anthracycline combined with cyclophosphamide followed by paclitaxel or docetaxel, and fluorouracil; AC-TCb: Anthracycline combined with cyclophosphamide followed by paclitaxel or docetaxel, and platinum; FEM: Fixed-effects model; NAT: Neoadjuvant therapy; TAC: Paclitaxel or docetaxel combined with anthracycline, and cyclophosphamide; REM: Random-effects model.