Effect of Estrogen Receptor Expression Level and Hormonal Therapy on Prognosis of Early Breast Cancer

DOI: https://doi.org/10.21203/rs.3.rs-703131/v1

Abstract

Purpose

Estrogen receptor (ER) expression in breast cancer plays an essential role in carcinogenesis and disease progression. Recently, tumors with low level (1-10%) of ER expression have been separately defined as ER Low Positive (ERlow). It is suggested that ERlow tumors might be morphologically and behaviorally different from tumors with high ER expression (ERhigh).

Methods

Retrospective analysis of a prospective cohort database was performed. Patients who underwent curative surgery for early breast cancer and had available medical records were included for analysis. Difference in clinicopathological characteristics, endocrine responsiveness and five-year recurrence-free survival was evaluated between different ER subgroups (ERhigh, ERlow, and ER-negative (ER-)).

Results

A total of 2162 breast cancer patients were included in the analysis, Tis and T1 stage. Among them, 1654 (76.5%) were ERhigh, 54 (2.5%) were ERlow, and 454 (21.0%) were ER- patients. ERlow cases were associated with smaller size, higher histologic grade, positive human epidermal growth factor receptor 2 (HER2), negative progesterone receptor, and higher Ki-67 expression. Recurrence rate was highest in ER- tumors and was inversely proportional to ER expression. Recurrence-free survival was not affected by hormonal therapy in the ERlow group (P = 0.418).

Conclusion

ERlow breast cancer showed distinct clinicopathological features. ERlow tumors seemed to have higher recurrence rates compared to ERhigh tumors, and they showed no significant benefit from hormonal therapy. Future large scale prospective studies are necessary to validate the treatment options for ERlow breast cancer.

Introduction

Breast cancer, the most common malignancy in women worldwide, is considered a heterogeneous disease with high degree of diversity.1 Risk stratification for recurrence after surgery depends on various clinicopathological factors including patient age, tumor size, lymph node involvement, and hormone receptor expression.2 Since the discovery of hormone receptors in the 1960s, estrogen receptor (ER) and progesterone receptor (PR) expression has remained essential in the decision-making algorithm for breast cancer treatment.3

ER positivity is closely associated with major hormonal risk factors of breast cancer.4 At the same time, ER-positive (ER+) disease exhibits distinct clinicopathological features such as older age, smaller size, lower grade, and most importantly, favorable prognosis.5,6 Yet the hallmark of ER expression is its predictive role in hormonal therapy response; adjuvant tamoxifen therapy for ER+ breast cancer has led to a significant decrease in recurrence and mortality.7

It is undebatable that ER-negative (ER) patients do not benefit from hormonal therapy; however, defining ER positivity with a clear cutoff point remains challenging.8 The traditional cutoff value for ER+ disease was over 10% of cells staining, which was later lowered to 1%; however, a recent update in the American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guideline recommends defining samples with low level (1%-10%) of ER expression separately as ER Low Positive (ERlow).9 Recent reports in the literature suggest that ERlow tumors might be morphologically and behaviorally different from tumors with high ER expression (ERhigh).1012 In the present study, we aim to compare ERhigh, ERlow, and ER subtypes of early breast cancer in terms of clinicopathological characteristics, endocrine responsiveness, and prognosis.

Patients And Methods

Study population

Retrospective analysis was performed on a prospective cohort of 2411 patients who underwent curative surgery for early stage breast cancer between January 2005 and December 2015 at (blinded for review). The inclusion criteria for the current study were as follows: (i) histologically confirmed stage 0 of ductal carcinoma in situ (DCIS) or stage 1 of invasive ductal carcinoma (IDC), (ii) available surgical records and pathology reports, and (iii) available immunohistochemistry (IHC) staining results on ER, PR, human epidermal growth factor receptor 2 (HER2) and Ki-67. Patients with contralateral advanced stage breast cancer were excluded from the study. A total of 2162 patients were included for analysis. This study was approved by the institutional review board of (blinded for review) (IRB No. B-2105-682-103).

Data collection

Demographic information of study participants was obtained through review of medical records. Surgical records were reviewed for operation date, method, and extent of axillary dissection. Information on tumor size, histological type, histological grade, lymphovascular invasion (LVI), lymph node metastasis, and pathological stage was retrieved from pathology reports. IHC staining was routinely performed for ER, PR, HER2, and Ki-67. Follow-up data was collected until each patient’s last visit to the hospital and included adjuvant therapy (radiation therapy, hormonal therapy, chemotherapy), recurrence status (date of recurrence, initial recurrence site, additional treatment), and survival status (date and cause of death). 5-year recurrence-free survival (RFS) was analyzed by censoring events at 5 years.

Immunohistochemistry staining

Hormone receptor status was determined by our pathologists who are fully dedicated to breast cancer pathology. Patients were separated into three groups based on IHC result of ER staining: (i) ERhigh, when ≥ 10% of tumor cell nuclei were immunoreactive, (ii) ERlow, with 1% − 9% of cells staining, and (iii) ER, if less than 1% of tumor cells showed IHC staining for ER.

Statistical analysis

All statistical analyses were performed using SPSS (version 23.0, IBM Inc., Armonk, NY, USA). Continuous variables were compared using Student’s t-test; categorical variables were compared using Chi-squared test or Fisher’s exact test. Survival analysis was conducted using Kaplan-Meier method and log-rank test. Hazard ratio for recurrence was obtained through Cox regression analysis. Subgroup analysis was performed for DCIS and IDC patients separately. All P-values were two-sided, and P < 0.05 was considered statistically significant.

Results

Among the 2162 patients included in the study, 1654 (76.5%) were ERhigh, 54 (2.5%) were ERlow, and 454 (21.0%) were ER. Clinicopathological characteristics of the study participants are summarized in Table 1. When compared to ERhigh cases, ERlow patients were associated with higher grade, negative PR, positive HER2, and higher Ki-67 expression. When compared to ER cases, ERlow patients were associated with younger age, lower grade, positive PR, positive HER2, and lower Ki-67 expression. ERlow breast cancer was smaller in size than both ERhigh and ER groups (P < 0.001 and P = 0.010, respectively).

Table 1

Clinicopathological characteristics according to ER expression in early breast cancer patients.

 

ER

 

P-value

 

ER

(N = 454)

ERlow

(N = 54)

ERhigh

(N = 1654)

Total

(N = 2162)

 

All

ERlow vs ER

ERlow vs ERhigh

Age, years

   

< 0.001

0.001

0.570

Mean (SD)

54.0 (11.1)

48.9 (10.5)

51.2 (11.0)

51.7 (11.1)

       

Median (range)

54 (25–85)

49 (29–72)

49 (25–88)

50 (25–88)

       

Sex (N (%))

   

0.326

-

1.000

Female

454 (100.0)

54 (100.0)

1644 (99.4)

2152 (99.5)

       

Male

0 (0.0)

0 (0.0)

10 (0.6)

10 (0.5)

       

Operation (N (%))

   

< 0.001

0.366

0.003

Breast conserving surgery

281 (61.9)

30 (55.6)

1217 (73.6)

1528 (70.7)

       

Total mastectomy

173 (38.1)

24 (44.4)

437 (26.4)

634 (29.3)

       

Axillary dissection (N (%))

   

< 0.001

0.130

0.482

Not done

40 (8.8)

9 (16.7)

299 (18.1)

348 (16.1)

       

Sentinel lymph node biopsy

399 (87.9)

43 (79.6)

1324 (80.0)

1766 (81.7)

       

Axillary lymph node dissection

15 (3.3)

2 (3.7)

31 (1.9)

48 (2.2)

       

Size, cm

         

< 0.001

0.010

< 0.001

Mean (SD)

1.0 (0.7)

0.8 (0.6)

1.2 (0.6)

1.1 (0.6)

       

Median (range)

1.1 (0.1–2.0)

0.6 (0.1–2.0)

1.2 (0.0–2.0)

1.1 (0.0–2.0)

       

Type (N (%))

   

0.001

0.404

0.870

Ductal carcinoma in situ

86 (18.9)

13 (24.1)

457 (27.6)

556 (25.7)

       

Invasive ductal carcinoma

357 (78.6)

39 (72.2)

1131 (68.4)

1527 (70.6)

       

Others

11 (2.4)

2 (3.7)

66 (4.0)

79 (3.7)

       

T stage (N (%))

   

< 0.001

0.270

< 0.001

Tis

86 (18.9)

13 (24.1)

457 (27.6)

556 (25.7)

       

T1mic

81 (17.8)

13 (24.1)

81 (4.9)

175 (8.1)

       

T1a

41 (9.0)

6 (11.1)

117 (7.1)

164 (7.6)

       

T1b

56 (12.3)

8 (14.8)

325 (19.6)

389 (18.0)

       

T1c

190 (41.9)

14 (25.9)

647 (40.7)

878 (40.6)

       

N stage (N (%))

   

< 0.001

0.249

0.904

Nx

41 (9.0)

8 (14.8)

297 (18.0)

346 (16.0)

       

N0

408 (89.9)

45 (83.3)

1311 (79.3)

1764 (81.6)

       

N1mic

5 (1.1)

1 (1.9)

46 (2.8)

52 (2.4)

       

Stage (N (%))

   

< 0.001

0.579

0.877

0

86 (18.9)

13 (24.1)

457 (27.6)

556 (25.7)

       

IA

363 (80.0)

40 (74.1)

1152 (69.6)

1555 (71.9)

       

IB

5 (1.1)

1 (1.9)

45 (2.7)

51 (2.4)

       

Grade (N (%))

   

< 0.001

< 0.001

0.017

G1

3 (0.7)

5 (9.3)

418 (25.3)

426 (19.7)

       

G2

88 (19.4)

17 (31.5)

513 (31.0)

618 (28.6)

       

G3

221 (48.7)

12 (22.2)

200 (12.1)

433 (20.0)

       

Unknown

142 (31.3)

20 (37.0)

523 (31.6)

685 (31.7)

       

Lymphovascular invasion (N (%))

   

0.055

0.057

0.056

Present

41 (9.0)

1 (1.9)

184 (11.1)

226 (10.5)

       

Absent

284 (62.6)

31 (57.4)

959 (58.0)

1274 (58.9)

       

Unknown

129 (28.4)

22 (40.7)

511 (30.9)

662 (30.6)

       

Progesterone receptor (N (%))

   

< 0.001

< 0.001

< 0.001

Positive

16 (3.5)

22 (40.7)

1491 (90.1)

1529 (70.7)

       

Negative

438 (96.5)

32 (59.3)

163 (9.9)

633 (29.3)

       

HER2 (N (%))

   

< 0.001

0.269

< 0.001

Negative

102 (22.5)

9 (16.7)

584 (35.3)

695 (32.1)

       

Equivocal

0 (0.0)

0 (0.0)

4 (0.2)

4 (0.2)

       

Positive

66 (14.5)

12 (22.2)

71 (4.3)

149 (6.9)

       

Not done

286 (63.0)

33 (61.1)

995 (60.2)

1314 (60.8)

       

Ki-67, %

               

Mean (SD)

26.7 (19.0)

18.1 (13.9)

9.1 (9.0)

13.0 (13.9)

 

< 0.001

< 0.001

< 0.001

Median (range)

20 (0–90)

15 (5–60)

5 (0–70)

7 (0–90)

       

Radiotherapy (N (%))

         

< 0.001

0.508

0.009

Done

263 (57.9)

27 (50.0)

1138 (68.8)

1428 (66.0)

       

Not done

186 (38.8)

25 (46.3)

488 (29.5)

689 (31.9)

       

Unknown

15 (3.3)

2 (3.7)

28 (1.7)

45 (2.1)

       

Hormonal therapy (N (%))

         

< 0.001

< 0.001

< 0.001

Done

20 (4.4)

37 (68.5)

1441 (87.1)

1498 (69.3)

       

Not done

434 (95.6)

17 (31.5)

213 (12.9)

664 (30.7)

       

Chemotherapy (N (%))

         

< 0.001

0.045

0.005

Done

242 (53.3)

21 (38.9)

373 (22.6)

636 (29.4)

       

Not done

212 (46.7)

33 (61.1)

1281 (77.4)

1526 (70.6)

       

Recurrence (N (%))

         

0.001

0.587

0.357

Yes

44 (9.7)

4 (7.4)

84 (5.1)

132 (6.1)

       

Local

16 (3.5)

2 (3.7)

34 (2.1)

52 (2.4)

       

Regional

7 (1.5)

0 (0.0)

5 (0.3)

12 (0.6)

       

Systemic

13 (2.9)

1 (1.9)

21 (1.3)

35 (1.6)

       
ER, estrogen receptor; ER, estrogen receptor negative; ERlow, estrogen receptor low positive; ERhigh, estrogen receptor high positive; HER2, human epidermal growth factor receptor 2

Postoperative treatment data was available for all cases. 87.1% (1441/1654) of ERhigh patients, 68.5% (37/54) of ERlow patients, and 4.4% (20/454) of ER patients received hormonal therapy (P < 0.001 between all groups). Hormonal therapy included selective estrogen receptor modulators and aromatase inhibitors. 22.6% (373/1654) of ERhigh patients, 38.9% (21/54) of ERlow patients, and 53.3% (242/454) of ER patients received adjuvant chemotherapy (P < 0.001 between all groups).

Follow-up information was available for 2161 patients (mean follow-up of 6.59 years, range 0.01–15.79 years). Five-year RFS was 5.1% (84/1654), 7.4% (4/54), and 9.7% (44/454) in ERhigh, ERlow, and ER groups, respectively (P < 0.001). Recurrence data included local recurrence, regional recurrence, and systemic recurrence. When two groups were compared to each other independently, RFS was significantly worse in ER cases compared to ERhigh cases (P < 0.001), but there was no statistically significant difference between ERlow and ERhigh cases (P = 0.597) or ERlow and ER cases (P = 0.400) (Fig. 1). Similar results were found in subgroup analysis of IDC patients; only ER patients showed worse RFS compared to ERhigh patients (P < 0.001), and no significant difference in recurrence was observed between ERlow and ERhigh patients (P = 0.613) or ERlow and ER patients (P = 0.385) (Fig. 2).

To evaluate endocrine responsiveness of ERhigh and ERlow patients, 5-year RFS was compared between patients with our without hormonal therapy (Fig. 3). ER patients were excluded from this analysis as hormonal therapy was routinely not included in their treatment plan. ERhigh patients showed significantly worse prognosis when hormonal therapy was omitted (P = 0.020). This difference was not observed in ERlow cases; there was no difference in recurrence between patients who received hormonal therapy and those who did not receive the treatment (P = 0.418).

Risk factors for recurrence in the study population were analyzed by Cox proportional regression (Table 2). In univariate analysis, younger age, higher grade, ER status, higher Ki-67 expression, and omission of hormonal therapy were associated with increased risk of recurrence. In multivariate analysis, all factors except ER status and Ki-67 expression remained statistically significant. Subgroup analysis was performed for DCIS and IDC patients. In the DCIS group, only age was associated with recurrence (P = 0.007). In the IDC group, univariate analysis revealed that younger age, higher grade, ER status, lower PR expression, higher Ki-67 expression, and omission of hormonal therapy were associated with higher recurrence rate. In multivariate analysis, only age and hormonal therapy remained statistically significant.

Table 2

Cox regression model for risk factors of recurrence in early breast cancer.

 

HR (95% CI)

P-value

HR (95% CI)

P-value

HR (95% CI)

P-value

HR (95% CI)

P-value

HR (95% CI)

P-value

HR (95% CI)

P-value

Age, years

                       

< 50

Ref.

 

Ref.

 

Ref.

 

Ref.

 

Ref.

 

Ref.

 

≥ 50

0.51 (0.35–0.73)

< 0.001

0.46 (0.32–0.66)

< 0.001

0.29 (0.12– 0.72)

0.007

0.29 (0.12– 0.72)

0.007

0.57 (0.38–0.86)

0.007

0.53 (0.36–0.80)

0.002

Type

                       

DCIS

Ref.

                     

IDC

1.20 (0.80–1.80)

0.390

                   

Grade

                       

1

Ref.

 

Ref.

         

Ref.

 

Ref.

 

2

2.06 (1.10–3.87)

0.025

1.90 (1.00–3.61)

0.050

       

2.06 (1.10–3.87)

0.025

1.89 (0.99–3.61)

0.054

3

3.07 (1.65–5.73)

< 0.001

2.18 (1.05–4.52)

0.036

       

3.08 (1.65–5.73)

< 0.001

2.12 (0.99–4.54)

0.052

LVI

                       

No

Ref.

             

Ref.

     

Yes

1.46 (0.90–2.37)

0.131

           

1.46 (0.90–2.37)

0.130

   

ER

                       

ERhigh

Ref.

 

Ref.

 

Ref.

     

Ref.

 

Ref.

 

ERlow

1.34 (0.49–3.65)

0.571

0.95 (0.50–1.82)

0.882

1.31 (0.18–9.63)

0.793

   

1.36 (0.43–4.33)

0.606

1.09 (0.29–4.14)

0.897

ER

1.96 (1.35–2.85)

< 0.001

0.94 (0.34–2.64)

0.907

0.74 (0.23–2.46)

0.626

   

2.29 (1.52–3.44)

< 0.001

1.27 (0.36–4.44)

0.707

PR

                       

Positive

Ref.

     

Ref.

     

Ref.

 

Ref.

 

Negative

1.20 (1.00–1.43)

0.054

   

0.81 (0.48–1.37)

0.426

   

1.62 (1.09–2.42)

0.018

0.52 (0.21–1.33)

0.175

HER2

                       

Positive

Ref.

             

Ref.

     

Negative

0.76 (0.27–2.19)

0.613

           

0.77 (0.38–1.57)

0.477

   

Ki-67

                       

< 14

Ref.

 

Ref.

 

Ref.

     

Ref.

 

Ref.

 

≥ 14

1.66 (1.18–2.34)

0.004

1.00 (0.64–1.57)

0.989

1.13 (0.46–2.76)

0.794

   

1.79 (1.21–2.64)

0.003

0.99 (0.60–1.65)

0.971

HT

                       

No

Ref.

 

Ref.

 

Ref.

     

Ref.

 

Ref.

 

Yes

0.50 (0.35–0.70)

< 0.001

0.45 (0.25–0.79)

0.006

0.75 (0.37–1.54)

0.754

   

0.40 (0.27–0.59)

< 0.001

0.30 (0.12–0.77)

0.012

CT

                       

No

Ref.

             

Ref.

     

Yes

1.06 (0.73–1.52)

0.777

           

1.00 (0.67–1.50)

0.985

   
DCIS, ductal carcinoma in situ; IDC, invasive ductal carcinoma; HR, hazard ratio; CI, confidence interval; LVI, lymphovascular invasion; ER, estrogen receptor; ER+, estrogen receptor positive; ERlow, estrogen receptor low positive; ER, estrogen receptor negative; PR, progesterone receptor; HER2, human epidermal growth factor receptor 2; HT, hormonal therapy; CT, chemotherapy

Discussion

ER plays an important role in the signaling pathway for breast cancer carcinogenesis and disease expression.13 Hormonal therapy targeting ER including selective estrogen receptor modulators, aromatase inhibitors, ER down-regulators, and ovarian suppression has led to significant improvement in the clinical outcome of breast cancer treatment.7 ER+ tumors show excellent response to hormonal therapy, and therapeutic effect depends on the proportion of ER expression.14,15 In contrast, ER tumors show no response to hormonal therapy; however, these tumors respond relatively better to chemotherapy compared to ER+ tumors.16 Therefore, it is critical to set an optimal cutoff point for ER positivity to properly select patients eligible for individualized treatment options.17

In 2010, the cutoff value for ER positivity was lowered to 1% from 10% by the ASCO/CAP guideline update.18 Although the currently accepted cutoff is 1%, multiple studies have since reported that ERlow tumors with ER expression less than 10% show characteristics closer to ER tumors, including questionable response to hormonal therapy.1012 The latest recommendation of the ASCO/CAP guideline to report these tumors separately as ER Low Positive reflects this concern. If ERlow breast cancer is indeed a distinct disease subtype closer to ER, ERlow patients currently classified as ER+ will not only receive unnecessary hormonal treatment with potential side effects, but they might also fail to receive chemotherapy that is needed.17

Several studies have addressed the clinicopathological features of ERlow tumors. Compared to ERhigh, ERlow breast cancer is associated with younger age, advanced stage, larger tumor size, higher HER2 expression, and lower PR expression.19,20 When morphologically analyzed, ERlow tumors exhibit features previously described for basal-like and triple-negative tumors, including higher grade, higher proliferation index, sheet-like growth pattern, intratumoral lymphocytic inflammatory infiltrate, and necrosis.12 In our current study, we focused specifically on early stage breast cancer, a novel approach not presented in previous literature. ERlow tumors showed higher grade, positive HER2, negative PR, and higher proliferation index compared to ERhigh tumors, which was consistent with previous studies. Age at diagnosis showed no statistically significant difference between ERlow and ERhigh groups, and tumor size was smallest in the ERlow group compared to both ERhigh and ER patients. Detailed morphological analysis was not performed in this study. Patients with ERhigh tumors were more likely to receive hormonal therapy compared to ERlow and ER groups; in contrast, a significantly small proportion of ERhigh patients received chemotherapy in comparison to their ERlow or ER counterparts. This result was in concordance with previous literature.17,19,20

Although limited data is available on the survival outcome of ERlow breast cancer, a few previous studies showed that ERlow patients exhibit significantly worse disease-free and overall survival rates compared to ERhigh patients, but similar to those who are ER.11,21,22 In the current study, the ERlow group had a slight, but not statistically significant, survival benefit over the ER group. At the same time, ERlow tumors showed worse prognosis compared to ERhigh tumors, yet also with no statistical significance. Recurrence rate showed a proportional decrease with ER expression level. In multivariate regression analysis, we failed to prove the effect of ER expression level on recurrence. This study was confined to DCIS and stage 1 IDC, and the overall recurrence rate was low. It is possible that the low proportion of recurrent cases hindered to show a clear difference between ER subgroups. Future prospective studies with larger cohorts might validate the difference in survival outcome between ERlow and ERhigh groups.

Most breast cancers exhibit either strong ER expression or its complete absence, and the number of patients in the ERlow subgroup is limited.23 Therefore, prospective data on the endocrine responsiveness of ERlow tumors is scarce.19 Yet many retrospective studies have suggested that primary breast cancer patients with low ER expression might not benefit significantly from hormonal therapy.17 Viale et al.21 compared disease-free and overall survival of ERlow and ER groups and reported that hormonal therapy had no effect on survival outcomes. In HER2-negative stage II/III breast cancer, ERlow tumors showed limited benefit from hormonal therapy and better response to neoadjuvant chemotherapy.24 In our current study, we found that hormonal therapy had no effect on recurrence in ERlow patients; on the contrary, ERhigh patients showed clear endocrine responsiveness. This suggests that hormonal therapy might have limited apparent benefit in early stage ERlow breast cancer.

ER+ tumors have been subjected to multigene assays to identify more aggressive types that are expected to benefit from additional chemotherapy.12 Our study sheds light on the possibility that early stage ERlow breast cancer might be a high risk subtype and potential candidate for chemotherapy. It is suggested that treatment options for ER tumors may be appropriate for some ERlow tumors; however, endocrine responsiveness of primary breast cancer patients with low ER expression needs to be further explored in prospective studies.20

This study has certain limitations. First, the study was limited by its retrospective design, and treatment options were not assigned in a randomized manner. Second, although the current study was performed on a large cohort, the sample size of the ERlow group was relatively small. It is known that majority of breast cancers show either completely absent or strongly positive ER staining, and tumors with low ER expression are rare. Future studies with larger study populations could possibly overcome this limitation and provide more information on ERlow tumors.

In conclusion, ERlow breast cancer shows distinct clinicopathological features compared to ERhigh and ER types. ERlow tumors seem to have higher recurrence rates compared to ERhigh tumors, although future large scale prospective studies are necessary. Similar to patients with ER tumors, those with ERlow tumors do not appear to benefit from hormonal therapy. Treatment options for ERlow breast cancer should be reconsidered, including omission of hormonal therapy and addition of adjuvant chemotherapy.

Declarations

Funding: Not applicable.

Conflict of interest: The authors declare that they have no conflict of interest.

Availability of data and material: The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.

Code availability: Not applicable

Ethical Approval: All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. The study was approved by the institution’s review board (IRB No. B-2105-682-103).

Consent to participate: Informed consent was obtained from all individual participants included in the study.

Consent for publish: Patients signed informed consent regarding publishing their data.

Authors’ contributions: Study concept and design: Eunyoung Kang, Eun-Kyu Kim, and Hee-Chul Shin. Acquisition of data: Sun Mi Kim, Mijung Jang, Bo La Yun, and So Yeon Park. Analysis and interpretation of data: Kyung-Hwak Yoon and Yeshong Park. Drafting of the manuscript: Kyung-Hwak Yoon and Yeshong Park. Critical revision of the manuscript for important intellectual content: Jee Hyun Kim, Se Hyun Kim, and Koung Jin Suh. Study supervision: Hee-Chul Shin. All authors have contributed to, read and approved the final manuscript for submission.

References

  1. Polyak K (2011) Heterogeneity in breast cancer. J Clin Invest 121(10):3786–3788
  2. Sestak I (2019) Risk stratification in early breast cancer in premenopausal and postmenopausal women: integrating genomic assays with clinicopathological features. Curr Opin Oncol 31(1):29–34
  3. Yip C-H, Rhodes A (2014) Estrogen and progesterone receptors in breast cancer. Future Oncol 10(14):2293–2301
  4. Balleine RL, Wilcken NR (2012) High-risk estrogen-receptor-positive breast cancer. Mol Diagn Ther 16(4):235–240
  5. Anderson WF, Chatterjee N, Ershler WB et al (2002) Estrogen receptor breast cancer phenotypes in the Surveillance, Epidemiology, and End Results database. Breast Cancer Res Treat 76(1):27–36
  6. Althuis MD, Fergenbaum JH, Garcia-Closas M et al (2004) Etiology of hormone receptor-defined breast cancer: a systematic review of the literature. Cancer Epidemiol Biomarkers Prev 13(10):1558–1568
  7. Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) (2005) Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet 365:1687–1717
  8. Davies E, Hiscox S (2011) New therapeutic approaches in breast cancer. Maturitas 68(2):121–128
  9. Allison KH, Hammond MEH, Dowsett M et al (2020) Estrogen and progesterone receptor testing in breast cancer: ASCO/CAP guideline update. J Clin Oncol 38:1346–1366
  10. Honma N, Horii R, Iwase T et al (2014) Proportion of estrogen or progesterone receptor expressing cells in breast cancers and response to endocrine therapy. Breast 23(6):754–762
  11. Balduzzi A, Bagnardi V, Rotmensz N et al (2014) Survival outcomes in breast cancer patients with low estrogen/progesterone receptor expression. Clin Breast Cancer 14(4):258–264
  12. Gloyeske NK, Dabbs DJ, Rohit B (2014) Low ER + Breast Cancer: Is This a Distinct Group? Am J Clin Pathol 141(5):697–701
  13. Heldring N, Pike A, Andersson S et al (2007) Estrogen receptors: how do they signal and what are their targets. Physiol Rev 87:905–931
  14. Van den Eynden GG, Colpaert CG, Vermeulen PB et al (2002) Comparative analysis of the biochemical and immunohistochemical determination of hormone receptors in invasive breast carcinoma influence of the tumor-stroma ratio. Pathol Res Pract 198:517–524
  15. Sparano JA, Paik S (2008) Development of the 21-gene assay and its application in clinical practice and clinical trials. J Clin Oncol 26(5):721–728
  16. Andre F, Broglio K, Roche H et al (2008) Estrogen receptor expression and efficacy of docetaxel-containing adjuvant chemotherapy in patients with node-positive breast cancer: results from a pooled analysis. J Clin Oncol 26:2636–2643
  17. Chen T, Zhang N, Moran MS et al (2018) Borderline ER positive primary breast cancer gains no significant survival benefit from endocrine therapy: a systematic review and meta-analysis. Clin Breast Cancer 18:1–8
  18. Hammond ME, Hayes DF, Dowsett M et al (2010) 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 28:2784–2795
  19. Yi M, Huo L, Koenig KB et al (2014) Which threshold for ER positivity? a retrospective study based on 9639 patients. Ann Oncol 25:1004–1011
  20. Poon IK, Tsang JY, Li J et al (2020) The significance of highlighting the oestrogen receptor low category in breast cancer. BJC 123:1223–1227
  21. Viale G, Regan MM, Maiorano E et al (2007) Prognostic and predictive value of centrally reviewed expression of estrogen and progesterone receptors in a randomized trial comparing letrozole and tamoxifen adjuvant therapy for postmenopausal early breast cancer: BIG 1–98. J Clin Oncol 25(25):3846–3852
  22. Ogawa Y, Moriya T, Kato Y et al (2004) Immunohistochemical assessment for estrogen receptor and progesterone receptor status in breast cancer: analysis for a cut-off point as the predictor for endocrine therapy. Breast Cancer 11(3):267–275
  23. Collins LC, Botero ML, Schnitt SJ (2005) Bimodal frequency distribution of estrogen receptor immunohistochemical staining results in breast cancer: an analysis of 825 cases. Am J Clin Pathol 123:16–20
  24. Fujii T, Kogawa T, Dong W et al (2017) Revisiting the definition of estrogen receptor positivity in HER2-negative primary breast cancer. Ann Oncol 28(10):2420–2428