The immune microenvironment and relation to outcome in patients with advanced breast cancer treated with docetaxel with or without gemcitabine

Figures & data

Table 1. Correlations of investigated biomarkers with PAM50 subtypes (n = 232)

	Total [n (%)]		Luminal A [n (%)]		Luminal B [n (%)]		Basal like [n (%)]		HER2E [n (%)]		P
Biomarker	Low	High	Low	High	Low	High	Low	High	Low	High
CD8 iTILs count ≤10 vs >10	150 (66)	79 (34)	54 (76)	17 (24)	51 (62)	31 (38)	17 (52)	16 (48)	28 (65)	15 (35)	0.08
CD8 sTILs count ≤30 vs >30	51 (22)	178 (78)	13 (18)	58 (82)	21 (26)	61 (74)	9 (27)	24 (73)	8 (19)	35 (81)	0.58
FOXP3 iTILs count <2 vs ≥2	132 (58)	95 (42)	54 (77)	16 (23)	47 (58)	34 (42)	9 (27)	24 (73)	22 (51)	21 (49)	<0.0001
FOXP3 sTILs count <3 vs ≥3	58 (26)	169 (74)	29 (41)	41 (59)	21 (26)	60 (74)	3 (9)	30 (91)	5 (12)	38 (88)	0.0004
LAG3 iTILs count 0 vs ≥1	188 (84)	37 (16)	66 (96)	3 (4)	71 (89)	9 (11)	18 (55)	15 (45)	33(77)	10 (23)	<0.0001
LAG3 sTILs count 0 vs ≥1	143 (64)	82 (36)	57 (83)	12 (17)	52 (65)	28 (35)	13 (39)	20 (61)	21 (49)	22 (51)	<0.0001
PD-1 iTILs count 0 vs ≥1	181 (80)	45 (20)	63 (91)	6 (9)	65 (79)	17 (21)	20 (63)	12 (38)	33 (77)	10 (23)	0.007
PD-1 sTILs count 0 vs ≥1	127 (56)	99 (44)	44 (64)	25 (36)	54 (66)	28 (34)	10 (31)	22 (69)	19 (44)	24 (56)	0.002
PD-L1 < 1% vs ≥1%	185 (87)	28 (13)	63 (98)	1 (2)	66 (88)	9 (12)	22 (69)	10 (31)	34 (81)	8 (10)	0.0004
HE TILs ≤1% vs >1%	135 (64)	76 (36)	45 (71)	18 (29)	55 (71)	22 (29)	15 (49)	17 (53)	20 (51)	19 (49)	0.02
CD163 TAM <56 vs ≥56	132(46.5)	92 (32.4)	41(63.1)	24 (36.9)	58(73.4)	21 (26.6)	6(18.8)	26 (81.2)	23 (59)	16 (41)	<0.001

Numbers of patients are shown and percentages of the given subtype in parentheses. Cases with missing biomarker scores not shown. iTILs: intratumoral tumor infiltrating lymphocytes, sTILs: stromal tumor infiltrating lymphocytes, HE: hematoxylin-eosin; TAM: tumor associated macrophages.

Table 2. Prognostic hazard ratios in the overall cohort for high vs low levels of immune biomarkers in univariate analysis

Biomarker (High vs Low)	HR (95% CI)
	TTP	P	OS	P
CD8 iTILs count ≤10 vs >10	1.04 (0.76–1.43)	0.81	1.10 (0.83–1.44)	0.51
CD8 sTILs count ≤30 vs >30	0.86 (0.60–1.24)	0.43	1.00 (0.73–1.37)	0.99
FOXP3 iTILs count <2 vs ≥2	0.99 (0.74–1.34)	0.96	1.21 (0.93–1.58)	0.15
FOXP3 sTILs count <3 vs ≥3	0.90 (0.64–1.25)	0.52	1.00 (0.74–1.34)	0.97
LAG3 iTILs count 0 vs ≥1	1.42 (0.95–2.14)	0.09	1.28 (0.90–1.82)	0.17
LAG3 sTILs count 0 vs ≥1	1.22 (0.89–1.67)	0.21	1.46 (1.11–1.93)	0.01
PD-1 iTILs count 0 vs ≥1	1.39 (0.97–1.96)	0.07	1.04 (0.75–1.45)	0.80
PD-1 sTILs count 0 vs ≥1	1.17 (0.87–1.57)	0.31	0.93 (0.71–1.21)	0.58
PD-L1 < 1% vs ≥1%	1.59 (1.03–2.44)	0.04	1.47 (0.98–2.20)	0.06
HE TILs ≤1% vs >1%	1.06 (0.78–1.45)	0.71	1.03 (0.78–1.37)	0.82

Abbreviations: HR: hazard ratio, TTP: time to progression, OS: overall survival, iTILs: intratumoral tumor infiltrating lymphocytes, sTILs: stromal tumor infiltrating lymphocytes, HE: hematoxylin-eosin.

Figure 1. Time to progression (TTP) and associations with CD8 levels in the SBG0102 trial population. A. CD8 iTILs and TTP in the overall cohort, B. CD8 iTILs and TTP in the non-luminal (BL and HER2E) subtypes C. TTP for the CD8 iTILs low group, stratified by treatment with docetaxel or docetaxel + gemcitabine (DG) D. TTP for the CD8 iTILs high group, stratified by treatment with docetaxel or DG. Corresponding figures for overall survival can be seen in Supplementary Figure S3. iTILs: intratumoral tumor infiltrating lymphocytes

Table 3. Predictive hazard ratios for treatment effect for TTP in patients treated with docetaxel + gemcitabine vs docetaxel alone. Values shown for multivariate analysis for the whole subset, and for the focused set of analyses performed on the non-luminal subset ^a Basal like + HER2E

	Whole cohort			Non-luminal subset^a
Biomarker	HR (95% CI)		Pinteraction	HR (95% CI)		Pinteraction
	Low	High		Low	High
CD8 iTILs count ≤10 vs >10	0.71 (0.49–1.02)	0.73 (0.43–1.22)	0.93	0.42 (0.21–0.81)	0.76 (0.33–1.74)	0.27
CD8 sTILs count ≤30 vs >30	0.80 (0.45–1.40)	0.70 (0.51–0.96)	0.79	0.31 (0.10–1.02)	0.63 (0.35–1.13)	0.29
FOXP3 iTILs count <2 vs ≥2	0.59 (0.39–0.89)	0.88 (0.56–1.38)	0.21	0.22 (0.09–0.52)	0.92 (0.47–1.80)	0.01
FOXP3 sTILs count <3 vs ≥3	0.76 (0.41–1.40)	0.72 (0.51–1.02)	0.87
LAG3 iTILs count 0 vs ≥1	0.69 (0.50–0.96)	0.77 (0.37–1.63)	0.79
LAG3 sTILs count 0 vs ≥1	0.71 (0.48–1.04)	0.69 (0.42–1.13)	0.96
PD-1 iTILs count 0 vs ≥1	0.68 (0.48–0.96)	0.88 (0.47–1.67)	0.48
PD-1 sTILs count 0 vs ≥1	0.75 (0.49–1.14)	0.66 (0.42–1.02)	0.66
PD-L1 < 1% vs ≥1%	0.68 (0.48–0.95)	0.85 (0.39–1.88)	0.60
HE TILs ≤1% vs >1%	0.66 (0.45–0.98)	0.90 (0.54–1.48)	0.35
CD163 TAM <56 vs ≥56	0.72 (0.47–1.10)	0.51 (0.32–0.83)	0.30	0.39 (0.16–0.93)	0.64 (0.32–1.30)	0.38

Abbreviations: HR: hazard ratio, TTP: time to progression, iTILs: intratumoral tumor infiltrating lymphocytes, sTILs: stromal tumor infiltrating lymphocytes, HE: hematoxylin-eosin, TAM: tumor associated macrophages.

Figure 2. Time to progression (TTP) and associations with FOXP-3 iTILs levels and treatment arm in the SBG0102 trial population (A+B) and in the nonluminal subtypes (C+D). A. TTP for the FOXP3 iTILs low group, stratified by treatment with docetaxel or docetaxel + gemcitabine (DG), B. TTP for the FOXP3 iTILs high group, stratified by treatment with docetaxel or docetaxel + gemcitabine, C. TTP for the FOXP3 iTILs low non-luminal group, stratified by treatment with docetaxel or docetaxel + gemcitabine. D. TTP for the FOXP3 iTILs high non-luminal group, stratified by treatment with docetaxel or DG. Corresponding figures for overall survival can be seen in Supplementary Figure S4. iTILs: intratumoral tumor infiltrating lymphocytes