Low Estrogen Receptor (ER)–Positive Breast Cancer and Neoadjuvant Systemic Chemotherapy: Is Response Similar to Typical ER-Positive or ER-Negative Disease?

Low Estrogen Receptor (ER)–Positive Breast Cancer and Neoadjuvant Systemic Chemotherapy: Is... Abstract Objectives Pathologic complete response (pCR) rate after neoadjuvant chemotherapy was compared between 141 estrogen receptor (ER)–negative (43%), 41 low ER+ (13%), 47 moderate ER+ (14%), and 98 high ER+ (30%) tumors. Methods Human epidermal growth factor receptor 2–positive cases, cases without semiquantitative ER score, and patients treated with neoadjuvant endocrine therapy alone were excluded. Results The pCR rate of low ER+ tumors was similar to the pCR rate of ER– tumors (37% and 26% for low ER and ER– respectively, P = .1722) but significantly different from the pCR rate of moderately ER+ (11%, P = .0049) and high ER+ tumors (4%, P < .0001). Patients with pCR had an excellent prognosis regardless of the ER status. In patients with residual disease (no pCR), the recurrence and death rate were higher in ER– and low ER+ cases compared with moderate and high ER+ cases. Conclusions Low ER+ breast cancers are biologically similar to ER– tumors. Semiquantitative ER H-score is an important determinant of response to neoadjuvant chemotherapy. Low ER+, Moderate ER+, High ER+, Neoadjuvant chemotherapy, Pathologic complete response, ER H-score, Immunohistochemistry The primary clinically relevant subsets of breast cancers are estrogen receptor (ER)–positive and ER– groups, with progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) status also playing a significant role in clinical management. The College of American Pathologists (CAP) and American Society of Clinical Oncology (ASCO) define ER+ tumors as tumors expressing ER (by immunohistochemistry) in 1% or more of the tumor cells.1 This low bar is set based on studies showing a beneficial response to antiestrogen therapy in such cancers.2 It has been recognized over the years that semiquantitative ER results provide more information than a mere positive and negative result, and ASCO/CAP also recommends providing semiquantitative results.1,3 However, there are only limited data on the clinical usefulness of semiquantitative hormone receptor results. A few studies have shown an increasing benefit of hormonal therapy with an increasing degree of ER expression.4 Semiquantitative hormone receptor results are now also used in multivariable models to provide additional information regarding chemotherapy benefit.5-8 Availability of semiquantitative results for ER allows us to explore the possibility that weakly or low ER+ tumors form a distinct subgroup. A few studies have shown that tumors with ER expression in less than 10% cells likely behave like ER– tumors.9-12 We have also shown that the morphologic features of low ER+ tumors are similar to the morphologic features of ER– tumors.13 In this study, we have evaluated the pathologic response to neoadjuvant chemotherapy in low ER+ tumors and compared it with ER– tumors, moderately ER+ tumors, and high ER+ tumors. We have further explored the differences in recurrence rate and survival with respect to the degree of ER expression. Materials and Methods After institutional review board approval from the University of Pittsburgh, a retrospective review of a prospectively maintained database was conducted on 614 patients who received neoadjuvant therapy from 2010 to 2014 at Magee-Womens Hospital of the University of Pittsburgh Medical Center. The following exclusion criteria were applied for case selection: lack of semiquantitative ER H-score, cases that received neoadjuvant hormonal therapy only (the majority of such cases were strongly ER+), and unequivocally HER2+ cases. The unequivocal HER2+ refers to cases with an immunohistochemical score of 3+ or fluorescence in situ hybridization amplified (by 2013 ASCO/CAP criteria) if the immunohistochemical score was 2+. After excluding these cases, 327 remaining cases formed the basis of this study. Patient charts were reviewed, with respect to pathology report, operative report, chemotherapy regimen, and clinical outcomes. ER+ patients received hormonal therapy after surgery in addition to the neoadjuvant chemotherapy, and ER– patients received only neoadjuvant chemotherapy as per standard protocol. Pathologic complete response (pCR) was defined as the absence of invasive tumor in the breast resection specimen and regional lymph nodes. Residual in situ carcinoma was allowed. In addition to pCR, estimated tumor size/volume reduction in the breast was calculated using the following equation: estimated percent tumor size/volume reduction = [(pretherapy clinical size – “revised” pathology size)/pretherapy clinical size] * 100. The “revised” pathology tumor size is calculated by multiplying the largest dimension of the gross tumor bed by the invasive tumor cellularity of the tumor bed in comparison to the pretherapy core biopsy sample.14 Although our institution now uses the international working group recommended residual cancer burden method, such information was not available for the cases used in this study.15 Hormone receptor values were reported using the semiquantitative histochemical or H-score method. This system is a sum of percent staining multiplied by intensity score (0 = absent, 1 = weak, 2 = moderate, 3 =strong), with the resulting score ranging from 0 to 300.16,17 Estrogen receptor values were grouped into four categories for the purposes of our analysis: ER– (H-score = 0), low ER+ (H-score 1-100), moderate ER+ (H-score 101-200), and high ER+ (H-score 201-300). Image 1 shows examples of the different categories. Groups were analyzed for overall pathologic complete response, tumor volume reduction, nodal status, and disease-free and overall survival. Image 1 View largeDownload slide Classification of breast cancers based on estrogen receptor (ER) reactivity. A, ER– tumor with H-score of 0 (percentage of cells staining 0, 100%; 1+, 0%; 2+, 0%; 3+, 0%). B, Low ER+ tumor with H-score of 60 (percentage of cells staining 0, 50%; 1+, 40%; 2+, 10%; 3+, 0%). C, Moderate ER+ tumor with H-score of 170 (percentage of cells staining 0, 10%; 1+, 30%; 2+, 40%; 3+, 20%). D, High ER+ tumor with H-score of 300 (percentage of cells staining 0, 0%; 1+, 0%; 2+, 0%; 3+, 100%). All photomicrographs at ×200. Image 1 View largeDownload slide Classification of breast cancers based on estrogen receptor (ER) reactivity. A, ER– tumor with H-score of 0 (percentage of cells staining 0, 100%; 1+, 0%; 2+, 0%; 3+, 0%). B, Low ER+ tumor with H-score of 60 (percentage of cells staining 0, 50%; 1+, 40%; 2+, 10%; 3+, 0%). C, Moderate ER+ tumor with H-score of 170 (percentage of cells staining 0, 10%; 1+, 30%; 2+, 40%; 3+, 20%). D, High ER+ tumor with H-score of 300 (percentage of cells staining 0, 0%; 1+, 0%; 2+, 0%; 3+, 100%). All photomicrographs at ×200. Mean follow-up time was 33.6 months (median, 31.6 months; range, 7.5-70.3 months). Kaplan-Meier survival curves for disease-free survival and overall survival were analyzed with respect to ER levels, and P values were obtained using the log-rank test. Statistical analysis was performed using the R Project for Statistical Computing (Vienna, Austria). For continuous variables, the P value was obtained from the two-sided Wilcoxon rank-sum test. For categorical variables, the P value was obtained from the two-sided Fisher exact test. Patients with missing/unknown information were excluded from the test. Confidence intervals were obtained from Wald normal approximation. Logistic regression was performed to predict pCR within ER+ tumors. Prediction performance of ER status, Magee Equation 3 (ME3),6,7 and their combination were compared by area under the curve (AUC) analysis. Results Of the 327 patients eligible for this study, there were 141 (43%) patients in the ER– group, 41 (13%) in the low ER group, 47 (14%) in the moderate ER group, and 98 (30%) in the high ER group. The pCR rates of ER–, low ER+, moderate ER+, and high ER+ tumors were 25.5%, 36.6%, 10.6%, and 4.1%, respectively Table 1. The pCR rate of low ER+ tumors was similar to that of ER– tumors (P = .1722) and significantly different from moderate (P = .0049) and high ER+ tumors (P < .0001). In addition to pCR, tumor size/volume reduction in the breast was also evaluated. The tumor size/volume reduction of 78% in low ER+ tumors was similar to the average size reduction in ER– tumors (70% average size reduction, P = .2358) and moderate ER+ tumors (71%, P = .3518) but was significantly different from the size reduction in high ER+ tumors (58%, P = .0012). Furthermore, each group was compared with the low ER+ group with respect to patient and tumor characteristics Table 2, Table 3, and Table 4. No statistically significant differences were identified between ER– and low ER+ tumors (Table 2). The patients with moderately ER+ tumors were slightly younger and more frequently premenopausal compared with the low ER+ tumor group (Table 3). The moderately and high ER+ tumors were more frequently PR+, showed higher PR H-scores, had a lower pretherapy nuclear grade, and had a lower Ki-67 labeling index compared with the low ER+ group (Tables 3 and 4). The high ER+ tumors were also more frequently of the lobular phenotype and showed a significantly higher number of white patients compared with the low ER+ tumors (Table 4). Table 1 Pathologic Complete Response Rate in Different Estrogen Receptor (ER) Score Categories ER Score (Category) No. Pathologic Complete Response, No. (%) P Value (Comparison With Low ER+ Cases) 0 (ER negative) 141 36 (26%) .1722 1-100 (low ER+) 41 15 (37%) Reference 101-200 (moderate ER+) 47 5 (11%) .0049a 201-300 (high ER+) 98 4 (4%) <.0001a ER Score (Category) No. Pathologic Complete Response, No. (%) P Value (Comparison With Low ER+ Cases) 0 (ER negative) 141 36 (26%) .1722 1-100 (low ER+) 41 15 (37%) Reference 101-200 (moderate ER+) 47 5 (11%) .0049a 201-300 (high ER+) 98 4 (4%) <.0001a ER, estrogen receptor. aStatistically significant. View Large Table 1 Pathologic Complete Response Rate in Different Estrogen Receptor (ER) Score Categories ER Score (Category) No. Pathologic Complete Response, No. (%) P Value (Comparison With Low ER+ Cases) 0 (ER negative) 141 36 (26%) .1722 1-100 (low ER+) 41 15 (37%) Reference 101-200 (moderate ER+) 47 5 (11%) .0049a 201-300 (high ER+) 98 4 (4%) <.0001a ER Score (Category) No. Pathologic Complete Response, No. (%) P Value (Comparison With Low ER+ Cases) 0 (ER negative) 141 36 (26%) .1722 1-100 (low ER+) 41 15 (37%) Reference 101-200 (moderate ER+) 47 5 (11%) .0049a 201-300 (high ER+) 98 4 (4%) <.0001a ER, estrogen receptor. aStatistically significant. View Large Table 2 Patient and Tumor Characteristics for “Low ER+” and ER– Casesa Characteristic Low ER+ (n = 41) ER– (n = 141) P Value Continuous variables, mean (SD)  Age, y 53.9 (12.0) 52.4 (11.5) .3685  Age at menarche, y 12.8 (1.5), unknown: 8 13.1 (1.8), unknown: 43 .3937  Body mass index, kg/m2 28.3 (5.5), unknown: 13 29.1 (9.7), unknown: 55 .7520  Pretherapy tumor size, cm 4.6 (4.4), unknown: 7 3.9 (3.6), unknown: 25 .4697  Ki-67 labeling index, % 74.2 (24.0), unknown: 1 70.9 (24.1), unknown: 13 .3446  Progesterone receptor H-score 6.1 (22.2) 0.9 (5.9) .2370 Categorical variables, No. (%)  Menopausal status   Premenopausal 16 (39.0) 60 (42.6) .8562   Postmenopausal 24 (58.5) 79 (56)   Unknown 1 (2.5) 2 (1.4)  Race   White 34 (82.9) 120 (85.1) .6077   Black 7 (17.1) 18 (12.8)   Asian 0 (0) 0 (0)   Other 0 (0) 3 (2.1)  Neoadjuvant chemotherapy regimen   ACT 22 (53.7) 62 (44.0) .2907   Other and unknown 19 (46.3) 79 (56.0)  Pretherapy lymph node status   Core biopsy positive 14 (34.1) 49 (34.8) .6880   Core biopsy negative 18 (43.9) 52 (36.8)   Unknown 9 (22.0) 40 (28.4)  Pretherapy nuclear grade   Nuclear grade 1 or 2 2 (4.9) 17 (12.1) .1662   Nuclear grade 3 37 (90.2) 106 (75.2)   Unknown 2 (4.9) 18 (12.7)  Histology   Ductal 40 (97.6) 132 (93.6) 1.000   Lobular 0 (0) 1 (0.7)   Others 1 (2.4) 8 (5.7)  Progesterone receptor status   Positive 4 (9.8) 7 (5.0) .2708   Negative 37 (90.2) 134 (95.0)   Unknown 0 (0) 0 (0)  HER2 status   Negative 39 (95.1) 137 (97.2) .6184   Equivocal 2 (4.9) 4 (2.8) Characteristic Low ER+ (n = 41) ER– (n = 141) P Value Continuous variables, mean (SD)  Age, y 53.9 (12.0) 52.4 (11.5) .3685  Age at menarche, y 12.8 (1.5), unknown: 8 13.1 (1.8), unknown: 43 .3937  Body mass index, kg/m2 28.3 (5.5), unknown: 13 29.1 (9.7), unknown: 55 .7520  Pretherapy tumor size, cm 4.6 (4.4), unknown: 7 3.9 (3.6), unknown: 25 .4697  Ki-67 labeling index, % 74.2 (24.0), unknown: 1 70.9 (24.1), unknown: 13 .3446  Progesterone receptor H-score 6.1 (22.2) 0.9 (5.9) .2370 Categorical variables, No. (%)  Menopausal status   Premenopausal 16 (39.0) 60 (42.6) .8562   Postmenopausal 24 (58.5) 79 (56)   Unknown 1 (2.5) 2 (1.4)  Race   White 34 (82.9) 120 (85.1) .6077   Black 7 (17.1) 18 (12.8)   Asian 0 (0) 0 (0)   Other 0 (0) 3 (2.1)  Neoadjuvant chemotherapy regimen   ACT 22 (53.7) 62 (44.0) .2907   Other and unknown 19 (46.3) 79 (56.0)  Pretherapy lymph node status   Core biopsy positive 14 (34.1) 49 (34.8) .6880   Core biopsy negative 18 (43.9) 52 (36.8)   Unknown 9 (22.0) 40 (28.4)  Pretherapy nuclear grade   Nuclear grade 1 or 2 2 (4.9) 17 (12.1) .1662   Nuclear grade 3 37 (90.2) 106 (75.2)   Unknown 2 (4.9) 18 (12.7)  Histology   Ductal 40 (97.6) 132 (93.6) 1.000   Lobular 0 (0) 1 (0.7)   Others 1 (2.4) 8 (5.7)  Progesterone receptor status   Positive 4 (9.8) 7 (5.0) .2708   Negative 37 (90.2) 134 (95.0)   Unknown 0 (0) 0 (0)  HER2 status   Negative 39 (95.1) 137 (97.2) .6184   Equivocal 2 (4.9) 4 (2.8) ACT, adriamycin, cyclophosphamide, taxane; ER, estrogen receptor; HER2, human epidermal growth factor receptor 2. aFor continuous variables, P value was obtained from the two-sided Wilcoxon rank-sum test. For categorical variables, P value was obtained from the two-sided Fisher exact test. Patients with missing/unknown information were excluded from test. View Large Table 2 Patient and Tumor Characteristics for “Low ER+” and ER– Casesa Characteristic Low ER+ (n = 41) ER– (n = 141) P Value Continuous variables, mean (SD)  Age, y 53.9 (12.0) 52.4 (11.5) .3685  Age at menarche, y 12.8 (1.5), unknown: 8 13.1 (1.8), unknown: 43 .3937  Body mass index, kg/m2 28.3 (5.5), unknown: 13 29.1 (9.7), unknown: 55 .7520  Pretherapy tumor size, cm 4.6 (4.4), unknown: 7 3.9 (3.6), unknown: 25 .4697  Ki-67 labeling index, % 74.2 (24.0), unknown: 1 70.9 (24.1), unknown: 13 .3446  Progesterone receptor H-score 6.1 (22.2) 0.9 (5.9) .2370 Categorical variables, No. (%)  Menopausal status   Premenopausal 16 (39.0) 60 (42.6) .8562   Postmenopausal 24 (58.5) 79 (56)   Unknown 1 (2.5) 2 (1.4)  Race   White 34 (82.9) 120 (85.1) .6077   Black 7 (17.1) 18 (12.8)   Asian 0 (0) 0 (0)   Other 0 (0) 3 (2.1)  Neoadjuvant chemotherapy regimen   ACT 22 (53.7) 62 (44.0) .2907   Other and unknown 19 (46.3) 79 (56.0)  Pretherapy lymph node status   Core biopsy positive 14 (34.1) 49 (34.8) .6880   Core biopsy negative 18 (43.9) 52 (36.8)   Unknown 9 (22.0) 40 (28.4)  Pretherapy nuclear grade   Nuclear grade 1 or 2 2 (4.9) 17 (12.1) .1662   Nuclear grade 3 37 (90.2) 106 (75.2)   Unknown 2 (4.9) 18 (12.7)  Histology   Ductal 40 (97.6) 132 (93.6) 1.000   Lobular 0 (0) 1 (0.7)   Others 1 (2.4) 8 (5.7)  Progesterone receptor status   Positive 4 (9.8) 7 (5.0) .2708   Negative 37 (90.2) 134 (95.0)   Unknown 0 (0) 0 (0)  HER2 status   Negative 39 (95.1) 137 (97.2) .6184   Equivocal 2 (4.9) 4 (2.8) Characteristic Low ER+ (n = 41) ER– (n = 141) P Value Continuous variables, mean (SD)  Age, y 53.9 (12.0) 52.4 (11.5) .3685  Age at menarche, y 12.8 (1.5), unknown: 8 13.1 (1.8), unknown: 43 .3937  Body mass index, kg/m2 28.3 (5.5), unknown: 13 29.1 (9.7), unknown: 55 .7520  Pretherapy tumor size, cm 4.6 (4.4), unknown: 7 3.9 (3.6), unknown: 25 .4697  Ki-67 labeling index, % 74.2 (24.0), unknown: 1 70.9 (24.1), unknown: 13 .3446  Progesterone receptor H-score 6.1 (22.2) 0.9 (5.9) .2370 Categorical variables, No. (%)  Menopausal status   Premenopausal 16 (39.0) 60 (42.6) .8562   Postmenopausal 24 (58.5) 79 (56)   Unknown 1 (2.5) 2 (1.4)  Race   White 34 (82.9) 120 (85.1) .6077   Black 7 (17.1) 18 (12.8)   Asian 0 (0) 0 (0)   Other 0 (0) 3 (2.1)  Neoadjuvant chemotherapy regimen   ACT 22 (53.7) 62 (44.0) .2907   Other and unknown 19 (46.3) 79 (56.0)  Pretherapy lymph node status   Core biopsy positive 14 (34.1) 49 (34.8) .6880   Core biopsy negative 18 (43.9) 52 (36.8)   Unknown 9 (22.0) 40 (28.4)  Pretherapy nuclear grade   Nuclear grade 1 or 2 2 (4.9) 17 (12.1) .1662   Nuclear grade 3 37 (90.2) 106 (75.2)   Unknown 2 (4.9) 18 (12.7)  Histology   Ductal 40 (97.6) 132 (93.6) 1.000   Lobular 0 (0) 1 (0.7)   Others 1 (2.4) 8 (5.7)  Progesterone receptor status   Positive 4 (9.8) 7 (5.0) .2708   Negative 37 (90.2) 134 (95.0)   Unknown 0 (0) 0 (0)  HER2 status   Negative 39 (95.1) 137 (97.2) .6184   Equivocal 2 (4.9) 4 (2.8) ACT, adriamycin, cyclophosphamide, taxane; ER, estrogen receptor; HER2, human epidermal growth factor receptor 2. aFor continuous variables, P value was obtained from the two-sided Wilcoxon rank-sum test. For categorical variables, P value was obtained from the two-sided Fisher exact test. Patients with missing/unknown information were excluded from test. View Large Table 3 Patient and Tumor Characteristics for “Low ER+” and Moderate ER+ Casesa Characteristic Low ER+ (n = 41) Moderate ER+ (n = 47) P Value Continuous variables, mean (SD)  Age, y 53.9 (12.0) 46.2 (8.6) .0015b  Age at menarche, y 12.8 (1.5), unknown: 8 12.5 (1.5), unknown: 3 .4562  Body mass index, kg/m2 28.3 (5.5), unknown: 13 28.9 (7.9), unknown: 8 .8140  Pretherapy tumor size, cm 4.6 (4.4), unknown: 7 4.6 (2.6), unknown: 1 .2975  Ki-67 labeling index, % 74.2 (24.0), unknown: 1 45.5 (27.9), unknown: 0 <.0001b  Progesterone receptor H-score 6.1 (22.2) 90.5 (75.8) <.0001b Categorical variables, No. (%)  Menopausal status   Premenopausal 16 (39.0) 36 (76.6) .0009b   Postmenopausal 24 (58.5) 11 (23.4)   Unknown 1 (2.5) 0 (0)  Race   White 34 (82.9) 43 (91.4) .0797   Black 7 (17.1) 2 (4.3)   Asian 0 (0) 0 (0)   Other 0 (0) 2 (4.3)  Neoadjuvant chemotherapy regimen   ACT 22 (53.7) 28 (59.6) .6676   Other and unknown 19 (46.3) 19 (40.4)  Pretherapy lymph node status   Core biopsy positive 14 (34.1) 21 (44.7) .3311   Core biopsy negative 18 (43.9) 15 (31.9)   Unknown 9 (22.0) 11 (23.4)  Pretherapy nuclear grade   Nuclear grade 1 or 2 2 (4.9) 21 (44.7) <.0001b   Nuclear grade 3 37 (90.2) 24 (51.0)   Unknown 2 (4.9) 2 (4.3)  Histology   Ductal 40 (97.6) 39 (83.0) .0565   Lobular 0 (0) 5 (10.6)   Others 1 (2.4) 3 (6.4)  Progesterone receptor status   Positive 4 (9.8) 41 (87.2) <.0001b   Negative 37 (90.2) 6 (12.8)   Unknown 0 (0) 0 (0)  HER2 status   Negative 39 (95.1) 39 (83.0) .0974   Equivocal 2 (4.9) 8 (17.0) Characteristic Low ER+ (n = 41) Moderate ER+ (n = 47) P Value Continuous variables, mean (SD)  Age, y 53.9 (12.0) 46.2 (8.6) .0015b  Age at menarche, y 12.8 (1.5), unknown: 8 12.5 (1.5), unknown: 3 .4562  Body mass index, kg/m2 28.3 (5.5), unknown: 13 28.9 (7.9), unknown: 8 .8140  Pretherapy tumor size, cm 4.6 (4.4), unknown: 7 4.6 (2.6), unknown: 1 .2975  Ki-67 labeling index, % 74.2 (24.0), unknown: 1 45.5 (27.9), unknown: 0 <.0001b  Progesterone receptor H-score 6.1 (22.2) 90.5 (75.8) <.0001b Categorical variables, No. (%)  Menopausal status   Premenopausal 16 (39.0) 36 (76.6) .0009b   Postmenopausal 24 (58.5) 11 (23.4)   Unknown 1 (2.5) 0 (0)  Race   White 34 (82.9) 43 (91.4) .0797   Black 7 (17.1) 2 (4.3)   Asian 0 (0) 0 (0)   Other 0 (0) 2 (4.3)  Neoadjuvant chemotherapy regimen   ACT 22 (53.7) 28 (59.6) .6676   Other and unknown 19 (46.3) 19 (40.4)  Pretherapy lymph node status   Core biopsy positive 14 (34.1) 21 (44.7) .3311   Core biopsy negative 18 (43.9) 15 (31.9)   Unknown 9 (22.0) 11 (23.4)  Pretherapy nuclear grade   Nuclear grade 1 or 2 2 (4.9) 21 (44.7) <.0001b   Nuclear grade 3 37 (90.2) 24 (51.0)   Unknown 2 (4.9) 2 (4.3)  Histology   Ductal 40 (97.6) 39 (83.0) .0565   Lobular 0 (0) 5 (10.6)   Others 1 (2.4) 3 (6.4)  Progesterone receptor status   Positive 4 (9.8) 41 (87.2) <.0001b   Negative 37 (90.2) 6 (12.8)   Unknown 0 (0) 0 (0)  HER2 status   Negative 39 (95.1) 39 (83.0) .0974   Equivocal 2 (4.9) 8 (17.0) ACT, adriamycin, cyclophosphamide, taxane; ER, estrogen receptor; HER2, human epidermal growth factor receptor 2. aFor continuous variables, P value was obtained from the two-sided Wilcoxon rank-sum test. For categorical variables, P value was obtained from the two-sided Fisher exact test. Patients with missing/unknown information were excluded from test. bStatistically significant. View Large Table 3 Patient and Tumor Characteristics for “Low ER+” and Moderate ER+ Casesa Characteristic Low ER+ (n = 41) Moderate ER+ (n = 47) P Value Continuous variables, mean (SD)  Age, y 53.9 (12.0) 46.2 (8.6) .0015b  Age at menarche, y 12.8 (1.5), unknown: 8 12.5 (1.5), unknown: 3 .4562  Body mass index, kg/m2 28.3 (5.5), unknown: 13 28.9 (7.9), unknown: 8 .8140  Pretherapy tumor size, cm 4.6 (4.4), unknown: 7 4.6 (2.6), unknown: 1 .2975  Ki-67 labeling index, % 74.2 (24.0), unknown: 1 45.5 (27.9), unknown: 0 <.0001b  Progesterone receptor H-score 6.1 (22.2) 90.5 (75.8) <.0001b Categorical variables, No. (%)  Menopausal status   Premenopausal 16 (39.0) 36 (76.6) .0009b   Postmenopausal 24 (58.5) 11 (23.4)   Unknown 1 (2.5) 0 (0)  Race   White 34 (82.9) 43 (91.4) .0797   Black 7 (17.1) 2 (4.3)   Asian 0 (0) 0 (0)   Other 0 (0) 2 (4.3)  Neoadjuvant chemotherapy regimen   ACT 22 (53.7) 28 (59.6) .6676   Other and unknown 19 (46.3) 19 (40.4)  Pretherapy lymph node status   Core biopsy positive 14 (34.1) 21 (44.7) .3311   Core biopsy negative 18 (43.9) 15 (31.9)   Unknown 9 (22.0) 11 (23.4)  Pretherapy nuclear grade   Nuclear grade 1 or 2 2 (4.9) 21 (44.7) <.0001b   Nuclear grade 3 37 (90.2) 24 (51.0)   Unknown 2 (4.9) 2 (4.3)  Histology   Ductal 40 (97.6) 39 (83.0) .0565   Lobular 0 (0) 5 (10.6)   Others 1 (2.4) 3 (6.4)  Progesterone receptor status   Positive 4 (9.8) 41 (87.2) <.0001b   Negative 37 (90.2) 6 (12.8)   Unknown 0 (0) 0 (0)  HER2 status   Negative 39 (95.1) 39 (83.0) .0974   Equivocal 2 (4.9) 8 (17.0) Characteristic Low ER+ (n = 41) Moderate ER+ (n = 47) P Value Continuous variables, mean (SD)  Age, y 53.9 (12.0) 46.2 (8.6) .0015b  Age at menarche, y 12.8 (1.5), unknown: 8 12.5 (1.5), unknown: 3 .4562  Body mass index, kg/m2 28.3 (5.5), unknown: 13 28.9 (7.9), unknown: 8 .8140  Pretherapy tumor size, cm 4.6 (4.4), unknown: 7 4.6 (2.6), unknown: 1 .2975  Ki-67 labeling index, % 74.2 (24.0), unknown: 1 45.5 (27.9), unknown: 0 <.0001b  Progesterone receptor H-score 6.1 (22.2) 90.5 (75.8) <.0001b Categorical variables, No. (%)  Menopausal status   Premenopausal 16 (39.0) 36 (76.6) .0009b   Postmenopausal 24 (58.5) 11 (23.4)   Unknown 1 (2.5) 0 (0)  Race   White 34 (82.9) 43 (91.4) .0797   Black 7 (17.1) 2 (4.3)   Asian 0 (0) 0 (0)   Other 0 (0) 2 (4.3)  Neoadjuvant chemotherapy regimen   ACT 22 (53.7) 28 (59.6) .6676   Other and unknown 19 (46.3) 19 (40.4)  Pretherapy lymph node status   Core biopsy positive 14 (34.1) 21 (44.7) .3311   Core biopsy negative 18 (43.9) 15 (31.9)   Unknown 9 (22.0) 11 (23.4)  Pretherapy nuclear grade   Nuclear grade 1 or 2 2 (4.9) 21 (44.7) <.0001b   Nuclear grade 3 37 (90.2) 24 (51.0)   Unknown 2 (4.9) 2 (4.3)  Histology   Ductal 40 (97.6) 39 (83.0) .0565   Lobular 0 (0) 5 (10.6)   Others 1 (2.4) 3 (6.4)  Progesterone receptor status   Positive 4 (9.8) 41 (87.2) <.0001b   Negative 37 (90.2) 6 (12.8)   Unknown 0 (0) 0 (0)  HER2 status   Negative 39 (95.1) 39 (83.0) .0974   Equivocal 2 (4.9) 8 (17.0) ACT, adriamycin, cyclophosphamide, taxane; ER, estrogen receptor; HER2, human epidermal growth factor receptor 2. aFor continuous variables, P value was obtained from the two-sided Wilcoxon rank-sum test. For categorical variables, P value was obtained from the two-sided Fisher exact test. Patients with missing/unknown information were excluded from test. bStatistically significant. View Large Table 4 Patient and Tumor Characteristics for “Low ER+” and High ER+ Casesa Characteristic Low ER+ (n = 41) High ER+ (n = 98) P Value Continuous variables, mean (SD)  Age, y 53.9 (12.0) 54.1 (11.4) .9374  Age at menarche, y 12.8 (1.5), unknown: 8 12.9 (1.5), unknown: 17 .4644  Body mass index, kg/m2 28.3 (5.5), unknown: 13 29.3 (6.7), unknown: 26 .6784  Pretherapy tumor size, cm 4.6 (4.4), unknown: 7 4.4 (2.2), unknown: 10 .3978  Ki-67 labeling index, % 74.2 (24.0), unknown: 1 34.1 (21), unknown: 5 <.0001b  Progesterone receptor H-score 6.1 (22.2) 138.6 (107) <.0001b Categorical variables, No. (%)  Menopausal status   Premenopausal 16 (39.0) 48 (49.0) .3471   Postmenopausal 24 (58.5) 48 (49.0)   Unknown 1 (2.5) 2 (2.0)  Race   White 34 (82.9) 92 (93.9) .0412b   Black 7 (17.1) 5 (5.1)   Asian 0 (0) 1 (1)   Other 0 (0) 0 (0)  Neoadjuvant chemotherapy regimen   ACT 22 (53.7) 56 (57.1) .7123   Other and unknown 19 (46.3) 42 (42.9)  Pretherapy lymph node status   Core biopsy positive 14 (34.1) 41 (41.8) .5292   Core biopsy negative 18 (43.9) 37 (37.8)   Unknown 9 (22.0) 20 (20.4)  Pretherapy nuclear grade   Nuclear grade 1 or 2 2 (4.9) 51 (52.0) <.0001b   Nuclear grade 3 37 (90.2) 35 (35.8)   Unknown 2 (4.9) 12 (12.2)  Histology   Ductal 40 (97.6) 83 (84.7) .0103b   Lobular 0 (0) 14 (14.3)   Others 1 (2.4) 1 (1.0)  Progesterone receptor status   Positive 4 (9.8) 84 (85.7) <.0001b   Negative 37 (90.2) 14 (14.3)   Unknown 0 (0) 0 (0)  HER2 status   Negative 39 (95.1) 89 (90.8) .5072   Equivocal 2 (4.9) 9 (9.2) Characteristic Low ER+ (n = 41) High ER+ (n = 98) P Value Continuous variables, mean (SD)  Age, y 53.9 (12.0) 54.1 (11.4) .9374  Age at menarche, y 12.8 (1.5), unknown: 8 12.9 (1.5), unknown: 17 .4644  Body mass index, kg/m2 28.3 (5.5), unknown: 13 29.3 (6.7), unknown: 26 .6784  Pretherapy tumor size, cm 4.6 (4.4), unknown: 7 4.4 (2.2), unknown: 10 .3978  Ki-67 labeling index, % 74.2 (24.0), unknown: 1 34.1 (21), unknown: 5 <.0001b  Progesterone receptor H-score 6.1 (22.2) 138.6 (107) <.0001b Categorical variables, No. (%)  Menopausal status   Premenopausal 16 (39.0) 48 (49.0) .3471   Postmenopausal 24 (58.5) 48 (49.0)   Unknown 1 (2.5) 2 (2.0)  Race   White 34 (82.9) 92 (93.9) .0412b   Black 7 (17.1) 5 (5.1)   Asian 0 (0) 1 (1)   Other 0 (0) 0 (0)  Neoadjuvant chemotherapy regimen   ACT 22 (53.7) 56 (57.1) .7123   Other and unknown 19 (46.3) 42 (42.9)  Pretherapy lymph node status   Core biopsy positive 14 (34.1) 41 (41.8) .5292   Core biopsy negative 18 (43.9) 37 (37.8)   Unknown 9 (22.0) 20 (20.4)  Pretherapy nuclear grade   Nuclear grade 1 or 2 2 (4.9) 51 (52.0) <.0001b   Nuclear grade 3 37 (90.2) 35 (35.8)   Unknown 2 (4.9) 12 (12.2)  Histology   Ductal 40 (97.6) 83 (84.7) .0103b   Lobular 0 (0) 14 (14.3)   Others 1 (2.4) 1 (1.0)  Progesterone receptor status   Positive 4 (9.8) 84 (85.7) <.0001b   Negative 37 (90.2) 14 (14.3)   Unknown 0 (0) 0 (0)  HER2 status   Negative 39 (95.1) 89 (90.8) .5072   Equivocal 2 (4.9) 9 (9.2) ACT, adriamycin, cyclophosphamide, taxane; ER, estrogen receptor; HER2, human epidermal growth factor receptor 2. aFor continuous variables, P value was obtained from the two-sided Wilcoxon rank-sum test. For categorical variables, P value was obtained from the two-sided Fisher exact test. Patients with missing/unknown information were excluded from test. bStatistically significant. View Large Table 4 Patient and Tumor Characteristics for “Low ER+” and High ER+ Casesa Characteristic Low ER+ (n = 41) High ER+ (n = 98) P Value Continuous variables, mean (SD)  Age, y 53.9 (12.0) 54.1 (11.4) .9374  Age at menarche, y 12.8 (1.5), unknown: 8 12.9 (1.5), unknown: 17 .4644  Body mass index, kg/m2 28.3 (5.5), unknown: 13 29.3 (6.7), unknown: 26 .6784  Pretherapy tumor size, cm 4.6 (4.4), unknown: 7 4.4 (2.2), unknown: 10 .3978  Ki-67 labeling index, % 74.2 (24.0), unknown: 1 34.1 (21), unknown: 5 <.0001b  Progesterone receptor H-score 6.1 (22.2) 138.6 (107) <.0001b Categorical variables, No. (%)  Menopausal status   Premenopausal 16 (39.0) 48 (49.0) .3471   Postmenopausal 24 (58.5) 48 (49.0)   Unknown 1 (2.5) 2 (2.0)  Race   White 34 (82.9) 92 (93.9) .0412b   Black 7 (17.1) 5 (5.1)   Asian 0 (0) 1 (1)   Other 0 (0) 0 (0)  Neoadjuvant chemotherapy regimen   ACT 22 (53.7) 56 (57.1) .7123   Other and unknown 19 (46.3) 42 (42.9)  Pretherapy lymph node status   Core biopsy positive 14 (34.1) 41 (41.8) .5292   Core biopsy negative 18 (43.9) 37 (37.8)   Unknown 9 (22.0) 20 (20.4)  Pretherapy nuclear grade   Nuclear grade 1 or 2 2 (4.9) 51 (52.0) <.0001b   Nuclear grade 3 37 (90.2) 35 (35.8)   Unknown 2 (4.9) 12 (12.2)  Histology   Ductal 40 (97.6) 83 (84.7) .0103b   Lobular 0 (0) 14 (14.3)   Others 1 (2.4) 1 (1.0)  Progesterone receptor status   Positive 4 (9.8) 84 (85.7) <.0001b   Negative 37 (90.2) 14 (14.3)   Unknown 0 (0) 0 (0)  HER2 status   Negative 39 (95.1) 89 (90.8) .5072   Equivocal 2 (4.9) 9 (9.2) Characteristic Low ER+ (n = 41) High ER+ (n = 98) P Value Continuous variables, mean (SD)  Age, y 53.9 (12.0) 54.1 (11.4) .9374  Age at menarche, y 12.8 (1.5), unknown: 8 12.9 (1.5), unknown: 17 .4644  Body mass index, kg/m2 28.3 (5.5), unknown: 13 29.3 (6.7), unknown: 26 .6784  Pretherapy tumor size, cm 4.6 (4.4), unknown: 7 4.4 (2.2), unknown: 10 .3978  Ki-67 labeling index, % 74.2 (24.0), unknown: 1 34.1 (21), unknown: 5 <.0001b  Progesterone receptor H-score 6.1 (22.2) 138.6 (107) <.0001b Categorical variables, No. (%)  Menopausal status   Premenopausal 16 (39.0) 48 (49.0) .3471   Postmenopausal 24 (58.5) 48 (49.0)   Unknown 1 (2.5) 2 (2.0)  Race   White 34 (82.9) 92 (93.9) .0412b   Black 7 (17.1) 5 (5.1)   Asian 0 (0) 1 (1)   Other 0 (0) 0 (0)  Neoadjuvant chemotherapy regimen   ACT 22 (53.7) 56 (57.1) .7123   Other and unknown 19 (46.3) 42 (42.9)  Pretherapy lymph node status   Core biopsy positive 14 (34.1) 41 (41.8) .5292   Core biopsy negative 18 (43.9) 37 (37.8)   Unknown 9 (22.0) 20 (20.4)  Pretherapy nuclear grade   Nuclear grade 1 or 2 2 (4.9) 51 (52.0) <.0001b   Nuclear grade 3 37 (90.2) 35 (35.8)   Unknown 2 (4.9) 12 (12.2)  Histology   Ductal 40 (97.6) 83 (84.7) .0103b   Lobular 0 (0) 14 (14.3)   Others 1 (2.4) 1 (1.0)  Progesterone receptor status   Positive 4 (9.8) 84 (85.7) <.0001b   Negative 37 (90.2) 14 (14.3)   Unknown 0 (0) 0 (0)  HER2 status   Negative 39 (95.1) 89 (90.8) .5072   Equivocal 2 (4.9) 9 (9.2) ACT, adriamycin, cyclophosphamide, taxane; ER, estrogen receptor; HER2, human epidermal growth factor receptor 2. aFor continuous variables, P value was obtained from the two-sided Wilcoxon rank-sum test. For categorical variables, P value was obtained from the two-sided Fisher exact test. Patients with missing/unknown information were excluded from test. bStatistically significant. View Large Since the prior studies define low ER as 1% to 10% ER+ cells, we also examined the pCR rate of tumors with H-scores 1 to 10 and 11 to 100. Of the 41 low ER+ tumors, 27 (66%) had H-scores 1 to 10 and 14 (34%) had H-scores 11 to 100. Nine (33%) of 27 tumors with H-scores 1 to 10 showed pCR compared with six (43%) of 14 tumors with H-scores 11 to 100 (P = .7337). Recurrence and survival data were available and are reported separately for patients who achieved pCR and those who did not. Of the 60 patients who achieved pCR, there was only one distant recurrence (recurrence rate of 3%) and one death during follow-up, with a survival rate of 97%. The single recurrence and death occurred in the ER– group. Among the 267 patients with residual disease after neoadjuvant chemotherapy, there were 66 (25%) recurrences, of which 56 (20%) were distant. There were 38 deaths, with an overall survival rate of 85%. The recurrence and death rate of low ER+ tumors were similar to the recurrence and death rate of ER– tumors but significantly different from the recurrence and death rate of moderate ER+ tumors and high ER+ tumors Table 5; Figure 1 and Figure 2. The difference in recurrence and death rate between low ER+ and other ER+ tumors was significant particularly within the posttherapy lymph node–positive subgroup Table 6 and Table 7. Table 5 Recurrence and Death Rate in Patients With Residual Disease (No pCR) (n = 267) Score No. Recurrence Death Patients Recurred, No. (%) P Value (Comparison to Low ER) Patients Died, No. (%) P Value (Comparison to Low ER) ER 0 105 35 (33) .6491 24 (23) .4470 ER 1-100 26 10 (38) Reference 8 (31) Reference ER 101-200 42 6 (14) .0378a 2 (5) .0051a ER 201-300 94 15 (16) .0260a 4 (4) .0005a Score No. Recurrence Death Patients Recurred, No. (%) P Value (Comparison to Low ER) Patients Died, No. (%) P Value (Comparison to Low ER) ER 0 105 35 (33) .6491 24 (23) .4470 ER 1-100 26 10 (38) Reference 8 (31) Reference ER 101-200 42 6 (14) .0378a 2 (5) .0051a ER 201-300 94 15 (16) .0260a 4 (4) .0005a ER, estrogen receptor; pCR, pathologic complete response. aStatistically significant. View Large Table 5 Recurrence and Death Rate in Patients With Residual Disease (No pCR) (n = 267) Score No. Recurrence Death Patients Recurred, No. (%) P Value (Comparison to Low ER) Patients Died, No. (%) P Value (Comparison to Low ER) ER 0 105 35 (33) .6491 24 (23) .4470 ER 1-100 26 10 (38) Reference 8 (31) Reference ER 101-200 42 6 (14) .0378a 2 (5) .0051a ER 201-300 94 15 (16) .0260a 4 (4) .0005a Score No. Recurrence Death Patients Recurred, No. (%) P Value (Comparison to Low ER) Patients Died, No. (%) P Value (Comparison to Low ER) ER 0 105 35 (33) .6491 24 (23) .4470 ER 1-100 26 10 (38) Reference 8 (31) Reference ER 101-200 42 6 (14) .0378a 2 (5) .0051a ER 201-300 94 15 (16) .0260a 4 (4) .0005a ER, estrogen receptor; pCR, pathologic complete response. aStatistically significant. View Large Figure 1 View largeDownload slide Disease-free survival plot of patients with residual disease (no pathologic complete response) (n = 267), categorized by estrogen receptor (ER) status. P value obtained from the log-rank test with low ER+ as a reference. P = .657 for ER–. P = .025 for moderate ER+. P = .006 for high ER+. Figure 1 View largeDownload slide Disease-free survival plot of patients with residual disease (no pathologic complete response) (n = 267), categorized by estrogen receptor (ER) status. P value obtained from the log-rank test with low ER+ as a reference. P = .657 for ER–. P = .025 for moderate ER+. P = .006 for high ER+. Figure 2 View largeDownload slide Overall survival plot of patients with residual disease (no pathologic complete response) (n = 267), categorized by estrogen receptor (ER) status. P value obtained from the log-rank test with low ER+ as a reference. P = .672 for ER–. P = .003 for moderate ER+. P = 0 for high ER+. Figure 2 View largeDownload slide Overall survival plot of patients with residual disease (no pathologic complete response) (n = 267), categorized by estrogen receptor (ER) status. P value obtained from the log-rank test with low ER+ as a reference. P = .672 for ER–. P = .003 for moderate ER+. P = 0 for high ER+. Table 6 Recurrence Rate in Patients With Residual Disease (No pCR) (n = 267), Categorized by Lymph Node Status Posttherapy Score Recurrences in Lymph Node Negative (n = 120) Recurrences in Lymph Node Positive (n = 147) P Value (Comparison to Low ER) Local, No. Distant, No. All, No./Total No. (%) Local, No. Distant, No. All, No./Total No. (%) ER 0 3 12 15/65 (23) 3 17 20/40 (50) LN negative: 1.000; LN positive: .7278 ER 1-100 0 4 4/16 (25) 1 5 6/10 (60) Reference ER 101-200 0 1 1/15 (7) 1 4 5/27 (19) LN negative: .3326; LN positive: .0377a ER 201-300 0 2 2/24 (8) 2 11 13/70 (19) LN negative: .1953; LN positive: .0098a Score Recurrences in Lymph Node Negative (n = 120) Recurrences in Lymph Node Positive (n = 147) P Value (Comparison to Low ER) Local, No. Distant, No. All, No./Total No. (%) Local, No. Distant, No. All, No./Total No. (%) ER 0 3 12 15/65 (23) 3 17 20/40 (50) LN negative: 1.000; LN positive: .7278 ER 1-100 0 4 4/16 (25) 1 5 6/10 (60) Reference ER 101-200 0 1 1/15 (7) 1 4 5/27 (19) LN negative: .3326; LN positive: .0377a ER 201-300 0 2 2/24 (8) 2 11 13/70 (19) LN negative: .1953; LN positive: .0098a ER, estrogen receptor; LN, lymph node negative; pCR, pathologic complete response. aStatistically significant. View Large Table 6 Recurrence Rate in Patients With Residual Disease (No pCR) (n = 267), Categorized by Lymph Node Status Posttherapy Score Recurrences in Lymph Node Negative (n = 120) Recurrences in Lymph Node Positive (n = 147) P Value (Comparison to Low ER) Local, No. Distant, No. All, No./Total No. (%) Local, No. Distant, No. All, No./Total No. (%) ER 0 3 12 15/65 (23) 3 17 20/40 (50) LN negative: 1.000; LN positive: .7278 ER 1-100 0 4 4/16 (25) 1 5 6/10 (60) Reference ER 101-200 0 1 1/15 (7) 1 4 5/27 (19) LN negative: .3326; LN positive: .0377a ER 201-300 0 2 2/24 (8) 2 11 13/70 (19) LN negative: .1953; LN positive: .0098a Score Recurrences in Lymph Node Negative (n = 120) Recurrences in Lymph Node Positive (n = 147) P Value (Comparison to Low ER) Local, No. Distant, No. All, No./Total No. (%) Local, No. Distant, No. All, No./Total No. (%) ER 0 3 12 15/65 (23) 3 17 20/40 (50) LN negative: 1.000; LN positive: .7278 ER 1-100 0 4 4/16 (25) 1 5 6/10 (60) Reference ER 101-200 0 1 1/15 (7) 1 4 5/27 (19) LN negative: .3326; LN positive: .0377a ER 201-300 0 2 2/24 (8) 2 11 13/70 (19) LN negative: .1953; LN positive: .0098a ER, estrogen receptor; LN, lymph node negative; pCR, pathologic complete response. aStatistically significant. View Large Table 7 Death Rate in Patients With Residual Disease (No pCR) (n = 267), Categorized by Lymph Node Status Posttherapy Score Deaths in LN-Negative Group (n = 120), No./Total No. (%) Deaths in LN-Positive Group (n = 147), No./Total No. (%) P Value (Comparison to Low ER) ER 0 9/65 (14) 15/40 (38) LN negative: .2751; LN positive: 1.000 ER 1-100 4/16 (25) 4/10 (40) Reference ER 101-200 1/15 (7) 1/27 (4) LN negative: .3326; LN positive: .0136a ER 201-300 0/24 (0) 4/70 (6) LN negative: .0199a; LN positive: .0071a Score Deaths in LN-Negative Group (n = 120), No./Total No. (%) Deaths in LN-Positive Group (n = 147), No./Total No. (%) P Value (Comparison to Low ER) ER 0 9/65 (14) 15/40 (38) LN negative: .2751; LN positive: 1.000 ER 1-100 4/16 (25) 4/10 (40) Reference ER 101-200 1/15 (7) 1/27 (4) LN negative: .3326; LN positive: .0136a ER 201-300 0/24 (0) 4/70 (6) LN negative: .0199a; LN positive: .0071a ER, estrogen receptor; LN, lymph node negative; pCR, pathologic complete response. aStatistically significant. View Large Table 7 Death Rate in Patients With Residual Disease (No pCR) (n = 267), Categorized by Lymph Node Status Posttherapy Score Deaths in LN-Negative Group (n = 120), No./Total No. (%) Deaths in LN-Positive Group (n = 147), No./Total No. (%) P Value (Comparison to Low ER) ER 0 9/65 (14) 15/40 (38) LN negative: .2751; LN positive: 1.000 ER 1-100 4/16 (25) 4/10 (40) Reference ER 101-200 1/15 (7) 1/27 (4) LN negative: .3326; LN positive: .0136a ER 201-300 0/24 (0) 4/70 (6) LN negative: .0199a; LN positive: .0071a Score Deaths in LN-Negative Group (n = 120), No./Total No. (%) Deaths in LN-Positive Group (n = 147), No./Total No. (%) P Value (Comparison to Low ER) ER 0 9/65 (14) 15/40 (38) LN negative: .2751; LN positive: 1.000 ER 1-100 4/16 (25) 4/10 (40) Reference ER 101-200 1/15 (7) 1/27 (4) LN negative: .3326; LN positive: .0136a ER 201-300 0/24 (0) 4/70 (6) LN negative: .0199a; LN positive: .0071a ER, estrogen receptor; LN, lymph node negative; pCR, pathologic complete response. aStatistically significant. View Large Logistic regression AUC analysis showed ER status predicts for pCR (AUC = 0.77); however, the ME3 model is even more predictive, with an AUC of 0.82 Figure 3. Figure 3 View largeDownload slide Logistic regression area under the curve (AUC) predicting pathologic complete response using Magee Equation 3 (ME3) and estrogen receptor (ER) status. ME3 results available on 177 ER+ patients are used for analysis. Figure 3 View largeDownload slide Logistic regression area under the curve (AUC) predicting pathologic complete response using Magee Equation 3 (ME3) and estrogen receptor (ER) status. ME3 results available on 177 ER+ patients are used for analysis. Discussion It is well known that breast cancer is a heterogeneous disease on the morphologic, immunohistologic, and molecular level. The different phenotypes express varying clinical behaviors. ER status is what distinguishes luminal breast cancer from other phenotypes. Approximately 70% to 75% of breast cancers are ER+, with a slightly higher percentage positivity seen in white and elderly populations and slightly lower in nonwhite and younger populations.18,19 Often, not much attention is paid to the degree of ER positivity, and this additional useful information is frequently lost in large clinical trials where the tumor groups are only referred to as ER+ and ER–. The semiquantitative scores for hormone receptors appear to be important for judging response not only to endocrine therapy but also to chemotherapy. These semiquantitative immunohistochemical scores are often part of the multivariable models to predict for chemotherapy response.5-8 Expensive multigene assays are also available to predict for chemotherapy benefit and frequently use quantitative hormone receptor gene expression levels for their predictive scores.20,21 In this study, we investigated the clinical usefulness of semiquantitative ER scoring by immunohistochemistry. We identified a group of ER+ tumors that have a distinct phenotype and response to neoadjuvant chemotherapy. In addition, we have also compared the patient and tumor characteristics of low ER+ tumors with other ER+ tumors and ER– tumors. Comparison of tumor and patient characteristics of low ER+ and ER– tumors showed no statistically significant differences (Table 2). These findings indicate close similarity between low ER+ and ER– tumors. Comparison of tumor and patient characteristics of low ER+ and moderately ER+ tumors showed a statistically significant difference in age, menopausal status, semiquantitative PR H-score, PR status, pretherapy nuclear grade, and Ki-67 labeling index (Table 3). The latter four differences confirm the close relationship between the semiquantitative ER H-score with PR H-score, PR status, nuclear grade, and tumor proliferation. The patients with moderately ER+ tumors were surprisingly younger and premenopausal. However, this aberration could be due to some selection bias for neoadjuvant chemotherapy in ER+ tumors. Comparison of tumor and patient characteristics of low ER+ and strongly ER+ tumors showed statistically significant differences in PR H-score, PR status, Ki-67 labeling index, pretherapy nuclear grade, histology, and race (Table 4). These statistically significant differences highlight the fact that strongly ER+ tumors are more frequent in white patients, are frequently of the lobular phenotype, have strong PR expression, and are of a lower grade with a low proliferation index.22-24 Strongly ER+ tumors appear to be biologically different from low ER+ tumors. A few other studies have explored the concept of low ER+ tumors. However, different definitions have been used to define low ER positivity. Most studies have used a percentage of positive cells rather than a semiquantitative H-score method to define low ER+ tumors. In a study by Iwamoto et al,10 most tumors with 1% to 9% ER+ cells showed a basal-like gene expression profile similar to ER– tumors. Deyarmin et al9 studied 26 tumors with 1% to 10% ER+ cells and found that 88% were either basal-like or HER2 enriched and had pathologic features similar to ER– tumors. Prabhu et al11 studied ER-related gene transcripts in 240 breast cancers. They found that 21 tumors with 1% to 10% ER+ cells by immunohistochemistry had a gene expression signature similar to ER– tumors, and the survival of patients within the low ER group was intermediate between high ER+ and ER– groups. Raghav and colleagues12 evaluated the effect of endocrine therapy and survival outcome in 1,257 patients previously classified as triple negative. Upon review, the tumors were classified as ER less than 1%, 1% to 5%, and 6% to 10% positive cells. The prognosis of the tumors with low ER expression, especially 1% to 5%, did not differ significantly from tumors with undetectable levels of ER. We have broadened the prior definitions by using an H-score of 1 to 100 to define low ER+ tumors. Since H-score takes into account both intensity of staining and percentage of positive cells, an H-score of 1 to 100 includes not only tumors with 1% to 10% positive cells but also tumors with more than 10% positive cells, often with weak intensity staining. In our prior study, we have taken the same cutoff (H-score of 1-100) to define the morphologic features of such tumors. The morphologic features of tumors with H-scores of 1 to 100 show similarity to triple-negative tumors with medullary/atypical medullary features and a high proliferation index.13 Our current study is focused on the response of such tumors to neoadjuvant chemotherapy. Our results indicate a high pCR rate for low ER+ tumors. Since the prior studies define low ER as 1% to 10% ER+ cells, we also examined the pCR rate of tumors with H-scores 1 to 10 and 11 to 100. No statistically significant difference was identified between the two groups of low ER+ tumors (see results above). As far as response to chemotherapy is concerned, multivariable models that include quantitative hormone receptor results and Ki-67 proliferation index have been shown to provide chemopredictive information.6,8 The multivariable model developed at our institution, the ME3, was more informative than ER status alone in predicting pCR in ER+ tumors (Figure 3). The results of our study are very similar to a recently published study by Fujii and colleagues.25 In a large study of 3,055 ER+/HER2-negative cases, Fujii et al25 showed a high likelihood of pCR for tumors when ER expression was seen in 1% to less than 10% of the cells. They further showed the benefit of adjuvant hormonal therapy only in patients with ER reactivity in more than or equal to 10% of the tumor cells. Based on their results, Fujii and colleagues25 questioned the current ASCO/CAP definition of ER positivity. In summary, low ER+ breast cancers are rare and represent approximately 5% of all breast cancers.13 Our study is one of the few to evaluate the pCR rate of low ER+ breast cancers. Low ER+ tumors appear to be a distinct subset of ER+ tumors that derive substantial benefit from chemotherapy. There are limited data on the benefit of endocrine therapy in such tumors, but future studies should specifically evaluate this subset for endocrine therapy benefit. Many clinical trials for women with triple-negative breast cancers exclude patients with low ER+ tumors. Our data support growing evidence that this subset of patients should be treated differently from those with high ER+ tumors, and this should be taken into consideration for future trial design. We recommend reporting semiquantitative immunohistochemical scores for hormone receptors as these scores ultimately help in therapeutic decision making. References 1. Hammond ME , Hayes DF , Dowsett M , et al. American Society of Clinical Oncology/College of American Pathologists guideline recommendations for immunohistochemical testing of estrogen and progesterone receptors in breast cancer . J Clin Oncol . 2010 ; 28 : 2784 - 2795 . Google Scholar CrossRef Search ADS PubMed 2. Harvey JM , Clark GM , Osborne CK , et al. Estrogen receptor status by immunohistochemistry is superior to the ligand-binding assay for predicting response to adjuvant endocrine therapy in breast cancer . J Clin Oncol . 1999 ; 17 : 1474 - 1481 . Google Scholar CrossRef Search ADS PubMed 3. Johnston SJ , Cheung KL . The role of primary endocrine therapy in older women with operable breast cancer . Future Oncol . 2015 ; 11 : 1555 - 1565 . Google Scholar CrossRef Search ADS PubMed 4. Morgan DA , Refalo NA , Cheung KL . Strength of ER-positivity in relation to survival in ER-positive breast cancer treated by adjuvant tamoxifen as sole systemic therapy . Breast . 2011 ; 20 : 215 - 219 . Google Scholar CrossRef Search ADS PubMed 5. Cuzick J , Dowsett M , Pineda S , et al. Prognostic value of a combined estrogen receptor, progesterone receptor, Ki-67, and human epidermal growth factor receptor 2 immunohistochemical score and comparison with the Genomic Health recurrence score in early breast cancer . J Clin Oncol . 2011 ; 29 : 4273 - 4278 . Google Scholar CrossRef Search ADS PubMed 6. Farrugia DJ , Landmann A , Zhu L , et al. Magee Equation 3 predicts pathologic response to neoadjuvant systemic chemotherapy in estrogen receptor positive, HER2 negative/equivocal breast tumors . Mod Pathol . 2017 ; 30 : 1078 - 1085 . Google Scholar CrossRef Search ADS PubMed 7. Klein ME , Dabbs DJ , Shuai Y , et al. Prediction of the Oncotype DX recurrence score: use of pathology-generated equations derived by linear regression analysis . Mod Pathol . 2013 ; 26 : 658 - 664 . Google Scholar CrossRef Search ADS PubMed 8. Sheri A , Smith IE , Hills M , et al. Relationship between IHC4 score and response to neo-adjuvant chemotherapy in estrogen receptor-positive breast cancer . Breast Cancer Res Treat . 2017 ; 164 : 395 - 400 . Google Scholar CrossRef Search ADS PubMed 9. Deyarmin B , Kane JL , Valente AL , et al. Effect of ASCO/CAP guidelines for determining ER status on molecular subtype . Ann Surg Oncol . 2013 ; 20 : 87 - 93 . Google Scholar CrossRef Search ADS PubMed 10. Iwamoto T , Booser D , Valero V , et al. Estrogen receptor (ER) mRNA and ER-related gene expression in breast cancers that are 1% to 10% ER-positive by immunohistochemistry . J Clin Oncol . 2012 ; 30 : 729 - 734 . Google Scholar CrossRef Search ADS PubMed 11. Prabhu JS , Korlimarla A , Desai K , et al. A majority of low (1-10%) ER positive breast cancers behave like hormone receptor negative tumors . J Cancer . 2014 ; 5 : 156 - 165 . Google Scholar CrossRef Search ADS PubMed 12. Raghav KP , Hernandez-Aya LF , Lei X , et al. Impact of low estrogen/progesterone receptor expression on survival outcomes in breast cancers previously classified as triple negative breast cancers . Cancer . 2012 ; 118 : 1498 - 1506 . Google Scholar CrossRef Search ADS PubMed 13. Gloyeske NC , Dabbs DJ , Bhargava R . Low ER+ breast cancer: is this a distinct group ? Am J Clin Pathol . 2014 ; 141 : 697 - 701 . Google Scholar CrossRef Search ADS PubMed 14. Bhargava R , Dabbs DJ , Beriwal S , et al. Semiquantitative hormone receptor level influences response to trastuzumab-containing neoadjuvant chemotherapy in HER2-positive breast cancer . Mod Pathol . 2011 ; 24 : 367 - 374 . Google Scholar CrossRef Search ADS PubMed 15. Provenzano E , Bossuyt V , Viale G , et al. ; Residual Disease Characterization Working Group of the Breast International Group–North American Breast Cancer Group Collaboration . Standardization of pathologic evaluation and reporting of postneoadjuvant specimens in clinical trials of breast cancer: recommendations from an international working group . Mod Pathol . 2015 ; 28 : 1185 - 1201 . Google Scholar CrossRef Search ADS PubMed 16. Flanagan MB , Dabbs DJ , Brufsky AM , et al. Histopathologic variables predict Oncotype DX recurrence score . Mod Pathol . 2008 ; 21 : 1255 - 1261 . Google Scholar CrossRef Search ADS PubMed 17. McCarty KS Jr , Miller LS , Cox EB , et al. Estrogen receptor analyses: correlation of biochemical and immunohistochemical methods using monoclonal antireceptor antibodies . Arch Pathol Lab Med . 1985 ; 109 : 716 - 721 . Google Scholar PubMed 18. Gapstur SM , Dupuis J , Gann P , et al. Hormone receptor status of breast tumors in black, Hispanic, and non-Hispanic white women: an analysis of 13,239 cases . Cancer . 1996 ; 77 : 1465 - 1471 . Google Scholar CrossRef Search ADS PubMed 19. McCarty KS Jr , Silva JS , Cox EB , et al. Relationship of age and menopausal status to estrogen receptor content in primary carcinoma of the breast . Ann Surg . 1983 ; 197 : 123 - 127 . Google Scholar CrossRef Search ADS PubMed 20. Paik S , Shak S , Tang G , et al. A multigene assay to predict recurrence of tamoxifen-treated, node-negative breast cancer . N Engl J Med . 2004 ; 351 : 2817 - 2826 . Google Scholar CrossRef Search ADS PubMed 21. Paik S , Tang G , Shak S , et al. Gene expression and benefit of chemotherapy in women with node-negative, estrogen receptor-positive breast cancer . J Clin Oncol . 2006 ; 24 : 3726 - 3734 . Google Scholar CrossRef Search ADS PubMed 22. Antoniades K , Spector H . Correlation of estrogen receptor levels with histology and cytomorphology in human mammary cancer . Am J Clin Pathol . 1979 ; 71 : 497 - 503 . Google Scholar CrossRef Search ADS PubMed 23. McCarty KS Jr , Barton TK , Fetter BF , et al. Correlation of estrogen and progesterone receptors with histologic differentiation in mammary carcinoma . Cancer . 1980 ; 46 : 2851 - 2858 . Google Scholar CrossRef Search ADS PubMed 24. Silfverswärd C , Gustafsson JA , Gustafsson SA , et al. Estrogen receptor concentrations in 269 cases of histologically classified human breast cancer . Cancer . 1980 ; 45 : 2001 - 2005 . Google Scholar CrossRef Search ADS PubMed 25. Fujii T , Kogawa T , Dong W , et al. Revisiting the definition of estrogen receptor positivity in HER2-negative primary breast cancer . Ann Oncol . 2017 ; 28 : 2420 - 2428 . Google Scholar CrossRef Search ADS PubMed © American Society for Clinical Pathology, 2018. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png American Journal of Clinical Pathology Oxford University Press

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Abstract

Abstract Objectives Pathologic complete response (pCR) rate after neoadjuvant chemotherapy was compared between 141 estrogen receptor (ER)–negative (43%), 41 low ER+ (13%), 47 moderate ER+ (14%), and 98 high ER+ (30%) tumors. Methods Human epidermal growth factor receptor 2–positive cases, cases without semiquantitative ER score, and patients treated with neoadjuvant endocrine therapy alone were excluded. Results The pCR rate of low ER+ tumors was similar to the pCR rate of ER– tumors (37% and 26% for low ER and ER– respectively, P = .1722) but significantly different from the pCR rate of moderately ER+ (11%, P = .0049) and high ER+ tumors (4%, P < .0001). Patients with pCR had an excellent prognosis regardless of the ER status. In patients with residual disease (no pCR), the recurrence and death rate were higher in ER– and low ER+ cases compared with moderate and high ER+ cases. Conclusions Low ER+ breast cancers are biologically similar to ER– tumors. Semiquantitative ER H-score is an important determinant of response to neoadjuvant chemotherapy. Low ER+, Moderate ER+, High ER+, Neoadjuvant chemotherapy, Pathologic complete response, ER H-score, Immunohistochemistry The primary clinically relevant subsets of breast cancers are estrogen receptor (ER)–positive and ER– groups, with progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) status also playing a significant role in clinical management. The College of American Pathologists (CAP) and American Society of Clinical Oncology (ASCO) define ER+ tumors as tumors expressing ER (by immunohistochemistry) in 1% or more of the tumor cells.1 This low bar is set based on studies showing a beneficial response to antiestrogen therapy in such cancers.2 It has been recognized over the years that semiquantitative ER results provide more information than a mere positive and negative result, and ASCO/CAP also recommends providing semiquantitative results.1,3 However, there are only limited data on the clinical usefulness of semiquantitative hormone receptor results. A few studies have shown an increasing benefit of hormonal therapy with an increasing degree of ER expression.4 Semiquantitative hormone receptor results are now also used in multivariable models to provide additional information regarding chemotherapy benefit.5-8 Availability of semiquantitative results for ER allows us to explore the possibility that weakly or low ER+ tumors form a distinct subgroup. A few studies have shown that tumors with ER expression in less than 10% cells likely behave like ER– tumors.9-12 We have also shown that the morphologic features of low ER+ tumors are similar to the morphologic features of ER– tumors.13 In this study, we have evaluated the pathologic response to neoadjuvant chemotherapy in low ER+ tumors and compared it with ER– tumors, moderately ER+ tumors, and high ER+ tumors. We have further explored the differences in recurrence rate and survival with respect to the degree of ER expression. Materials and Methods After institutional review board approval from the University of Pittsburgh, a retrospective review of a prospectively maintained database was conducted on 614 patients who received neoadjuvant therapy from 2010 to 2014 at Magee-Womens Hospital of the University of Pittsburgh Medical Center. The following exclusion criteria were applied for case selection: lack of semiquantitative ER H-score, cases that received neoadjuvant hormonal therapy only (the majority of such cases were strongly ER+), and unequivocally HER2+ cases. The unequivocal HER2+ refers to cases with an immunohistochemical score of 3+ or fluorescence in situ hybridization amplified (by 2013 ASCO/CAP criteria) if the immunohistochemical score was 2+. After excluding these cases, 327 remaining cases formed the basis of this study. Patient charts were reviewed, with respect to pathology report, operative report, chemotherapy regimen, and clinical outcomes. ER+ patients received hormonal therapy after surgery in addition to the neoadjuvant chemotherapy, and ER– patients received only neoadjuvant chemotherapy as per standard protocol. Pathologic complete response (pCR) was defined as the absence of invasive tumor in the breast resection specimen and regional lymph nodes. Residual in situ carcinoma was allowed. In addition to pCR, estimated tumor size/volume reduction in the breast was calculated using the following equation: estimated percent tumor size/volume reduction = [(pretherapy clinical size – “revised” pathology size)/pretherapy clinical size] * 100. The “revised” pathology tumor size is calculated by multiplying the largest dimension of the gross tumor bed by the invasive tumor cellularity of the tumor bed in comparison to the pretherapy core biopsy sample.14 Although our institution now uses the international working group recommended residual cancer burden method, such information was not available for the cases used in this study.15 Hormone receptor values were reported using the semiquantitative histochemical or H-score method. This system is a sum of percent staining multiplied by intensity score (0 = absent, 1 = weak, 2 = moderate, 3 =strong), with the resulting score ranging from 0 to 300.16,17 Estrogen receptor values were grouped into four categories for the purposes of our analysis: ER– (H-score = 0), low ER+ (H-score 1-100), moderate ER+ (H-score 101-200), and high ER+ (H-score 201-300). Image 1 shows examples of the different categories. Groups were analyzed for overall pathologic complete response, tumor volume reduction, nodal status, and disease-free and overall survival. Image 1 View largeDownload slide Classification of breast cancers based on estrogen receptor (ER) reactivity. A, ER– tumor with H-score of 0 (percentage of cells staining 0, 100%; 1+, 0%; 2+, 0%; 3+, 0%). B, Low ER+ tumor with H-score of 60 (percentage of cells staining 0, 50%; 1+, 40%; 2+, 10%; 3+, 0%). C, Moderate ER+ tumor with H-score of 170 (percentage of cells staining 0, 10%; 1+, 30%; 2+, 40%; 3+, 20%). D, High ER+ tumor with H-score of 300 (percentage of cells staining 0, 0%; 1+, 0%; 2+, 0%; 3+, 100%). All photomicrographs at ×200. Image 1 View largeDownload slide Classification of breast cancers based on estrogen receptor (ER) reactivity. A, ER– tumor with H-score of 0 (percentage of cells staining 0, 100%; 1+, 0%; 2+, 0%; 3+, 0%). B, Low ER+ tumor with H-score of 60 (percentage of cells staining 0, 50%; 1+, 40%; 2+, 10%; 3+, 0%). C, Moderate ER+ tumor with H-score of 170 (percentage of cells staining 0, 10%; 1+, 30%; 2+, 40%; 3+, 20%). D, High ER+ tumor with H-score of 300 (percentage of cells staining 0, 0%; 1+, 0%; 2+, 0%; 3+, 100%). All photomicrographs at ×200. Mean follow-up time was 33.6 months (median, 31.6 months; range, 7.5-70.3 months). Kaplan-Meier survival curves for disease-free survival and overall survival were analyzed with respect to ER levels, and P values were obtained using the log-rank test. Statistical analysis was performed using the R Project for Statistical Computing (Vienna, Austria). For continuous variables, the P value was obtained from the two-sided Wilcoxon rank-sum test. For categorical variables, the P value was obtained from the two-sided Fisher exact test. Patients with missing/unknown information were excluded from the test. Confidence intervals were obtained from Wald normal approximation. Logistic regression was performed to predict pCR within ER+ tumors. Prediction performance of ER status, Magee Equation 3 (ME3),6,7 and their combination were compared by area under the curve (AUC) analysis. Results Of the 327 patients eligible for this study, there were 141 (43%) patients in the ER– group, 41 (13%) in the low ER group, 47 (14%) in the moderate ER group, and 98 (30%) in the high ER group. The pCR rates of ER–, low ER+, moderate ER+, and high ER+ tumors were 25.5%, 36.6%, 10.6%, and 4.1%, respectively Table 1. The pCR rate of low ER+ tumors was similar to that of ER– tumors (P = .1722) and significantly different from moderate (P = .0049) and high ER+ tumors (P < .0001). In addition to pCR, tumor size/volume reduction in the breast was also evaluated. The tumor size/volume reduction of 78% in low ER+ tumors was similar to the average size reduction in ER– tumors (70% average size reduction, P = .2358) and moderate ER+ tumors (71%, P = .3518) but was significantly different from the size reduction in high ER+ tumors (58%, P = .0012). Furthermore, each group was compared with the low ER+ group with respect to patient and tumor characteristics Table 2, Table 3, and Table 4. No statistically significant differences were identified between ER– and low ER+ tumors (Table 2). The patients with moderately ER+ tumors were slightly younger and more frequently premenopausal compared with the low ER+ tumor group (Table 3). The moderately and high ER+ tumors were more frequently PR+, showed higher PR H-scores, had a lower pretherapy nuclear grade, and had a lower Ki-67 labeling index compared with the low ER+ group (Tables 3 and 4). The high ER+ tumors were also more frequently of the lobular phenotype and showed a significantly higher number of white patients compared with the low ER+ tumors (Table 4). Table 1 Pathologic Complete Response Rate in Different Estrogen Receptor (ER) Score Categories ER Score (Category) No. Pathologic Complete Response, No. (%) P Value (Comparison With Low ER+ Cases) 0 (ER negative) 141 36 (26%) .1722 1-100 (low ER+) 41 15 (37%) Reference 101-200 (moderate ER+) 47 5 (11%) .0049a 201-300 (high ER+) 98 4 (4%) <.0001a ER Score (Category) No. Pathologic Complete Response, No. (%) P Value (Comparison With Low ER+ Cases) 0 (ER negative) 141 36 (26%) .1722 1-100 (low ER+) 41 15 (37%) Reference 101-200 (moderate ER+) 47 5 (11%) .0049a 201-300 (high ER+) 98 4 (4%) <.0001a ER, estrogen receptor. aStatistically significant. View Large Table 1 Pathologic Complete Response Rate in Different Estrogen Receptor (ER) Score Categories ER Score (Category) No. Pathologic Complete Response, No. (%) P Value (Comparison With Low ER+ Cases) 0 (ER negative) 141 36 (26%) .1722 1-100 (low ER+) 41 15 (37%) Reference 101-200 (moderate ER+) 47 5 (11%) .0049a 201-300 (high ER+) 98 4 (4%) <.0001a ER Score (Category) No. Pathologic Complete Response, No. (%) P Value (Comparison With Low ER+ Cases) 0 (ER negative) 141 36 (26%) .1722 1-100 (low ER+) 41 15 (37%) Reference 101-200 (moderate ER+) 47 5 (11%) .0049a 201-300 (high ER+) 98 4 (4%) <.0001a ER, estrogen receptor. aStatistically significant. View Large Table 2 Patient and Tumor Characteristics for “Low ER+” and ER– Casesa Characteristic Low ER+ (n = 41) ER– (n = 141) P Value Continuous variables, mean (SD)  Age, y 53.9 (12.0) 52.4 (11.5) .3685  Age at menarche, y 12.8 (1.5), unknown: 8 13.1 (1.8), unknown: 43 .3937  Body mass index, kg/m2 28.3 (5.5), unknown: 13 29.1 (9.7), unknown: 55 .7520  Pretherapy tumor size, cm 4.6 (4.4), unknown: 7 3.9 (3.6), unknown: 25 .4697  Ki-67 labeling index, % 74.2 (24.0), unknown: 1 70.9 (24.1), unknown: 13 .3446  Progesterone receptor H-score 6.1 (22.2) 0.9 (5.9) .2370 Categorical variables, No. (%)  Menopausal status   Premenopausal 16 (39.0) 60 (42.6) .8562   Postmenopausal 24 (58.5) 79 (56)   Unknown 1 (2.5) 2 (1.4)  Race   White 34 (82.9) 120 (85.1) .6077   Black 7 (17.1) 18 (12.8)   Asian 0 (0) 0 (0)   Other 0 (0) 3 (2.1)  Neoadjuvant chemotherapy regimen   ACT 22 (53.7) 62 (44.0) .2907   Other and unknown 19 (46.3) 79 (56.0)  Pretherapy lymph node status   Core biopsy positive 14 (34.1) 49 (34.8) .6880   Core biopsy negative 18 (43.9) 52 (36.8)   Unknown 9 (22.0) 40 (28.4)  Pretherapy nuclear grade   Nuclear grade 1 or 2 2 (4.9) 17 (12.1) .1662   Nuclear grade 3 37 (90.2) 106 (75.2)   Unknown 2 (4.9) 18 (12.7)  Histology   Ductal 40 (97.6) 132 (93.6) 1.000   Lobular 0 (0) 1 (0.7)   Others 1 (2.4) 8 (5.7)  Progesterone receptor status   Positive 4 (9.8) 7 (5.0) .2708   Negative 37 (90.2) 134 (95.0)   Unknown 0 (0) 0 (0)  HER2 status   Negative 39 (95.1) 137 (97.2) .6184   Equivocal 2 (4.9) 4 (2.8) Characteristic Low ER+ (n = 41) ER– (n = 141) P Value Continuous variables, mean (SD)  Age, y 53.9 (12.0) 52.4 (11.5) .3685  Age at menarche, y 12.8 (1.5), unknown: 8 13.1 (1.8), unknown: 43 .3937  Body mass index, kg/m2 28.3 (5.5), unknown: 13 29.1 (9.7), unknown: 55 .7520  Pretherapy tumor size, cm 4.6 (4.4), unknown: 7 3.9 (3.6), unknown: 25 .4697  Ki-67 labeling index, % 74.2 (24.0), unknown: 1 70.9 (24.1), unknown: 13 .3446  Progesterone receptor H-score 6.1 (22.2) 0.9 (5.9) .2370 Categorical variables, No. (%)  Menopausal status   Premenopausal 16 (39.0) 60 (42.6) .8562   Postmenopausal 24 (58.5) 79 (56)   Unknown 1 (2.5) 2 (1.4)  Race   White 34 (82.9) 120 (85.1) .6077   Black 7 (17.1) 18 (12.8)   Asian 0 (0) 0 (0)   Other 0 (0) 3 (2.1)  Neoadjuvant chemotherapy regimen   ACT 22 (53.7) 62 (44.0) .2907   Other and unknown 19 (46.3) 79 (56.0)  Pretherapy lymph node status   Core biopsy positive 14 (34.1) 49 (34.8) .6880   Core biopsy negative 18 (43.9) 52 (36.8)   Unknown 9 (22.0) 40 (28.4)  Pretherapy nuclear grade   Nuclear grade 1 or 2 2 (4.9) 17 (12.1) .1662   Nuclear grade 3 37 (90.2) 106 (75.2)   Unknown 2 (4.9) 18 (12.7)  Histology   Ductal 40 (97.6) 132 (93.6) 1.000   Lobular 0 (0) 1 (0.7)   Others 1 (2.4) 8 (5.7)  Progesterone receptor status   Positive 4 (9.8) 7 (5.0) .2708   Negative 37 (90.2) 134 (95.0)   Unknown 0 (0) 0 (0)  HER2 status   Negative 39 (95.1) 137 (97.2) .6184   Equivocal 2 (4.9) 4 (2.8) ACT, adriamycin, cyclophosphamide, taxane; ER, estrogen receptor; HER2, human epidermal growth factor receptor 2. aFor continuous variables, P value was obtained from the two-sided Wilcoxon rank-sum test. For categorical variables, P value was obtained from the two-sided Fisher exact test. Patients with missing/unknown information were excluded from test. View Large Table 2 Patient and Tumor Characteristics for “Low ER+” and ER– Casesa Characteristic Low ER+ (n = 41) ER– (n = 141) P Value Continuous variables, mean (SD)  Age, y 53.9 (12.0) 52.4 (11.5) .3685  Age at menarche, y 12.8 (1.5), unknown: 8 13.1 (1.8), unknown: 43 .3937  Body mass index, kg/m2 28.3 (5.5), unknown: 13 29.1 (9.7), unknown: 55 .7520  Pretherapy tumor size, cm 4.6 (4.4), unknown: 7 3.9 (3.6), unknown: 25 .4697  Ki-67 labeling index, % 74.2 (24.0), unknown: 1 70.9 (24.1), unknown: 13 .3446  Progesterone receptor H-score 6.1 (22.2) 0.9 (5.9) .2370 Categorical variables, No. (%)  Menopausal status   Premenopausal 16 (39.0) 60 (42.6) .8562   Postmenopausal 24 (58.5) 79 (56)   Unknown 1 (2.5) 2 (1.4)  Race   White 34 (82.9) 120 (85.1) .6077   Black 7 (17.1) 18 (12.8)   Asian 0 (0) 0 (0)   Other 0 (0) 3 (2.1)  Neoadjuvant chemotherapy regimen   ACT 22 (53.7) 62 (44.0) .2907   Other and unknown 19 (46.3) 79 (56.0)  Pretherapy lymph node status   Core biopsy positive 14 (34.1) 49 (34.8) .6880   Core biopsy negative 18 (43.9) 52 (36.8)   Unknown 9 (22.0) 40 (28.4)  Pretherapy nuclear grade   Nuclear grade 1 or 2 2 (4.9) 17 (12.1) .1662   Nuclear grade 3 37 (90.2) 106 (75.2)   Unknown 2 (4.9) 18 (12.7)  Histology   Ductal 40 (97.6) 132 (93.6) 1.000   Lobular 0 (0) 1 (0.7)   Others 1 (2.4) 8 (5.7)  Progesterone receptor status   Positive 4 (9.8) 7 (5.0) .2708   Negative 37 (90.2) 134 (95.0)   Unknown 0 (0) 0 (0)  HER2 status   Negative 39 (95.1) 137 (97.2) .6184   Equivocal 2 (4.9) 4 (2.8) Characteristic Low ER+ (n = 41) ER– (n = 141) P Value Continuous variables, mean (SD)  Age, y 53.9 (12.0) 52.4 (11.5) .3685  Age at menarche, y 12.8 (1.5), unknown: 8 13.1 (1.8), unknown: 43 .3937  Body mass index, kg/m2 28.3 (5.5), unknown: 13 29.1 (9.7), unknown: 55 .7520  Pretherapy tumor size, cm 4.6 (4.4), unknown: 7 3.9 (3.6), unknown: 25 .4697  Ki-67 labeling index, % 74.2 (24.0), unknown: 1 70.9 (24.1), unknown: 13 .3446  Progesterone receptor H-score 6.1 (22.2) 0.9 (5.9) .2370 Categorical variables, No. (%)  Menopausal status   Premenopausal 16 (39.0) 60 (42.6) .8562   Postmenopausal 24 (58.5) 79 (56)   Unknown 1 (2.5) 2 (1.4)  Race   White 34 (82.9) 120 (85.1) .6077   Black 7 (17.1) 18 (12.8)   Asian 0 (0) 0 (0)   Other 0 (0) 3 (2.1)  Neoadjuvant chemotherapy regimen   ACT 22 (53.7) 62 (44.0) .2907   Other and unknown 19 (46.3) 79 (56.0)  Pretherapy lymph node status   Core biopsy positive 14 (34.1) 49 (34.8) .6880   Core biopsy negative 18 (43.9) 52 (36.8)   Unknown 9 (22.0) 40 (28.4)  Pretherapy nuclear grade   Nuclear grade 1 or 2 2 (4.9) 17 (12.1) .1662   Nuclear grade 3 37 (90.2) 106 (75.2)   Unknown 2 (4.9) 18 (12.7)  Histology   Ductal 40 (97.6) 132 (93.6) 1.000   Lobular 0 (0) 1 (0.7)   Others 1 (2.4) 8 (5.7)  Progesterone receptor status   Positive 4 (9.8) 7 (5.0) .2708   Negative 37 (90.2) 134 (95.0)   Unknown 0 (0) 0 (0)  HER2 status   Negative 39 (95.1) 137 (97.2) .6184   Equivocal 2 (4.9) 4 (2.8) ACT, adriamycin, cyclophosphamide, taxane; ER, estrogen receptor; HER2, human epidermal growth factor receptor 2. aFor continuous variables, P value was obtained from the two-sided Wilcoxon rank-sum test. For categorical variables, P value was obtained from the two-sided Fisher exact test. Patients with missing/unknown information were excluded from test. View Large Table 3 Patient and Tumor Characteristics for “Low ER+” and Moderate ER+ Casesa Characteristic Low ER+ (n = 41) Moderate ER+ (n = 47) P Value Continuous variables, mean (SD)  Age, y 53.9 (12.0) 46.2 (8.6) .0015b  Age at menarche, y 12.8 (1.5), unknown: 8 12.5 (1.5), unknown: 3 .4562  Body mass index, kg/m2 28.3 (5.5), unknown: 13 28.9 (7.9), unknown: 8 .8140  Pretherapy tumor size, cm 4.6 (4.4), unknown: 7 4.6 (2.6), unknown: 1 .2975  Ki-67 labeling index, % 74.2 (24.0), unknown: 1 45.5 (27.9), unknown: 0 <.0001b  Progesterone receptor H-score 6.1 (22.2) 90.5 (75.8) <.0001b Categorical variables, No. (%)  Menopausal status   Premenopausal 16 (39.0) 36 (76.6) .0009b   Postmenopausal 24 (58.5) 11 (23.4)   Unknown 1 (2.5) 0 (0)  Race   White 34 (82.9) 43 (91.4) .0797   Black 7 (17.1) 2 (4.3)   Asian 0 (0) 0 (0)   Other 0 (0) 2 (4.3)  Neoadjuvant chemotherapy regimen   ACT 22 (53.7) 28 (59.6) .6676   Other and unknown 19 (46.3) 19 (40.4)  Pretherapy lymph node status   Core biopsy positive 14 (34.1) 21 (44.7) .3311   Core biopsy negative 18 (43.9) 15 (31.9)   Unknown 9 (22.0) 11 (23.4)  Pretherapy nuclear grade   Nuclear grade 1 or 2 2 (4.9) 21 (44.7) <.0001b   Nuclear grade 3 37 (90.2) 24 (51.0)   Unknown 2 (4.9) 2 (4.3)  Histology   Ductal 40 (97.6) 39 (83.0) .0565   Lobular 0 (0) 5 (10.6)   Others 1 (2.4) 3 (6.4)  Progesterone receptor status   Positive 4 (9.8) 41 (87.2) <.0001b   Negative 37 (90.2) 6 (12.8)   Unknown 0 (0) 0 (0)  HER2 status   Negative 39 (95.1) 39 (83.0) .0974   Equivocal 2 (4.9) 8 (17.0) Characteristic Low ER+ (n = 41) Moderate ER+ (n = 47) P Value Continuous variables, mean (SD)  Age, y 53.9 (12.0) 46.2 (8.6) .0015b  Age at menarche, y 12.8 (1.5), unknown: 8 12.5 (1.5), unknown: 3 .4562  Body mass index, kg/m2 28.3 (5.5), unknown: 13 28.9 (7.9), unknown: 8 .8140  Pretherapy tumor size, cm 4.6 (4.4), unknown: 7 4.6 (2.6), unknown: 1 .2975  Ki-67 labeling index, % 74.2 (24.0), unknown: 1 45.5 (27.9), unknown: 0 <.0001b  Progesterone receptor H-score 6.1 (22.2) 90.5 (75.8) <.0001b Categorical variables, No. (%)  Menopausal status   Premenopausal 16 (39.0) 36 (76.6) .0009b   Postmenopausal 24 (58.5) 11 (23.4)   Unknown 1 (2.5) 0 (0)  Race   White 34 (82.9) 43 (91.4) .0797   Black 7 (17.1) 2 (4.3)   Asian 0 (0) 0 (0)   Other 0 (0) 2 (4.3)  Neoadjuvant chemotherapy regimen   ACT 22 (53.7) 28 (59.6) .6676   Other and unknown 19 (46.3) 19 (40.4)  Pretherapy lymph node status   Core biopsy positive 14 (34.1) 21 (44.7) .3311   Core biopsy negative 18 (43.9) 15 (31.9)   Unknown 9 (22.0) 11 (23.4)  Pretherapy nuclear grade   Nuclear grade 1 or 2 2 (4.9) 21 (44.7) <.0001b   Nuclear grade 3 37 (90.2) 24 (51.0)   Unknown 2 (4.9) 2 (4.3)  Histology   Ductal 40 (97.6) 39 (83.0) .0565   Lobular 0 (0) 5 (10.6)   Others 1 (2.4) 3 (6.4)  Progesterone receptor status   Positive 4 (9.8) 41 (87.2) <.0001b   Negative 37 (90.2) 6 (12.8)   Unknown 0 (0) 0 (0)  HER2 status   Negative 39 (95.1) 39 (83.0) .0974   Equivocal 2 (4.9) 8 (17.0) ACT, adriamycin, cyclophosphamide, taxane; ER, estrogen receptor; HER2, human epidermal growth factor receptor 2. aFor continuous variables, P value was obtained from the two-sided Wilcoxon rank-sum test. For categorical variables, P value was obtained from the two-sided Fisher exact test. Patients with missing/unknown information were excluded from test. bStatistically significant. View Large Table 3 Patient and Tumor Characteristics for “Low ER+” and Moderate ER+ Casesa Characteristic Low ER+ (n = 41) Moderate ER+ (n = 47) P Value Continuous variables, mean (SD)  Age, y 53.9 (12.0) 46.2 (8.6) .0015b  Age at menarche, y 12.8 (1.5), unknown: 8 12.5 (1.5), unknown: 3 .4562  Body mass index, kg/m2 28.3 (5.5), unknown: 13 28.9 (7.9), unknown: 8 .8140  Pretherapy tumor size, cm 4.6 (4.4), unknown: 7 4.6 (2.6), unknown: 1 .2975  Ki-67 labeling index, % 74.2 (24.0), unknown: 1 45.5 (27.9), unknown: 0 <.0001b  Progesterone receptor H-score 6.1 (22.2) 90.5 (75.8) <.0001b Categorical variables, No. (%)  Menopausal status   Premenopausal 16 (39.0) 36 (76.6) .0009b   Postmenopausal 24 (58.5) 11 (23.4)   Unknown 1 (2.5) 0 (0)  Race   White 34 (82.9) 43 (91.4) .0797   Black 7 (17.1) 2 (4.3)   Asian 0 (0) 0 (0)   Other 0 (0) 2 (4.3)  Neoadjuvant chemotherapy regimen   ACT 22 (53.7) 28 (59.6) .6676   Other and unknown 19 (46.3) 19 (40.4)  Pretherapy lymph node status   Core biopsy positive 14 (34.1) 21 (44.7) .3311   Core biopsy negative 18 (43.9) 15 (31.9)   Unknown 9 (22.0) 11 (23.4)  Pretherapy nuclear grade   Nuclear grade 1 or 2 2 (4.9) 21 (44.7) <.0001b   Nuclear grade 3 37 (90.2) 24 (51.0)   Unknown 2 (4.9) 2 (4.3)  Histology   Ductal 40 (97.6) 39 (83.0) .0565   Lobular 0 (0) 5 (10.6)   Others 1 (2.4) 3 (6.4)  Progesterone receptor status   Positive 4 (9.8) 41 (87.2) <.0001b   Negative 37 (90.2) 6 (12.8)   Unknown 0 (0) 0 (0)  HER2 status   Negative 39 (95.1) 39 (83.0) .0974   Equivocal 2 (4.9) 8 (17.0) Characteristic Low ER+ (n = 41) Moderate ER+ (n = 47) P Value Continuous variables, mean (SD)  Age, y 53.9 (12.0) 46.2 (8.6) .0015b  Age at menarche, y 12.8 (1.5), unknown: 8 12.5 (1.5), unknown: 3 .4562  Body mass index, kg/m2 28.3 (5.5), unknown: 13 28.9 (7.9), unknown: 8 .8140  Pretherapy tumor size, cm 4.6 (4.4), unknown: 7 4.6 (2.6), unknown: 1 .2975  Ki-67 labeling index, % 74.2 (24.0), unknown: 1 45.5 (27.9), unknown: 0 <.0001b  Progesterone receptor H-score 6.1 (22.2) 90.5 (75.8) <.0001b Categorical variables, No. (%)  Menopausal status   Premenopausal 16 (39.0) 36 (76.6) .0009b   Postmenopausal 24 (58.5) 11 (23.4)   Unknown 1 (2.5) 0 (0)  Race   White 34 (82.9) 43 (91.4) .0797   Black 7 (17.1) 2 (4.3)   Asian 0 (0) 0 (0)   Other 0 (0) 2 (4.3)  Neoadjuvant chemotherapy regimen   ACT 22 (53.7) 28 (59.6) .6676   Other and unknown 19 (46.3) 19 (40.4)  Pretherapy lymph node status   Core biopsy positive 14 (34.1) 21 (44.7) .3311   Core biopsy negative 18 (43.9) 15 (31.9)   Unknown 9 (22.0) 11 (23.4)  Pretherapy nuclear grade   Nuclear grade 1 or 2 2 (4.9) 21 (44.7) <.0001b   Nuclear grade 3 37 (90.2) 24 (51.0)   Unknown 2 (4.9) 2 (4.3)  Histology   Ductal 40 (97.6) 39 (83.0) .0565   Lobular 0 (0) 5 (10.6)   Others 1 (2.4) 3 (6.4)  Progesterone receptor status   Positive 4 (9.8) 41 (87.2) <.0001b   Negative 37 (90.2) 6 (12.8)   Unknown 0 (0) 0 (0)  HER2 status   Negative 39 (95.1) 39 (83.0) .0974   Equivocal 2 (4.9) 8 (17.0) ACT, adriamycin, cyclophosphamide, taxane; ER, estrogen receptor; HER2, human epidermal growth factor receptor 2. aFor continuous variables, P value was obtained from the two-sided Wilcoxon rank-sum test. For categorical variables, P value was obtained from the two-sided Fisher exact test. Patients with missing/unknown information were excluded from test. bStatistically significant. View Large Table 4 Patient and Tumor Characteristics for “Low ER+” and High ER+ Casesa Characteristic Low ER+ (n = 41) High ER+ (n = 98) P Value Continuous variables, mean (SD)  Age, y 53.9 (12.0) 54.1 (11.4) .9374  Age at menarche, y 12.8 (1.5), unknown: 8 12.9 (1.5), unknown: 17 .4644  Body mass index, kg/m2 28.3 (5.5), unknown: 13 29.3 (6.7), unknown: 26 .6784  Pretherapy tumor size, cm 4.6 (4.4), unknown: 7 4.4 (2.2), unknown: 10 .3978  Ki-67 labeling index, % 74.2 (24.0), unknown: 1 34.1 (21), unknown: 5 <.0001b  Progesterone receptor H-score 6.1 (22.2) 138.6 (107) <.0001b Categorical variables, No. (%)  Menopausal status   Premenopausal 16 (39.0) 48 (49.0) .3471   Postmenopausal 24 (58.5) 48 (49.0)   Unknown 1 (2.5) 2 (2.0)  Race   White 34 (82.9) 92 (93.9) .0412b   Black 7 (17.1) 5 (5.1)   Asian 0 (0) 1 (1)   Other 0 (0) 0 (0)  Neoadjuvant chemotherapy regimen   ACT 22 (53.7) 56 (57.1) .7123   Other and unknown 19 (46.3) 42 (42.9)  Pretherapy lymph node status   Core biopsy positive 14 (34.1) 41 (41.8) .5292   Core biopsy negative 18 (43.9) 37 (37.8)   Unknown 9 (22.0) 20 (20.4)  Pretherapy nuclear grade   Nuclear grade 1 or 2 2 (4.9) 51 (52.0) <.0001b   Nuclear grade 3 37 (90.2) 35 (35.8)   Unknown 2 (4.9) 12 (12.2)  Histology   Ductal 40 (97.6) 83 (84.7) .0103b   Lobular 0 (0) 14 (14.3)   Others 1 (2.4) 1 (1.0)  Progesterone receptor status   Positive 4 (9.8) 84 (85.7) <.0001b   Negative 37 (90.2) 14 (14.3)   Unknown 0 (0) 0 (0)  HER2 status   Negative 39 (95.1) 89 (90.8) .5072   Equivocal 2 (4.9) 9 (9.2) Characteristic Low ER+ (n = 41) High ER+ (n = 98) P Value Continuous variables, mean (SD)  Age, y 53.9 (12.0) 54.1 (11.4) .9374  Age at menarche, y 12.8 (1.5), unknown: 8 12.9 (1.5), unknown: 17 .4644  Body mass index, kg/m2 28.3 (5.5), unknown: 13 29.3 (6.7), unknown: 26 .6784  Pretherapy tumor size, cm 4.6 (4.4), unknown: 7 4.4 (2.2), unknown: 10 .3978  Ki-67 labeling index, % 74.2 (24.0), unknown: 1 34.1 (21), unknown: 5 <.0001b  Progesterone receptor H-score 6.1 (22.2) 138.6 (107) <.0001b Categorical variables, No. (%)  Menopausal status   Premenopausal 16 (39.0) 48 (49.0) .3471   Postmenopausal 24 (58.5) 48 (49.0)   Unknown 1 (2.5) 2 (2.0)  Race   White 34 (82.9) 92 (93.9) .0412b   Black 7 (17.1) 5 (5.1)   Asian 0 (0) 1 (1)   Other 0 (0) 0 (0)  Neoadjuvant chemotherapy regimen   ACT 22 (53.7) 56 (57.1) .7123   Other and unknown 19 (46.3) 42 (42.9)  Pretherapy lymph node status   Core biopsy positive 14 (34.1) 41 (41.8) .5292   Core biopsy negative 18 (43.9) 37 (37.8)   Unknown 9 (22.0) 20 (20.4)  Pretherapy nuclear grade   Nuclear grade 1 or 2 2 (4.9) 51 (52.0) <.0001b   Nuclear grade 3 37 (90.2) 35 (35.8)   Unknown 2 (4.9) 12 (12.2)  Histology   Ductal 40 (97.6) 83 (84.7) .0103b   Lobular 0 (0) 14 (14.3)   Others 1 (2.4) 1 (1.0)  Progesterone receptor status   Positive 4 (9.8) 84 (85.7) <.0001b   Negative 37 (90.2) 14 (14.3)   Unknown 0 (0) 0 (0)  HER2 status   Negative 39 (95.1) 89 (90.8) .5072   Equivocal 2 (4.9) 9 (9.2) ACT, adriamycin, cyclophosphamide, taxane; ER, estrogen receptor; HER2, human epidermal growth factor receptor 2. aFor continuous variables, P value was obtained from the two-sided Wilcoxon rank-sum test. For categorical variables, P value was obtained from the two-sided Fisher exact test. Patients with missing/unknown information were excluded from test. bStatistically significant. View Large Table 4 Patient and Tumor Characteristics for “Low ER+” and High ER+ Casesa Characteristic Low ER+ (n = 41) High ER+ (n = 98) P Value Continuous variables, mean (SD)  Age, y 53.9 (12.0) 54.1 (11.4) .9374  Age at menarche, y 12.8 (1.5), unknown: 8 12.9 (1.5), unknown: 17 .4644  Body mass index, kg/m2 28.3 (5.5), unknown: 13 29.3 (6.7), unknown: 26 .6784  Pretherapy tumor size, cm 4.6 (4.4), unknown: 7 4.4 (2.2), unknown: 10 .3978  Ki-67 labeling index, % 74.2 (24.0), unknown: 1 34.1 (21), unknown: 5 <.0001b  Progesterone receptor H-score 6.1 (22.2) 138.6 (107) <.0001b Categorical variables, No. (%)  Menopausal status   Premenopausal 16 (39.0) 48 (49.0) .3471   Postmenopausal 24 (58.5) 48 (49.0)   Unknown 1 (2.5) 2 (2.0)  Race   White 34 (82.9) 92 (93.9) .0412b   Black 7 (17.1) 5 (5.1)   Asian 0 (0) 1 (1)   Other 0 (0) 0 (0)  Neoadjuvant chemotherapy regimen   ACT 22 (53.7) 56 (57.1) .7123   Other and unknown 19 (46.3) 42 (42.9)  Pretherapy lymph node status   Core biopsy positive 14 (34.1) 41 (41.8) .5292   Core biopsy negative 18 (43.9) 37 (37.8)   Unknown 9 (22.0) 20 (20.4)  Pretherapy nuclear grade   Nuclear grade 1 or 2 2 (4.9) 51 (52.0) <.0001b   Nuclear grade 3 37 (90.2) 35 (35.8)   Unknown 2 (4.9) 12 (12.2)  Histology   Ductal 40 (97.6) 83 (84.7) .0103b   Lobular 0 (0) 14 (14.3)   Others 1 (2.4) 1 (1.0)  Progesterone receptor status   Positive 4 (9.8) 84 (85.7) <.0001b   Negative 37 (90.2) 14 (14.3)   Unknown 0 (0) 0 (0)  HER2 status   Negative 39 (95.1) 89 (90.8) .5072   Equivocal 2 (4.9) 9 (9.2) Characteristic Low ER+ (n = 41) High ER+ (n = 98) P Value Continuous variables, mean (SD)  Age, y 53.9 (12.0) 54.1 (11.4) .9374  Age at menarche, y 12.8 (1.5), unknown: 8 12.9 (1.5), unknown: 17 .4644  Body mass index, kg/m2 28.3 (5.5), unknown: 13 29.3 (6.7), unknown: 26 .6784  Pretherapy tumor size, cm 4.6 (4.4), unknown: 7 4.4 (2.2), unknown: 10 .3978  Ki-67 labeling index, % 74.2 (24.0), unknown: 1 34.1 (21), unknown: 5 <.0001b  Progesterone receptor H-score 6.1 (22.2) 138.6 (107) <.0001b Categorical variables, No. (%)  Menopausal status   Premenopausal 16 (39.0) 48 (49.0) .3471   Postmenopausal 24 (58.5) 48 (49.0)   Unknown 1 (2.5) 2 (2.0)  Race   White 34 (82.9) 92 (93.9) .0412b   Black 7 (17.1) 5 (5.1)   Asian 0 (0) 1 (1)   Other 0 (0) 0 (0)  Neoadjuvant chemotherapy regimen   ACT 22 (53.7) 56 (57.1) .7123   Other and unknown 19 (46.3) 42 (42.9)  Pretherapy lymph node status   Core biopsy positive 14 (34.1) 41 (41.8) .5292   Core biopsy negative 18 (43.9) 37 (37.8)   Unknown 9 (22.0) 20 (20.4)  Pretherapy nuclear grade   Nuclear grade 1 or 2 2 (4.9) 51 (52.0) <.0001b   Nuclear grade 3 37 (90.2) 35 (35.8)   Unknown 2 (4.9) 12 (12.2)  Histology   Ductal 40 (97.6) 83 (84.7) .0103b   Lobular 0 (0) 14 (14.3)   Others 1 (2.4) 1 (1.0)  Progesterone receptor status   Positive 4 (9.8) 84 (85.7) <.0001b   Negative 37 (90.2) 14 (14.3)   Unknown 0 (0) 0 (0)  HER2 status   Negative 39 (95.1) 89 (90.8) .5072   Equivocal 2 (4.9) 9 (9.2) ACT, adriamycin, cyclophosphamide, taxane; ER, estrogen receptor; HER2, human epidermal growth factor receptor 2. aFor continuous variables, P value was obtained from the two-sided Wilcoxon rank-sum test. For categorical variables, P value was obtained from the two-sided Fisher exact test. Patients with missing/unknown information were excluded from test. bStatistically significant. View Large Since the prior studies define low ER as 1% to 10% ER+ cells, we also examined the pCR rate of tumors with H-scores 1 to 10 and 11 to 100. Of the 41 low ER+ tumors, 27 (66%) had H-scores 1 to 10 and 14 (34%) had H-scores 11 to 100. Nine (33%) of 27 tumors with H-scores 1 to 10 showed pCR compared with six (43%) of 14 tumors with H-scores 11 to 100 (P = .7337). Recurrence and survival data were available and are reported separately for patients who achieved pCR and those who did not. Of the 60 patients who achieved pCR, there was only one distant recurrence (recurrence rate of 3%) and one death during follow-up, with a survival rate of 97%. The single recurrence and death occurred in the ER– group. Among the 267 patients with residual disease after neoadjuvant chemotherapy, there were 66 (25%) recurrences, of which 56 (20%) were distant. There were 38 deaths, with an overall survival rate of 85%. The recurrence and death rate of low ER+ tumors were similar to the recurrence and death rate of ER– tumors but significantly different from the recurrence and death rate of moderate ER+ tumors and high ER+ tumors Table 5; Figure 1 and Figure 2. The difference in recurrence and death rate between low ER+ and other ER+ tumors was significant particularly within the posttherapy lymph node–positive subgroup Table 6 and Table 7. Table 5 Recurrence and Death Rate in Patients With Residual Disease (No pCR) (n = 267) Score No. Recurrence Death Patients Recurred, No. (%) P Value (Comparison to Low ER) Patients Died, No. (%) P Value (Comparison to Low ER) ER 0 105 35 (33) .6491 24 (23) .4470 ER 1-100 26 10 (38) Reference 8 (31) Reference ER 101-200 42 6 (14) .0378a 2 (5) .0051a ER 201-300 94 15 (16) .0260a 4 (4) .0005a Score No. Recurrence Death Patients Recurred, No. (%) P Value (Comparison to Low ER) Patients Died, No. (%) P Value (Comparison to Low ER) ER 0 105 35 (33) .6491 24 (23) .4470 ER 1-100 26 10 (38) Reference 8 (31) Reference ER 101-200 42 6 (14) .0378a 2 (5) .0051a ER 201-300 94 15 (16) .0260a 4 (4) .0005a ER, estrogen receptor; pCR, pathologic complete response. aStatistically significant. View Large Table 5 Recurrence and Death Rate in Patients With Residual Disease (No pCR) (n = 267) Score No. Recurrence Death Patients Recurred, No. (%) P Value (Comparison to Low ER) Patients Died, No. (%) P Value (Comparison to Low ER) ER 0 105 35 (33) .6491 24 (23) .4470 ER 1-100 26 10 (38) Reference 8 (31) Reference ER 101-200 42 6 (14) .0378a 2 (5) .0051a ER 201-300 94 15 (16) .0260a 4 (4) .0005a Score No. Recurrence Death Patients Recurred, No. (%) P Value (Comparison to Low ER) Patients Died, No. (%) P Value (Comparison to Low ER) ER 0 105 35 (33) .6491 24 (23) .4470 ER 1-100 26 10 (38) Reference 8 (31) Reference ER 101-200 42 6 (14) .0378a 2 (5) .0051a ER 201-300 94 15 (16) .0260a 4 (4) .0005a ER, estrogen receptor; pCR, pathologic complete response. aStatistically significant. View Large Figure 1 View largeDownload slide Disease-free survival plot of patients with residual disease (no pathologic complete response) (n = 267), categorized by estrogen receptor (ER) status. P value obtained from the log-rank test with low ER+ as a reference. P = .657 for ER–. P = .025 for moderate ER+. P = .006 for high ER+. Figure 1 View largeDownload slide Disease-free survival plot of patients with residual disease (no pathologic complete response) (n = 267), categorized by estrogen receptor (ER) status. P value obtained from the log-rank test with low ER+ as a reference. P = .657 for ER–. P = .025 for moderate ER+. P = .006 for high ER+. Figure 2 View largeDownload slide Overall survival plot of patients with residual disease (no pathologic complete response) (n = 267), categorized by estrogen receptor (ER) status. P value obtained from the log-rank test with low ER+ as a reference. P = .672 for ER–. P = .003 for moderate ER+. P = 0 for high ER+. Figure 2 View largeDownload slide Overall survival plot of patients with residual disease (no pathologic complete response) (n = 267), categorized by estrogen receptor (ER) status. P value obtained from the log-rank test with low ER+ as a reference. P = .672 for ER–. P = .003 for moderate ER+. P = 0 for high ER+. Table 6 Recurrence Rate in Patients With Residual Disease (No pCR) (n = 267), Categorized by Lymph Node Status Posttherapy Score Recurrences in Lymph Node Negative (n = 120) Recurrences in Lymph Node Positive (n = 147) P Value (Comparison to Low ER) Local, No. Distant, No. All, No./Total No. (%) Local, No. Distant, No. All, No./Total No. (%) ER 0 3 12 15/65 (23) 3 17 20/40 (50) LN negative: 1.000; LN positive: .7278 ER 1-100 0 4 4/16 (25) 1 5 6/10 (60) Reference ER 101-200 0 1 1/15 (7) 1 4 5/27 (19) LN negative: .3326; LN positive: .0377a ER 201-300 0 2 2/24 (8) 2 11 13/70 (19) LN negative: .1953; LN positive: .0098a Score Recurrences in Lymph Node Negative (n = 120) Recurrences in Lymph Node Positive (n = 147) P Value (Comparison to Low ER) Local, No. Distant, No. All, No./Total No. (%) Local, No. Distant, No. All, No./Total No. (%) ER 0 3 12 15/65 (23) 3 17 20/40 (50) LN negative: 1.000; LN positive: .7278 ER 1-100 0 4 4/16 (25) 1 5 6/10 (60) Reference ER 101-200 0 1 1/15 (7) 1 4 5/27 (19) LN negative: .3326; LN positive: .0377a ER 201-300 0 2 2/24 (8) 2 11 13/70 (19) LN negative: .1953; LN positive: .0098a ER, estrogen receptor; LN, lymph node negative; pCR, pathologic complete response. aStatistically significant. View Large Table 6 Recurrence Rate in Patients With Residual Disease (No pCR) (n = 267), Categorized by Lymph Node Status Posttherapy Score Recurrences in Lymph Node Negative (n = 120) Recurrences in Lymph Node Positive (n = 147) P Value (Comparison to Low ER) Local, No. Distant, No. All, No./Total No. (%) Local, No. Distant, No. All, No./Total No. (%) ER 0 3 12 15/65 (23) 3 17 20/40 (50) LN negative: 1.000; LN positive: .7278 ER 1-100 0 4 4/16 (25) 1 5 6/10 (60) Reference ER 101-200 0 1 1/15 (7) 1 4 5/27 (19) LN negative: .3326; LN positive: .0377a ER 201-300 0 2 2/24 (8) 2 11 13/70 (19) LN negative: .1953; LN positive: .0098a Score Recurrences in Lymph Node Negative (n = 120) Recurrences in Lymph Node Positive (n = 147) P Value (Comparison to Low ER) Local, No. Distant, No. All, No./Total No. (%) Local, No. Distant, No. All, No./Total No. (%) ER 0 3 12 15/65 (23) 3 17 20/40 (50) LN negative: 1.000; LN positive: .7278 ER 1-100 0 4 4/16 (25) 1 5 6/10 (60) Reference ER 101-200 0 1 1/15 (7) 1 4 5/27 (19) LN negative: .3326; LN positive: .0377a ER 201-300 0 2 2/24 (8) 2 11 13/70 (19) LN negative: .1953; LN positive: .0098a ER, estrogen receptor; LN, lymph node negative; pCR, pathologic complete response. aStatistically significant. View Large Table 7 Death Rate in Patients With Residual Disease (No pCR) (n = 267), Categorized by Lymph Node Status Posttherapy Score Deaths in LN-Negative Group (n = 120), No./Total No. (%) Deaths in LN-Positive Group (n = 147), No./Total No. (%) P Value (Comparison to Low ER) ER 0 9/65 (14) 15/40 (38) LN negative: .2751; LN positive: 1.000 ER 1-100 4/16 (25) 4/10 (40) Reference ER 101-200 1/15 (7) 1/27 (4) LN negative: .3326; LN positive: .0136a ER 201-300 0/24 (0) 4/70 (6) LN negative: .0199a; LN positive: .0071a Score Deaths in LN-Negative Group (n = 120), No./Total No. (%) Deaths in LN-Positive Group (n = 147), No./Total No. (%) P Value (Comparison to Low ER) ER 0 9/65 (14) 15/40 (38) LN negative: .2751; LN positive: 1.000 ER 1-100 4/16 (25) 4/10 (40) Reference ER 101-200 1/15 (7) 1/27 (4) LN negative: .3326; LN positive: .0136a ER 201-300 0/24 (0) 4/70 (6) LN negative: .0199a; LN positive: .0071a ER, estrogen receptor; LN, lymph node negative; pCR, pathologic complete response. aStatistically significant. View Large Table 7 Death Rate in Patients With Residual Disease (No pCR) (n = 267), Categorized by Lymph Node Status Posttherapy Score Deaths in LN-Negative Group (n = 120), No./Total No. (%) Deaths in LN-Positive Group (n = 147), No./Total No. (%) P Value (Comparison to Low ER) ER 0 9/65 (14) 15/40 (38) LN negative: .2751; LN positive: 1.000 ER 1-100 4/16 (25) 4/10 (40) Reference ER 101-200 1/15 (7) 1/27 (4) LN negative: .3326; LN positive: .0136a ER 201-300 0/24 (0) 4/70 (6) LN negative: .0199a; LN positive: .0071a Score Deaths in LN-Negative Group (n = 120), No./Total No. (%) Deaths in LN-Positive Group (n = 147), No./Total No. (%) P Value (Comparison to Low ER) ER 0 9/65 (14) 15/40 (38) LN negative: .2751; LN positive: 1.000 ER 1-100 4/16 (25) 4/10 (40) Reference ER 101-200 1/15 (7) 1/27 (4) LN negative: .3326; LN positive: .0136a ER 201-300 0/24 (0) 4/70 (6) LN negative: .0199a; LN positive: .0071a ER, estrogen receptor; LN, lymph node negative; pCR, pathologic complete response. aStatistically significant. View Large Logistic regression AUC analysis showed ER status predicts for pCR (AUC = 0.77); however, the ME3 model is even more predictive, with an AUC of 0.82 Figure 3. Figure 3 View largeDownload slide Logistic regression area under the curve (AUC) predicting pathologic complete response using Magee Equation 3 (ME3) and estrogen receptor (ER) status. ME3 results available on 177 ER+ patients are used for analysis. Figure 3 View largeDownload slide Logistic regression area under the curve (AUC) predicting pathologic complete response using Magee Equation 3 (ME3) and estrogen receptor (ER) status. ME3 results available on 177 ER+ patients are used for analysis. Discussion It is well known that breast cancer is a heterogeneous disease on the morphologic, immunohistologic, and molecular level. The different phenotypes express varying clinical behaviors. ER status is what distinguishes luminal breast cancer from other phenotypes. Approximately 70% to 75% of breast cancers are ER+, with a slightly higher percentage positivity seen in white and elderly populations and slightly lower in nonwhite and younger populations.18,19 Often, not much attention is paid to the degree of ER positivity, and this additional useful information is frequently lost in large clinical trials where the tumor groups are only referred to as ER+ and ER–. The semiquantitative scores for hormone receptors appear to be important for judging response not only to endocrine therapy but also to chemotherapy. These semiquantitative immunohistochemical scores are often part of the multivariable models to predict for chemotherapy response.5-8 Expensive multigene assays are also available to predict for chemotherapy benefit and frequently use quantitative hormone receptor gene expression levels for their predictive scores.20,21 In this study, we investigated the clinical usefulness of semiquantitative ER scoring by immunohistochemistry. We identified a group of ER+ tumors that have a distinct phenotype and response to neoadjuvant chemotherapy. In addition, we have also compared the patient and tumor characteristics of low ER+ tumors with other ER+ tumors and ER– tumors. Comparison of tumor and patient characteristics of low ER+ and ER– tumors showed no statistically significant differences (Table 2). These findings indicate close similarity between low ER+ and ER– tumors. Comparison of tumor and patient characteristics of low ER+ and moderately ER+ tumors showed a statistically significant difference in age, menopausal status, semiquantitative PR H-score, PR status, pretherapy nuclear grade, and Ki-67 labeling index (Table 3). The latter four differences confirm the close relationship between the semiquantitative ER H-score with PR H-score, PR status, nuclear grade, and tumor proliferation. The patients with moderately ER+ tumors were surprisingly younger and premenopausal. However, this aberration could be due to some selection bias for neoadjuvant chemotherapy in ER+ tumors. Comparison of tumor and patient characteristics of low ER+ and strongly ER+ tumors showed statistically significant differences in PR H-score, PR status, Ki-67 labeling index, pretherapy nuclear grade, histology, and race (Table 4). These statistically significant differences highlight the fact that strongly ER+ tumors are more frequent in white patients, are frequently of the lobular phenotype, have strong PR expression, and are of a lower grade with a low proliferation index.22-24 Strongly ER+ tumors appear to be biologically different from low ER+ tumors. A few other studies have explored the concept of low ER+ tumors. However, different definitions have been used to define low ER positivity. Most studies have used a percentage of positive cells rather than a semiquantitative H-score method to define low ER+ tumors. In a study by Iwamoto et al,10 most tumors with 1% to 9% ER+ cells showed a basal-like gene expression profile similar to ER– tumors. Deyarmin et al9 studied 26 tumors with 1% to 10% ER+ cells and found that 88% were either basal-like or HER2 enriched and had pathologic features similar to ER– tumors. Prabhu et al11 studied ER-related gene transcripts in 240 breast cancers. They found that 21 tumors with 1% to 10% ER+ cells by immunohistochemistry had a gene expression signature similar to ER– tumors, and the survival of patients within the low ER group was intermediate between high ER+ and ER– groups. Raghav and colleagues12 evaluated the effect of endocrine therapy and survival outcome in 1,257 patients previously classified as triple negative. Upon review, the tumors were classified as ER less than 1%, 1% to 5%, and 6% to 10% positive cells. The prognosis of the tumors with low ER expression, especially 1% to 5%, did not differ significantly from tumors with undetectable levels of ER. We have broadened the prior definitions by using an H-score of 1 to 100 to define low ER+ tumors. Since H-score takes into account both intensity of staining and percentage of positive cells, an H-score of 1 to 100 includes not only tumors with 1% to 10% positive cells but also tumors with more than 10% positive cells, often with weak intensity staining. In our prior study, we have taken the same cutoff (H-score of 1-100) to define the morphologic features of such tumors. The morphologic features of tumors with H-scores of 1 to 100 show similarity to triple-negative tumors with medullary/atypical medullary features and a high proliferation index.13 Our current study is focused on the response of such tumors to neoadjuvant chemotherapy. Our results indicate a high pCR rate for low ER+ tumors. Since the prior studies define low ER as 1% to 10% ER+ cells, we also examined the pCR rate of tumors with H-scores 1 to 10 and 11 to 100. No statistically significant difference was identified between the two groups of low ER+ tumors (see results above). As far as response to chemotherapy is concerned, multivariable models that include quantitative hormone receptor results and Ki-67 proliferation index have been shown to provide chemopredictive information.6,8 The multivariable model developed at our institution, the ME3, was more informative than ER status alone in predicting pCR in ER+ tumors (Figure 3). The results of our study are very similar to a recently published study by Fujii and colleagues.25 In a large study of 3,055 ER+/HER2-negative cases, Fujii et al25 showed a high likelihood of pCR for tumors when ER expression was seen in 1% to less than 10% of the cells. They further showed the benefit of adjuvant hormonal therapy only in patients with ER reactivity in more than or equal to 10% of the tumor cells. Based on their results, Fujii and colleagues25 questioned the current ASCO/CAP definition of ER positivity. In summary, low ER+ breast cancers are rare and represent approximately 5% of all breast cancers.13 Our study is one of the few to evaluate the pCR rate of low ER+ breast cancers. Low ER+ tumors appear to be a distinct subset of ER+ tumors that derive substantial benefit from chemotherapy. There are limited data on the benefit of endocrine therapy in such tumors, but future studies should specifically evaluate this subset for endocrine therapy benefit. Many clinical trials for women with triple-negative breast cancers exclude patients with low ER+ tumors. 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For permissions, please e-mail: journals.permissions@oup.com This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices)

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American Journal of Clinical PathologyOxford University Press

Published: May 8, 2018

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