Table 1.

TILs as biomarkers in breast cancer: subtype-specific prognostic and outcome measures.

Subtype	Setting	Setting/Population Details	N	Subgroup	Outcome Measure	Outcomes		p Value	Study Ref. No.
TNBC	early BC	cancer treated with AChT	2148	10% sTILs increment	iDFS	HR 0.87 (95% CI: 0.83 to 0.91)		<0.000001	[16]
					dDFS	HR 0.83 (95% CI: 0.79 to 0.88)		<0.000001
					OS	HR 0.84 (95% CI: 0.79 to 0.89)		<0.000001
		node-negative cancer treated with AChT	706	sTILs ≥ 30% vs. <30%	3-year iDFS	92% (95% CI: 0.89–0.96) vs. 88% (95% CI: 0.85–0.90)		<0.0001
					3-year dDFS	97% (95% CI: 0.95–0.99) vs. 91% (95% CI: 0.88–0.83)		<0.0001
					3-year OS	99% (95% CI: 0.97–1.00) vs. 95% (95% CI: 0.93–0.97)		<0.0001
		cancer treated with NAChT	906	sTILs < 10%	pCR	31%		<0.0001	[17]
				sTILs 11–59%		31%
				sTILs ≥ 60%		50%
				10% sTILs increment	DFS	HR 0.93 (95% CI: 0.87–0.98)		0.011
					OS	HR 0.92 (95% CI: (0.86–0.99)		0.032
		stage I–III treated with NAChT	134	TILs > 20% vs. <20%	5-year RFS	100% vs. 82.6%		<0.001	[18]
					5-year OS	100% vs. 90.1%		<0.007
		cancer treated with NAChIT	117	sTILs ≥ 30% vs. <30%	pCR	78% vs. 45% (OR: 4.39; 95% CI: 1.63–11.82)		0.003	[19]
			174	TILs ≥ 11% vs. <11%	iDFS	HR 0.55 (95% CI: 0.28–1.07)		0.0079	[21]
		stage I without (N)AChT	1041	sTILs ≥ 30% vs. <30%	BCSS	96% vs. 87% HR 0.45 (95% CI: 0.26–0.77)		ND	[24]
		stage I cancer in elderly patients treated without ChT	74	≥30% sTILs	5-year iDFS	91% (95% CI: 84% to 96%)		ND	[22]
					5-year dDFS	97% (95% CI: 93% to 100%)
					5-year OS	98% (95% CI: 95% to 100%)
		cancer in elderly patients treated without ChT	476	10% sTILs increment	iDFS	HR 0.93 (95% CI: 0.82–0.97)		0.012
					dDFS	HR 0.86 (95% CI: 0.77–0.95)		<0.01
					OS	HR 0.88 (95% CI: 0.79–0.98)		0.015
		cancer in young patients treated without ChT	441	10% sTILs increment	OS	HR 0.82 (95%CI 95% CI: 0.77–0.88)		<0.001	[23]
				sTILs < 30%	cumulative incidence of a distant metastases or death	38.4% (95% CI: 32.1 to 44.6)		ND
				sTILs > 75%		2.1% (95% CI: 0 to 5.0)
	advanced/metastatic BC	Immunotherapy in metastatic BC	228	sTILs ≥ 10% vs. <10%	ORR	18.6% vs. 6.1%		0.012	[29]
HER2+	early BC	cancer treated with AChT + T	866	sTILs < 20%; 9 weeks of T vs. sTILs < 20%; 1 year of T	5-year dDFS	88.8% vs. 93.3% (HR 1.75, 95% CI: 1.09–2.8)		0.02	[33]
				sTILs ≥ 20%; 9 weeks of T vs. sTILs ≥ 20%; 1 year of T		97.6% vs. 93.7% (HR 0.23, 95% CI: 0.05–1.09)		0.064
		cancer treated with AChT + T	4097	10% TILs increment	recurrence risk	HR 0.87 (95%CI: 0.84–0.9)		<0.0001	[34]
		node positive cancer treated with anthracycline ChT	297	10% sTILs increment	DFS	ND		0.042	[32]
					OS	ND		0.018
		cancer treated with NAChT + anti-HER agent	9145	high TILs vs. low TILs	pCR	pooled OR 2.19 (95% CI: 1.06–4.52)		0.035	[35]
					DFS	pooled HR 0.95 (95% CI: 0.92–0.98)		0.0003
					OS	pooled HR 0.93 (95% CI: 0.87–0.99)		0.01
		cancer treated with NAChT + T, L or T + L	1256	high TILs vs. low TILs	pCR	OR 2.46 (95% CI: 1.36–4.43)		0.035	[36]
		cancer treated with NAChT/AChT	1801	10% TILs increment	pCR	pooled OR 1.27 (95% CI: 1.19–1.35)		0.01	[37]
			1985		OS	HR 0.92 (95% CI: 0.89–0.95)		0.06
		cancer treated with NAChT +/− T	107	TILs ≤ 25% vs. >25%	DFS	HR 3.23 (95% CI: 1.05–9.93)		0.03	[9]
		cancer treated with NAChT + T/P or both or T + P alone	243	TILs < 5%	pCR	TH	0%	TH 0.157 THP 0.240 HP 0.413 TP 0.685 combined 0.062	[38]
						THP	28.6%
						HP	0%
						TP	12.5%
						combined TH, HP, TP	4.3%
				TILs 5–49%		TH	36.4%
						THP	48.9%
						HP	19.9%
						TP	25%
						combined TH, HP, TP	26.9%
				TILs ≥ 50%		TH	33.3%
						THP	22.2%
						HP	20%
						TP	28.6%
						combined TH, HP, TP	26.7%
		cancer treated with ChT + T + P	213	10% TILs increment	pCR	OR: 1.12 (95% CI: 0.95–1.31)		0.17	[39]
					EFS	adjusted OR: 0.75 (95% CI: 0.56 –1.00)		0.05
	advanced/metastatic BC	cancer treated with ChT + T +/− P	678	10% sTILs increment	OS	adjusted HR 0.89 (95% CI: 0.83–0.96)		0.0014	[42]
				sTILs > 20% vs. ≤20%		HR 0.76, 95%CI: 0.6–0.96		0.021
		cancer treated with ChT+ T or L	614	sTILs < 5% vs. ≥5%	PFS	HR 1.04 (95% CI: 0.84–1.28)		0.74	[43]
Luminal BC	early BC	cancer treated with NAChT	1366	TILs < 11%	pCR	6%	OR 1.31 (95% CI: 1.23–1.41)	<0.0001	[17]
				TILs 11–59%		11%
				TILs ≥ 60%		28%
			832	TILs < 11% vs. ≥11%	OS	HR 1.1 (95% CI: 1.02–1.19)		0.011
			1597	high TILs vs. low TILs	pCR	OR: 1.154 (95% CI: 0.789 –1.690)		0.46	[47]
			1829		OS	HR 1.077 (95% CI: 1.016 –1.141)		0.012
		cancer treated with NAChT and ET + nivolumab	344	sTILs ≥ 1% vs. <1%	pCR	ND		ND	[48]
	early and advanced BC	single hormone receptor-positive BC	197	TILs > 10% vs. <10%	risk of death	HR 3.14 (95% CI: 1.37–7.19)		0.006	[52]
DCIS		carcinoma in situ treated with any treatment	534	dense touching TILs vs. sparse touching TILs	recurrence-free interval	HR 2.573 (95% CI: 1.412–4.69)		0.002	[54]
		carcinoma in situ treated with any treatment	283	TILs > 17% vs. <17%	recurrence risk	HR 2.97 (95% CI: 1.17–7.51)		0.02	[55]
		carcinoma in situ treated with surgery +/− RT; HT	2941	TILs ≥ 50% vs. <50%	ipsilateral in situ or invasive recurrence	OR: 2.05 (95% CI: 1.03–4.08)		0.402	[57]

Legend: AChT—adjuvant chemotherapy; BCSS—breast cancer-specific survival; ChT—chemotherapy; HT—hormonotherapy; L—lapatinib; NAChT—neoadjuvant chemotherapy; NAChIT—neoadjuvant chemo-immuno therapy; ND—no data; ORR—objective response rate; P—pertuzumab; RFS—relapse-free survival; RT—radiotherapy; T—trastuzumab.