A Real-World Data Retrospective Cohort Study of Low Estrogen Receptor-Positive Early Breast Cancer: Natural History and Treatment Outcomes

Figures & data

Table 1 Cohort Description

Characteristic	Total Cohort (N = 4697)	Triple Negative (N = 634)	ER^+- Low (N = 83)	ER^+- Intermediate (N = 36)	ER^+- High (N = 3944)	p. Overall
Gender, no. (%)						0.084
Female	4659 (99.2)	634 (100.0)	83 (100.0)	36 (100.0)	3906 (99.0)
Male	38 (0.8)	0 (0.0)	0 (0.0)	0 (0.0)	38 (1.0)
Race, no. (%)						<0.001
White	3126 (66.6)	388 (61.2)	50 (60.2)	24 (66.7)	2664 (67.5)
Black or African American	432 (9.2)	122 (19.2)	16 (19.3)	6 (16.7)	288 (7.3)
Asian	123 (2.6)	9 (1.4)	1 (1.2)	1 (2.8)	112 (2.8)
Other Race	633 (13.5)	72 (11.4)	7 (8.4)	5 (13.9)	549 (13.9)
“Missing”	383 (8.2)	43 (6.8)	9 (10.8)	0 (0.0)	331 (8.4)
Ethnicity, no. (%)						0.334
Hispanic or Latino	308 (6.6)	51 (8.0)	7 (8.4)	3 (8.3)	247 (6.3)
Non-Hispanic	4389 (93.4)	583 (92.0)	76 (91.6)	33 (91.7)	3697 (93.7)
MenopausalStatus, no. (%)						0.023
N/A - patient is male	37 (0.8)	0 (0.0)	0 (0.0)	0 (0.0)	37 (0.9)
Perimenopausal	114 (2.4)	16 (2.5)	1 (1.2)	2 (5.6)	95 (2.4)
Postmenopausal	3400 (72.4)	436 (68.8)	54 (65.1)	24 (66.7)	2886 (73.2)
Premenopausal	843 (17.9)	126 (19.9)	21 (25.3)	5 (13.9)	691 (17.5)
Unknown/not documented	303 (6.5)	56 (8.8)	7 (8.4)	5 (13.9)	235 (6.0)
Histology_, no. (%)						0.001
Ductal	3829 (81.5)	581 (91.6)	75 (90.4)	31 (86.1)	3142 (79.7)
Lobular	579 (12.3)	10 (1.6)	3 (3.6)	2 (5.6)	564 (14.3)
Mixed	107 (2.3)	9 (1.4)	1 (1.2)	1 (2.8)	96 (2.4)
Other	176 (3.7)	33 (5.2)	4 (4.8)	2 (5.6)	137 (3.5)
“Missing”	6 (0.1)	1 (0.2)	0 (0.0)	0 (0.0)	5 (0.1)
TumorGrade_, no. (%)						<0.001
Grade 1	1144 (24.4)	10 (1.6)	4 (4.8)	3 (8.3)	1127 (28.6)
Grade 2	2247 (47.8)	113 (17.8)	15 (18.1)	11 (30.6)	2108 (53.4)
Grade 3	1267 (27.0)	508 (80.1)	61 (73.5)	22 (61.1)	676 (17.1)
“Missing”	39 (0.8)	3 (0.5)	3 (3.6)	0 (0.0)	33 (0.8)
KI67, no. (%)						<0.001
<20%	1161 (24.7)	28 (4.4)	10 (12.0)	1 (2.8)	1122 (28.4)
≥20%	1112 (23.7)	285 (45.0)	30 (36.1)	14 (38.9)	783 (19.9)
“Missing”	2424 (51.6)	321 (50.6)	43 (51.8)	21 (58.3)	2039 (51.7)
Clinical_T_stage, no. (%)						<0.001
1	893 (19.0)	110 (17.4)	14 (16.9)	5 (13.9)	764 (19.4)
2	537 (11.4)	135 (21.3)	16 (19.3)	7 (19.4)	379 (9.6)
3	223 (4.7)	64 (10.1)	6 (7.2)	3 (8.3)	150 (3.8)
“Missing”	3044 (64.8)	325 (51.3)	47 (56.6)	21 (58.3)	2651 (67.2)
Clinical_N_stage, no. (%)						<0.001
0	1095 (23.3)	160 (25.2)	19 (22.9)	9 (25.0)	907 (23.0)
1	338 (7.2)	100 (15.8)	10 (12.0)	4 (11.1)	224 (5.7)
2	94 (2.0)	31 (4.9)	3 (3.6)	1 (2.8)	59 (1.5)
“Missing”	3170 (67.5)	343 (54.1)	51 (61.4)	22 (61.1)	2754 (69.8)
Radiotherapy, no. (%)						0.922
No/unknown	1709 (36.4)	237 (37.4)	29 (34.9)	14 (38.9)	1429 (36.2)
Yes	2988 (63.6)	397 (62.6)	54 (65.1)	22 (61.1)	2515 (63.8)
Endocrine Therapy, no. (%)						0.000
No	938 (20.0)	588 (92.7)	42 (50.6)	8 (22.2)	300 (7.6)
Yes	3759 (80.0)	46 (7.3)	41 (49.4)	28 (77.8)	3644 (92.4)
Chemotherapy, no. (%)						<0.001
Anthracycline without taxane	56 (1.2)	12 (1.9)	0 (0.0)	3 (8.3)	41 (1.0)
Taxane without anthracycline	593 (12.6)	132 (20.8)	15 (18.1)	4 (11.1)	442 (11.2)
Taxane and anthracycline	746 (15.9)	270 (42.6)	36 (43.4)	19 (52.8)	421 (10.7)
Other	81 (1.7)	13 (2.1)	0 (0.0)	2 (5.6)	66 (1.7)
No info on chemotherapy	3221 (68.6)	207 (32.6)	32 (38.6)	8 (22.2)	2974 (75.4)
Surgery, no. (%)						<0.001
Mastectomy	2885 (61.4)	330 (52.1)	42 (50.6)	20 (55.6)	2493 (63.2)
Other	1704 (36.3)	280 (44.2)	41 (49.4)	16 (44.4)	1367 (34.7)
“Missing”	108 (2.3)	24 (3.8)	0 (0.0)	0 (0.0)	84 (2.1)
Age (mean age in years)	63.0 [53.1;71.5]	58.7 [50.1;67.6]	54.9 [44.4;67.0]	60.7 [54.6;66.1]	63.9 [53.9;72.1]	<0.001
Follow_up (mean time in months)	36.0 [17.0;60.0]	34.0 [16.0;58.0]	30.5 [14.2;57.8]	30.0 [16.5;51.0]	37.0 [17.0;60.0]	0.073

Notes: Triple negative defined as ER and PR <1% staining; ER⁺-low 1–9.99% staining; ER⁺-intermediate 10%-19.99%; ER⁺-high ≥20% staining.

Abbreviations: ER, estrogen receptor; PR, progesterone receptor.

Figure 1 Clinical outcomes of patients with ER⁺ and TNBC BCs. Triple negative was defined as ER/PR < 1% staining and HER2- (ie, IHC 0/1+ and non-amplified); ER⁺ ≥ 1% staining. Panel (A) shows recurrence-free survival; panel (B) shows overall survival.

Abbreviations: BC, breast cancer; CI, confidence interval; ER, estrogen receptor; HR, hormone receptor; HER2, human epidermal growth factor receptor 2; IHC, immunohistochemistry; PR, progesterone receptor, NE, not estimated.

Table 2 Comparison Between ER⁺-Low and ER⁺-Intermediate Groups

Characteristic	ER^+- Low (N = 83)	ER^+- Intermediate (N = 36)	p. Overall
Race, no. (%)			0.273
White	50 (60.2)	24 (66.7)
Black or African American	16 (19.3)	6 (16.7)
Asian	1 (1.2)	1 (2.8)
Other Race	7 (8.4)	5 (13.9)
“Missing”	9 (10.8)	0 (0.0)
Ethnicity, no. (%)			1.000
Hispanic or Latino	7 (8.4)	3 (8.3)
Non-Hispanic	76 (91.6)	33 (91.7)
MenopausalStatus, no. (%)			0.245
Perimenopausal	1 (1.2)	2 (5.6)
Postmenopausal	54 (65.1)	24 (66.7)
Premenopausal	21 (25.3)	5 (13.9)
Unknown/not documented	7 (8.4)	5 (13.9)
Histology_, no. (%)			0.941
Ductal	75 (90.4)	31 (86.1)
Lobular	3 (3.6)	2 (5.6)
Mixed	1 (1.2)	1 (2.8)
Other	4 (4.8)	2 (5.6)
TumorGrade_, no. (%)			0.225
Grade 1	4 (4.8)	3 (8.3)
Grade 2	15 (18.1)	11 (30.6)
Grade 3	61 (73.5)	22 (61.1)
“Missing”	3 (3.6)	0 (0.0)
KI67, no. (%)			0.306
<20	10 (12.0)	1 (2.8)
≥20	30 (36.1)	14 (38.9)
“Missing”	43 (51.8)	21 (58.3)
Clinical_T_stage, no. (%)			0.985
1	14 (16.9)	5 (13.9)
2	16 (19.3)	7 (19.4)
3	6 (7.2)	3 (8.3)
“Missing”	47 (56.6)	21 (58.3)
Clinical_N_stage, no. (%)			1.000
0	19 (22.9)	9 (25.0)
1	10 (12.0)	4 (11.1)
2	3 (3.6)	1 (2.8)
“Missing”	51 (61.4)	22 (61.1)
PrimaryRadiotherapy, no. (%)			0.838
No/unknown	29 (34.9)	14 (38.9)
Yes	54 (65.1)	22 (61.1)
EndocrineTherapy, no. (%)			0.007
No	42 (50.6)	8 (22.2)
Yes	41 (49.4)	28 (77.8)
Chemotherapy, no. (%)			0.004
Anthracycline without taxane	0 (0.0)	3 (8.3)
Taxane without anthracycline	15 (18.1)	4 (11.1)
Taxane and anthracycline	36 (43.4)	19 (52.8)
Other	0 (0.0)	2 (5.6)
No info on chemotherapy	32 (38.6)	8 (22.2)
Surgery, no. (%)			0.766
Mastectomy	42 (50.6)	20 (55.6)
Other	41 (49.4)	16 (44.4)
Age (mean age in years)	54.9 [44.4;67.0]	60.7 [54.6;66.1]	0.130

Note: ER+-low 1–9.99 staining and ER+-intermediate 10–19.99.

Abbreviation: Estrogen receptor, ER.

Figure 2 Clinical outcomes of patients with TN, ER⁺-low, ER⁺-intermediate, and ER⁺-high BCs. Triple negative was defined as ER and PR < 1% staining,; ER⁺-low, 1–9.99% staining; ER⁺-intermediate, 10–19.99%; ER⁺-high ≥ 20% staining. Panel (A) shows recurrence-free survival; panel (B) shows overall survival.

Abbreviations: BC, breast cancer; CI, confidence interval; ER, estrogen receptor; HR, hormone receptor; HER2, human epidermal growth factor receptor 2; NE, not estimated; TN, triple negative.

Table 3 Cox Proportional Hazards Regression -Comparative Analysis of Recurrence-Free Survival (RFS) and Overall Survival of ER⁺-1–19.9% Vs ER⁺-≥20% Staining

Recurrence-Free Survival Analysis of Maximum Likelihood Estimates
Parameter		Degree of Freedom	Parameter Estimate	Standard Error	Chi-Square	P value	Hazard Ratio	95% Hazard Ratio Confidence Limits
ER^+-≥20%	Ref ER^+-1–19.9%	1	−0.59231	0.26311	5.0678	0.024	0.553	0.330	0.926
Age under 50	Ref (50 or above)	1	−0.14587	0.15137	0.9286	0.335	0.864	0.642	1.163
Endocrine therapy	Ref (no)	1	−0.89719	0.17325	26.8186	<0.001	0.408	0.290	0.573
Primary radiotherapy	Ref (no)	1	−0.55534	0.11269	24.2846	<0.001	0.574	0.460	0.716
Overall Survival Analysis of Maximum Likelihood Estimates
ER^+-≥20%	Ref ER^+-1–19.9%	1	−0.69144	0.30380	5.1799	0.023	0.501	0.276	0.908
Age under 50	Ref (50 or above)	1	−0.60046	0.20565	8.5258	0.004	0.549	0.367	0.821
Endocrine therapy	Ref (no)	1	−0.79007	0.20488	14.8702	0.001	0.454	0.304	0.678
Primary radiotherapy	Ref (no)	1	−0.63333	0.13218	22.9577	<0.001	0.531	0.410	0.688

Notes: Fitting model to the test set, at 3 years recurrence-free survival, Harrell’s c-statistic = 0.677. Fitting model to the test set, at 3 years overall survival, Harrell’s c-statistic = 0.698.

Abbreviations: CI, confidence interval, CI; ER, estrogen receptor; Ref, reference.

Table 4 Endocrine Therapy Treatment Effect (Univariate Analysis)

		Recurrence-Free Survival			Overall Survival
Parameter	Patients, No.	Events, No.	HR (95% CI)	P value	Events, No.	HR (95% CI)	P value
Patient who received ET
ER^+-low (1–9.99%)	41	5	Ref	Ref	3	Ref	Ref
ER^+-intermediate (10–19.9%)	28	5	1.47 (0.42, 5.08)	0.545	5	2.57 (0.61, 10.77)	0.196
Patient who did not receive ET
ER^+-low (1–9.99%)	42	16	Ref	Ref	10	Ref	Ref
ER^+-intermediate (10–19.9%)	8	2	0.38 (0.05,2.86)	0.346	1	n/a	n/a

Abbreviations: CI, confidence interval; ER, estrogen receptor; HR, hazard ratio; n/a, not applicable; Ref, reference, inadequate sample size to estimate.

Figure 3 Clinical outcomes of patients ER⁺-1–19.9% staining and ER⁺-≥ 20% staining. Panel (A) shows recurrence-free survival for the training set, which includes two-thirds of evaluable patients; panel (B) shows recurrence-free survival for the test set, which includes one-third of evaluable patients; panel (C) shows overall survival. For the training set; panel (D) shows overall survival for the test set.

Abbreviations: BC, breast cancer; CI, confidence interval; ER, estrogen receptor; HER2, human epidermal growth factor receptor 2; NE, not estimated; TN, triple negative.