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

Article information

Cancer Res Treat. 2022;54(4):1081-1090
Publication date (electronic) : 2021 November 17
doi : https://doi.org/10.4143/crt.2021.890
1Department of Surgery, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Korea
2Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Korea
3Department of Radiology, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Korea
4Department of Pathology, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Korea
Correspondence: Hee-Chul Shin, Department of Surgery, Seoul National University Bundang Hospital, 82 Gumi-ro 173beon-gil, Bundang-gu, Seongnam 13620, Korea, Tel: 82-31-787-7097, Fax: 82-31-787-4055, E-mail: dradam77@naver.com
*

Kyung-Hwak Yoon and Yeshong Park contributed equally to this work.

Received 2021 August 7; Accepted 2021 November 15.

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).

Materials and 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 2,162 breast cancer patients were included in the analysis, Tis and T1 stage. Among them, 1,654 (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, 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.

Materials and Methods

1. Study population

Retrospective analysis was performed on a prospective cohort of 2,411 patients who underwent curative surgery for early stage breast cancer between January 2005 and December 2015 at Seoul National University Bundang Hospital. The inclusion criteria for the current study were as follows: (1) histologically confirmed stage 0 of ductal carcinoma in situ (DCIS) or stage I of invasive ductal carcinoma (IDC), (2) available surgical records and pathology reports, and (3) 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 2,162 patients were included for analysis.

2. 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, 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.

3. 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: (1) ERhigh, when ≥ 10% of tumor cell nuclei were immunoreactive, (2) ERlow, with 1%–9% of cells staining, and (3) ER, if less than 1% of tumor cells showed IHC staining for ER.

4. Statistical analysis

All statistical analyses were performed using SPSS ver. 23.0 (IBM Corp., Armonk, NY). Continuous variables were compared using Student’s t test; categorical variables were compared using chi-square test or Fisher 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 2,162 patients included in the study, 1,654 (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).

Clinicopathological characteristics according to ER expression in early breast cancer patients

Postoperative treatment data was available for all cases. Eighty seven point one percentage (1,441/1,654) 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 ER modulators and aromatase inhibitors. 22.6% (373/1,654) 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 2,161 patients (mean follow-up of 6.59 years; range, 0.01 to 15.79 years). Five-year recurrence rate was 5.1% (84/1,654), 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).

Fig. 1

Survival analysis between different estrogen receptor (ER) subgroups in early breast cancer patients. Difference in 5-year recurrence-free survival between ERhigh/ERlow/ER (A), ERhigh/ER (B), ERhigh/ERlow (C), and ERlow/ER (D) patients. ER, estrogen receptor negative; ERhigh, estrogen receptor high positive; ERlow, estrogen receptor low positive.

Fig. 2

Survival analysis between different estrogen receptor (ER) subgroups in early stage invasive ductal carcinoma patients. Difference in 5-year recurrence-free survival between ERhigh/ERlow/ER (A), ERhigh/ER (B), ERhigh/ERlow (C), and ERlow/ER (D) patients. ER, estrogen receptor negative; ERhigh, estrogen receptor high positive; ERlow, estrogen receptor low positive.

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 betweenpatients who received hormonal therapy and those who did not receive the treatment (p=0.418).

Fig. 3

Effect of estrogen receptor (ER) expression level on hormonal therapy (HT) response. (A) Difference in 5-year recurrence-free survival in ERhigh patients. (B) Difference in 5-year recurrence-free survival in ERlow patients. ERhigh, estrogen receptor high positive; ERlow, estrogen receptor low positive.

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.

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

Discussion

ER plays an important role in the signaling pathway for breast cancer carcinogenesis and disease expression [13]. Hormonal therapy targeting ER including selective ER 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 I 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.

Notes

Ethical Statement

This study was approved by the institutional review board of (blinded for review) (IRB No. B-2105-682-103). All procedures performed were in accordance with the ethical standards of the institutional review board and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Informed consent was obtained from all individual participants included in the study.

Author Contributions

Conceived and designed the analysis: Kang E, Kim EK, Shin HC.

Collected the data: Kim SM, Jang M, Yun BL, Park SY.

Contributed data or analysis tools: Yoon KH, Park Y.

Performed the analysis: Yoon KH, Park Y.

Wrote the paper: Yoon KH, Park Y.

Critical revision of the manuscript for important intellectual content: Kim JH, Kim SH, Suh KJ.

Study supervision: Shin HC.

Conflicts of Interest

Conflict of interest relevant to this article was not reported.

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Article information Continued

Fig. 1

Survival analysis between different estrogen receptor (ER) subgroups in early breast cancer patients. Difference in 5-year recurrence-free survival between ERhigh/ERlow/ER (A), ERhigh/ER (B), ERhigh/ERlow (C), and ERlow/ER (D) patients. ER, estrogen receptor negative; ERhigh, estrogen receptor high positive; ERlow, estrogen receptor low positive.

Fig. 2

Survival analysis between different estrogen receptor (ER) subgroups in early stage invasive ductal carcinoma patients. Difference in 5-year recurrence-free survival between ERhigh/ERlow/ER (A), ERhigh/ER (B), ERhigh/ERlow (C), and ERlow/ER (D) patients. ER, estrogen receptor negative; ERhigh, estrogen receptor high positive; ERlow, estrogen receptor low positive.

Fig. 3

Effect of estrogen receptor (ER) expression level on hormonal therapy (HT) response. (A) Difference in 5-year recurrence-free survival in ERhigh patients. (B) Difference in 5-year recurrence-free survival in ERlow patients. ERhigh, estrogen receptor high positive; ERlow, estrogen receptor low positive.

Table 1

Clinicopathological characteristics according to ER expression in early breast cancer patients

ER p-value


ER (n=454) ERlow (n=54) ERhigh (n=1,654) Total (n=2,162) Total ERlow vs. ER ERlow vs. ERhigh
Age (yr)

 Mean±SD 54.0±11.1 48.9±10.5 51.2±11.0 51.7±11.1 < 0.001 0.001 0.570

 Median (range) 54 (25–85) 49 (29–72) 49 (25–88) 50 (25–88)

Sex

 Female 454 (100) 54 (100) 1,644 (99.4) 2,152 (99.5) 0.326 - > 0.99

 Male 0 0 10 (0.6) 10 (0.5)

Operation

 Breast conserving surgery 281 (61.9) 30 (55.6) 1,217 (73.6) 1,528 (70.7) < 0.001 0.366 0.003

 Total mastectomy 173 (38.1) 24 (44.4) 437 (26.4) 634 (29.3)

Axillary dissection

 Not done 40 (8.8) 9 (16.7) 299 (18.1) 348 (16.1) < 0.001 0.130 0.482

 Sentinel lymph node biopsy 399 (87.9) 43 (79.6) 1,324 (80.0) 1,766 (81.7)

 Axillary lymph node dissection 15 (3.3) 2 (3.7) 31 (1.9) 48 (2.2)

Size (cm)

 Mean±SD 1.0±0.7 0.8±0.6 1.2±0.6 1.1±0.6 < 0.001 0.010 < 0.001

 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

 Ductal carcinoma in situ 86 (18.9) 13 (24.1) 457 (27.6) 556 (25.7) 0.001 0.404 0.870

 Invasive ductal carcinoma 357 (78.6) 39 (72.2) 1,131 (68.4) 1,527 (70.6)

 Others 11 (2.4) 2 (3.7) 66 (4.0) 79 (3.7)

T category

 Tis 86 (18.9) 13 (24.1) 457 (27.6) 556 (25.7) < 0.001 0.270 < 0.001

 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 category

 Nx 41 (9.0) 8 (14.8) 297 (18.0) 346 (16.0) < 0.001 0.249 0.904

 N0 408 (89.9) 45 (83.3) 1,311 (79.3) 1,764 (81.6)

 N1mic 5 (1.1) 1 (1.9) 46 (2.8) 52 (2.4)

Stage

 0 86 (18.9) 13 (24.1) 457 (27.6) 556 (25.7) < 0.001 0.579 0.877

 IA 363 (80.0) 40 (74.1) 1,152 (69.6) 1,555 (71.9)

 IB 5 (1.1) 1 (1.9) 45 (2.7) 51 (2.4)

Grade

 G1 3 (0.7) 5 (9.3) 418 (25.3) 426 (19.7) < 0.001 < 0.001 0.017

 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

 Present 41 (9.0) 1 (1.9) 184 (11.1) 226 (10.5) 0.055 0.057 0.056

 Absent 284 (62.6) 31 (57.4) 959 (58.0) 1,274 (58.9)

 Unknown 129 (28.4) 22 (40.7) 511 (30.9) 662 (30.6)

Progesterone receptor

 Positive 16 (3.5) 22 (40.7) 1,491 (90.1) 1,529 (70.7) < 0.001 < 0.001 < 0.001

 Negative 438 (96.5) 32 (59.3) 163 (9.9) 633 (29.3)

HER2

 Negative 102 (22.5) 9 (16.7) 584 (35.3) 695 (32.1) < 0.001 0.269 < 0.001

 Equivocal 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) 1,314 (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

 Done 263 (57.9) 27 (50.0) 1,138 (68.8) 1,428 (66.0) < 0.001 0.508 0.009

 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

 Done 20 (4.4) 37 (68.5) 1,441 (87.1) 1,498 (69.3) < 0.001 < 0.001 < 0.001

 Not done 434 (95.6) 17 (31.5) 213 (12.9) 664 (30.7)

Chemotherapy

 Done 242 (53.3) 21 (38.9) 373 (22.6) 636 (29.4) < 0.001 0.045 0.005

 Not done 212 (46.7) 33 (61.1) 1,281 (77.4) 1,526 (70.6)

Recurrence

 Yes 44 (9.7) 4 (7.4) 84 (5.1) 132 (6.1) 0.001 0.587 0.357

 Local 16 (3.5) 2 (3.7) 34 (2.1) 52 (2.4)

 Regional 7 (1.5) 0 5 (0.3) 12 (0.6)

 Systemic 13 (2.9) 1 (1.9) 21 (1.3) 35 (1.6)

Values are presented as number (%) unless otherwise indicated. ER, estrogen receptor; ER, estrogen receptor negative; ERhigh, estrogen receptor high positive; ERlow, estrogen receptor low positive; HER2, human epidermal growth factor receptor 2; SD, standard deviation.

Table 2

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

Total DCIS IDC



Univariate Multivariate Univariate Multivariate Univariate Multivariate






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 (yr)

 < 50 Reference Reference Reference Reference Reference Reference

 ≥ 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 Reference

 IDC 1.20 (0.80–1.80) 0.390 - - - - - - - - - -

Grade

 1 Reference Reference Reference Reference

 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 Reference Reference

 Yes 1.46 (0.90–2.37) 0.131 - - - - - - 1.46 (0.90–2.37) 0.130 - -

ER

 ERhigh Reference Reference Reference Reference Reference

 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 Reference Reference Reference Reference

 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 Reference Reference

 Negative 0.76 (0.27–2.19) 0.613 - - - - - - 0.77 (0.38–1.57) 0.477 - -

Ki-67

 < 14 Reference Reference Reference Reference Reference

 ≥ 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 Reference Reference Reference Reference Reference

 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 Reference Reference

 Yes 1.06 (0.73–1.52) 0.777 - - - - - - 1.00 (0.67–1.50) 0.985 - -

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