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Journal of Breast Disease > Volume 10(1); 2022 > Article
Lim, Lee, Kim, Cho, Yang, Park, Kim, Sin, Seo, and Gwak: Progesterone Receptor Expression as a Prognostic Factor in Luminal B Breast Cancer

Abstract

Purpose

The luminal subtype of breast cancer has heterogeneous biological characteristics with respect to the expression of estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor-2 (HER2), and Ki-67. We analyzed luminal B breast cancer subcategorized by PR expression and identified clinically relevant prognostic factors.

Methods

We collected the clinical and pathologic data of 247 breast cancer patients (stage 1-4) who were diagnosed with luminal B subtype, defined as ER- and/or PR-positive and/or HER2-positive and with a high Ki-67 proliferation index (>14%). We classified them into PR intact and PR low groups according to PR expression pattern. We also analyzed the clinical and pathological data of each group, including age at diagnosis, tumor size, node metastasis, breast and axillary operative method, margin involvement, tumor-node-metastasis (TNM) stage, histological grade, nuclear grade, number of tumors, and expression of ER, PR, Ki-67, and Bcl-2; evaluated recurrence or metastatic characteristics; and analyzed disease-free survival (DFS) and overall survival (OS) in both groups.

Results

Among the 247 luminal B breast cancer patients (stage 1-4), 141 were classified into the PR intact group (57.1%) and 106 into the PR low group (42.9%). The PR low group was associated with age >50 years (p=0.001), low Bcl-2 expression (p<0.001), and high proportion of mastectomies (p<0.001). DFS and OS were significantly lower in the PR low group (p=0.025 and 0.024, respectively).

Conclusion

This study showed that decreased in PR expression (PR low group) in luminal B breast cancer was related to poor prognosis compared to normal PR expression (PR intact group).

INTRODUCTION

Over five decades of research on hormonal responsiveness of breast cancer has led to the identification of estrogen receptor (ER) and progesterone receptor (PR) as key prognostic and predictive factors in breast cancer [1]. During the last 20 years, extensive studies on gene expression profiling of breast cancer have led to its classification into five intrinsic molecular subtypes: luminal A, luminal B, human epidermal growth factor receptor-2 (HER2)-enriched, basal-like, and normal-like. This has had a crucial impact on our understanding of breast cancer biology [2].
Expert panelists at the 13th St. Gallen International Consensus Conference (2013) on the treatment of primary early breast cancer accepted that clinical and pathological factors such as ER, PR, HER2, and Ki-67 allow surrogate subtype classification and have clinical implications for systemic therapy selection [3].
Luminal B breast cancer is a subtype of breast cancer characterized by high histologic grade, low ER-related gene expression, or high HER2-related gene expression, and frequent resistance to anti-hormonal therapies such as tamoxifen [4]. Therefore, luminal B breast cancer is the most heterogeneous subtype, that is, HER2-positive/negative disease and PR positive/negative disease. The treatment for luminal B breast cancer is determined by the expression of various prognostic and predictive factors for which both anti-hormonal therapy and chemotherapy are considered. In the case of HER2-positive disease, anti-HER2 therapy is also considered in addition to chemotherapy [5].
Chemotherapy and endocrine therapy are the two choices for systemic adjuvant treatment for luminal B breast cancer. As earlier studies have indicated that luminal B subtype is relatively insensitive to endocrine therapy compared to luminal A subtype and to chemotherapy compared to HER2-enriched and basal-like subtypes, luminal B breast cancer patients should be selected with consideration of its pros and cons [6-9]. This study was conducted to investigate the prognostic value of PR expression in luminal B breast cancer patients.

METHODS

We collected the clinical and pathologic data of breast cancer patients who were treated between February 2000 and December 2015 at a single medical institute. We identified 269 women with the highrisk luminal B subtype defined as ER- and/or PR-positive and/or HER2-positive with a high Ki-67 proliferation index (>14%). We excluded 22 patients with stage 0 breast cancer. We further classified the remaining patients into PR intact and PR low groups by expression pattern.
The PR intact group was defined by an Allred score for PR of 7 or 8, while the PR low group was defined by an Allred score for PR of 6 or less than 6 regardless of ER expression. We also analyzed the clinical and pathological data of each group, including age at diagnosis, tumor size, node metastasis, breast and axillary operative methods, tumor type, tumor-node-metastasis (TNM) stage, histological grade (HG), nuclear grade (NG), vascular invasion (VI), lymphatic invasion (LI), neural invasion (NI), number of tumors, and expression of ER, PR, Ki-67, and Bcl-2. We also evaluated recurrence or metastatic characteristics and analyzed the disease-free survival (DFS) and overall survival (OS) rates of each subgroup. This study was approved by the Institutional Review Board of Inje University Sanggye Paik Hospital (No.2021-06-010), which waived the need for informed consent due to its retrospective nature, and was performed according to the ethical standards of the Declaration of Helsinki.

Immunohistochemical (IHC) staining for ER, PR, Bcl-2, and Ki-67

Mouse monoclonal antibodies, ER NCL-L-ER-6F11 and PR NCLL-PGR-312 (Leica Microsystems Inc., Newcastle Upon Tyne, UK) diluted 1:80 in a 20% normal goat serum solution (diluted in Tris-buffered saline) were used as the primary antibodies for the ER and PR assays, respectively. The secondary antibody used was goat anti-mouse peroxidase-conjugated immunoglobulin, while 3,3’-diaminobenzidine tetrahydrochloride was used as the chromogen. ER and PR expression were scored as 0, 1+, 2+, and 3+ according to the staining intensity along with a description of the percentage related to the proportion of stained nuclei in 10 high-power fields. ER and PR positivity were defined as any positive score or a percentage greater than zero. We then converted the intensity scores and proportion percentages to Allred scores.
IHC staining for Bcl-2 and Ki-67 was performed using the avidin-biotin peroxidase complex method with a Vectastain ABC Elite kit (Vector Laboratories, Burlingame, USA) and aminoethylcarbazole as the chromogen. The sections were counterstained with Mayer’s hematoxylin and incubated in monoclonal mouse anti-human Bcl-2 oncoprotein (1:100; Dako, Glostrup, Denmark) to assess Bcl-2 expression, and brown nuclear immunostaining was performed. The sections were also incubated with monoclonal mouse anti-human Ki-67 antigen (1:100; Dako) for Ki-67 measurements, and brown nuclear immunostaining was performed. Bcl-2 overexpression was defined as a Bcl-2 level >33%. We sorted the low proliferative group based on a Ki-67 cut-off value of 20%, which was previously described as the best cut-off for stratifying high-risk luminal breast cancer patients [10].

IHC staining for HER2

IHC of the HER2 protein was performed on 4-μm-thick paraffin-embedded tissue sections on poly-L-lysine-coated slides. After deparaffinization and blocking of endogenous peroxidase, HER2 immunostaining was performed using rabbit anti-human c-erbB-2 oncoprotein (Dako, Carpinteria, USA) as the primary antibody at a 1:100 dilution. Binding of the primary antibody was detected using a Dako Quick-Staining, Labeled Streptavidin-Biotin System (Dako), and 3,3′-diaminobenzidine chromogen was added. Each slide was scored in a blinded fashion by two pathologists according to the manufacturer’s recommended criteria. Immunostaining was read in a semiquantitative manner and graded as follows: 0, 1+, 2+, and 3+. Intensity scores of 0 or 1+ were designated as negative expression, while 3+ was designated as positive expression for HER2/neu. A score of 2+ was considered equivocal, and corresponding samples were subjected to fluorescence in situ hybridization (FISH) or silver in situ hybridization (SISH) [10, 11].

FISH or SISH for HER2

HER2 FISH was performed on 3.5-μm-thick consecutive sections of tissue microarray paraffin blocks using 20-μL aliquots of locus specific identifier (LSI) HER2/centromere enumerator probe (CEP) 17 probes (Vysis Inc., Downer Grove, USA). A minimum 2-fold increase in HER2 signaling over CEP17 signaling detected in the tumor cell using the LSI HER2 probe was considered as the criterion for gene amplification [10]. SISH was performed using the Ventana Benchmark automated instrument (Ventana Medical Systems, Tucson, USA), according to the manufacturer’s protocols for INFORM HER2 DNA (Ventana Medical Systems, Tucson, USA) and CEP17 probes. Testing for HER2 gene and CEP17 was performed on sequential sections. The two sections were then baked at 60°C for 20 minutes. The HER2 DNA probe was denatured at 95°C for 12 minutes, and hybridization was performed at 52°C for 2 hours. The CEP17 probe was denatured at 95°C for 12 minutes, and hybridization was performed at 44°C for 2 hours. After hybridization, appropriate stringency washes were performed three times at 72°C for the HER2 probe and three times at 59°C for the CEP17 probe. Both dinitrophenol (DNP)-labeled probes were visualized using a rabbit anti-DNP primary antibody and an ultraView SISH Detection Kit (Ventana Medical Systems). The slides were counterstained with hematoxylin and examined under light microscopy. The HER2 gene amplification status was evaluated in a blinded manner according to American Society of Clinical Oncology/College of American Pathologists guidelines [11].

Statistical methods

The chi-square test was used to analyze the clinicopathological factors affecting prognosis of the PR intact and PR low groups. OS was defined as the time interval from the date of breast cancer surgery to the date of death of any cause or the last follow-up date. DFS was defined as the time interval from the date of breast cancer surgery to the date of distant metastasis [12]. The differences in DFS and OS rates between the PR intact and PR low groups were analyzed using the Kaplan-Meier method. Univariate analysis of the clinicopathological factors affecting the prognosis of both groups was conducted using the log-rank test. The Cox multivariate hazard regression model was used for the multivariate analysis. MedCalc statistical software ver. 15.5 software (MedCalc Software, Ostend, Belgium) was used for the statistical analysis. Statistical significance was set at p-value < 0.05.

RESULTS

The demographic and clinical characteristics of luminal B subtype breast cancer patients are shown in Table 1. Among the 247 luminal B breast cancer patients, 141 were classified into the PR intact group (57.1%) and 106 into the PR low group (42.9%). The median age of the 247 patients was 51 years (range, 24-87). The distribution of patients over 50 years of age was much higher in the PR low group (p= 0.001). TNM stage distribution did not differ significantly between the two groups. However, there were significant intergroup differences in breast operations. The incidence of mastectomy surgery was 17.7% in the PR intact group and 44.3% in the PR low group (p< 0.001).
The pathological characteristics of each group are presented in Table 2. There were no significant intergroup differences in number of tumors, margin involvement, HG, NG, LI, VI, NI, and HER2 positivity. Univariate analysis revealed that the PR low group was associated with high Ki-67 levels and low Bcl-2 levels. The percentage of patients with Ki-67 expression levels over the 20% cutoff was 46.1% in the PR intact group and 61.3% in the PR low group (p= 0.018). Additionally, a higher percentage of patients in the PR low group had a Bcl-2 expression level less than the 33% cutoff (34.9%) (p< 0.001).
Table 3 compares the recurrence sites by group. Among the 247 luminal B breast cancer patients, 26 had locoregional recurrence, 58 had systemic recurrence, 42 had bone metastasis, and 25 had lung metastasis. Luminal B breast cancer is well known for its recurrence in the lungs and bones. Liver metastasis was significantly different between the two groups (p= 0.016).
The results of survival analysis based on the level of PR expression were as follows: the PR intact group had a better OS tendency than the PR low group (p= 0.024) (Figure 1A). Moreover, the PR intact group had significantly better DFS than the PR low group (p= 0.025) (Figure 1B). Through OS and DFS analysis, it can be seen that the PR low group had worse prognosis.
The multivariate analysis confirmed that PR expression, vascular invasion, age over 50 years at diagnosis, and stage were independent prognostic factors for OS in cases of nonmetastatic luminal B breast cancer (Table 4).

DISCUSSION

Luminal B subtypes are hormone-dependent breast cancers, but their prognosis is relatively worse than that of luminal A subtypes because the majority are HER2-positive or have high Ki-67 expression. The luminal B breast cancer subtype accounts for approximately 40% of all breast cancers and is known to have better prognosis than non-luminal breast cancer due to hormone receptor positivity, but it shows aggressive clinical features similar to non-luminal breast cancer. However, untreated luminal B subtypes cancer patients showed survival rates similar to those with non-luminal subtypes cancer [13].
Li et al. [14] reported that 48.1% of luminal B subtype breast cancer patients experienced recurrence and metastasis. A previous study reported that the luminal B subtype easily disseminated to the bones and lungs. Regarding the time-dependent risk of developing metastasis, the luminal B subtype accounts for a relatively high rate of early metastasis (< 5 years) compared to late metastasis (>5 years) [13-16]. Several previous studies suggested that the luminal B subtype is characterized by lower expressions of ER and PR and high histologic grade compared to the luminal A subtype [17]. Additionally, multi-gene expression assays reported that the luminal B subtype is associated with higher expression of proliferation-related genes, cell cycle-related genes, and ER- and PR-regulated genes [18].
Here we validated the luminal B subtype characteristics and confirmed the predictive and prognostic value of PR expression for the luminal B subtype. The PR low group showed worse prognosis than the other group, consistent with the findings of a previous study [19]. Additionally, the proportion of patients over 50 years of age was significantly higher in the PR low group than in the PR intact group. Although there are no reports on the relationship between PR expression and age, estrogen is an essential factors for PR expression. Blood estrogen levels are very low in postmenopausal women over 50 years of age than in premenopausal women due to ovarian shutdown. As PR expression is affected by estrogen, it is reasonable to suspect that the decrease in PR expression in postmenopausal women is related to the decrease in blood estrogen concentrations. In addition, a decrease in ER expression also affects PR transcription; hence, a decrease in PR expression is often observed in subtypes with reduced ER expression [20].
We also observed that the PR low group showed a higher proportion of Ki-67 (>20%) and Bcl-2 (< 33%) levels, which indicates poor prognosis. Many studies have reported that the prognostic value of Ki-67 and HER2 expressions is statistically significant in luminal B subtype breast cancer patients [21-24]. Bcl-2, which is expressed in the normal breast glandular epithelium, is upregulated by estrogen transcriptional induction. As Bcl-2 expression is a downstream signal of the estrogen signaling pathway, it was predicted that decreased PR expression is associated with decreased Bcl-2 expression [24,25]. One study reported that, for the recurrence pattern of the luminal B subtype, there were significant increase in single bone metastasis in the luminal B breast cancer patients [14]. In our study, bone, lung, liver, and brain metastases were more common in the PR low group than in the PR intact group, but only liver metastasis was statistically significant in the univariate analysis. The proportion of mastectomy was significantly higher in the PR low group than in the PR intact group. Regardless of the number of tumors or the TNM stage, the rate of mastectomy was higher in the PR low group, which seemed to be related to the actual practice of mastectomy in the 50 or older age group.
In the survival analysis of this study, both OS and DFS of the PR low group were lower than those of the PR intact group. In addition, a low PR was analyzed as an independent predictor of OS in a multivariate model. This result suggests that the PR low group may be resistant to both endocrine therapy and chemotherapy. According to the study by Cancello et al. [19], PR is an important predictive and prognostic factor for the luminal B breast cancer subtype. The results of our study are consistent with those of this study, but they also analyzed HER2 status [24]. Many researchers previously agreed that PR expression is dependent on ER activity, and the absence of PR indicates resistance to hormone therapy along with ER dysfunction. However, PR loss is relevant to hyperactive crosstalk between ER and growth factor signaling, such as epidermal growth factor receptor and HER2, which feature significantly shorter DFS rates [26]. Adjuvant chemotherapy for early breast cancer patients with ER and lymph node positivity should be carefully considered to maximize its clinical benefit. Thus, we suggest that since the prognosis of the PR low group was worse than that of the PR intact group, the PR low group would benefit more from adjuvant chemotherapy.
Our study has some limitations. First, it was a retrospective study. Second, it used the clinical data of a small number of breast cancer patients; therefore, its statistical power may be lower than that of relatively prospective large-scale clinical studies. In the future, large-scale clinical trials including more patients with the luminal B breast cancer subtype should be conducted to confirm our results. Finally, our data were collected over a period of 15 years at a single medical institution; over this long-term period, changes in surgical trends occurred such as increased neoadjuvant chemotherapy, target drug development, and anti-hormonal therapy development. It is necessary to consider the possibility that the development of these treatment-related factors has influenced prognosis.
In conclusion, our study presented PR status as a possible prognostic factor in the luminal B breast cancer subtype, for which a low PR expression can be a predictive factor for worse prognosis. Therefore, clinicians may consider systemic chemotherapy when choosing an appropriate treatment.

CONFLICT OF INTEREST

The authors declare that they have no competing interests.

Figure 1.
(A) Overall survival of the luminal B subtype of breast cancer by PR expression status. (B) Disease-free survival of the luminal B subtype of breast cancer by PR expression status. PR = progesterone receptor.
jbd-10-1-46f1.jpg
Table 1.
Demographic and clinical characteristics of the luminal B subtype of breast cancer by PR expression status
Characteristic PR intact (n = 141) PR low (n = 106) p-value
No. (%) No. (%)
Age (yr) ≤ 50 92 (65.2) 48 (45.3) 0.001*
> 50 49 (34.8) 58 (54.7)
TNM stage I 47 (33.3) 30 (28.3) 0.261
II 70 (49.6) 48 (45.3)
III 21 (14.9) 22 (20.8)
IV 3 (2.1) 6 (5.7)
Breast operations BCS 115 (81.6) 58 (54.7) < 0.001*
Mastectomy 25 (17.7) 47 (44.3)
Not done 1 (0.7) 1 (0.9)
Axilla operations SLNB 63 (44.7) 36 (34.0) 0.186
ALND 77 (54.6) 68 (64.2)
Not done 1 (0.7) 2 (1.9)

PR=progesterone receptor; TNM=tumor-node-metastasis; BCS=breast conserving surgery; SLNB=sentinel lymph node biopsy; ALND=axillary lymph node dissection.

* p-value is statistically significant.

Table 2.
Pathologic characteristics of the luminal B subtype of breast cancer according to PR expression status
Characteristic PR intact (n = 141) PR low (n = 106) p-value
No. (%) No. (%)
No. of tumor Single 123 (87.2) 91 (85.8) 0.752
Multiple 18 (12.8) 15 (14.2)
Margin Clear 130 (92.2) 98 (92.5) 0.941
Involved 11 (7.8) 8 (7.5)
HG I 2 (1.4) 1 (0.9) 0.826
II 32 (22.7) 23 (21.7)
III 90 (63.8) 65 (61.3)
N/A 17 (12.1) 17 (16.0)
NG I 75 (53.2) 60 (56.6) 0.136
II 43 (30.5) 29 (27.4)
III 6 (4.3) 0
N/A 17 (12.1) 17 (16.0)
LI No 51 (36.2) 37 (34.9) 0.837
Yes 90 (63.8) 69 (65.1)
VI No 116 (82.3) 79 (74.5) 0.140
Yes 25 (17.7) 27 (25.5)
NI No 95 (67.4) 71 (67.0) 0.997
Yes 21 (14.9) 16 (15.1)
N/A 25 (17.7) 19 (17.9)
Ki 67 ≤ 20% 76 (53.9) 41 (38.7) 0.018*
> 20% 65 (46.1) 65 (61.3)
Bcl-2 ≤ 33% 20 (14.2) 37 (34.9) < 0.001*
> 33% 121 (85.8) 69 (65.1)
HER2 FISH 1 84 (59.6) 48 (45.3) 0.063
2 41 (29.1) 38 (35.8)
N/A 16 (11.3) 20 (18.9)

PR=progesterone receptor; HG=histologic grade; NG=nuclear grade; LI=lymphatic invasion; VI=vascular invasion; NI=neural invasion; HER2=human epidermal growth factor-2; FISH=fluorescence in situ hybridization; N/A=not available.

* p-value is statistically significant.

Table 3.
Recurrence sites of the luminal B subtype of breast cancer according to PR expression status
Site PR intact (n = 141) PR low (n = 106) p-value
No. (%) No. (%)
Breast No 129 (91.5) 94 (88.7) 0.461
Yes 12 (8.5) 12 (11.3)
Bone No 122 (86.5) 83 (78.3) 0.089
Yes 19 (13.5) 23 (21.7)
Lung No 130 (92.2) 92 (86.8) 0.164
Yes 11 (7.8) 14 (13.2)
Liver No 130 (92.2) 87 (82.1) 0.016*
Yes 11 (7.8) 19 (17.9)
Brain No 138 (97.9) 101 (95.3) 0.256
Yes 3 (2.1) 5 (4.7)
Axilla No 137 (97.2) 101 (95.3) 0.436
Yes 4 (2.8) 5 (4.7)

PR=progesterone receptor.

* p-value is statistically significant.

Table 4.
Multivariant analysis of prognostic factor related to PR expression of the nonmetastatic luminal B subtype of breast cancer
Variable Odds ratio (95% CI)* p-value
Stage 1 reference 0.002
Stage 2 0.556 (0.081-3.808) 0.550
Stage 3 4.866 (0.670-35.326) 0.118
Vascular invasion 5.663 (1.762-18.202) 0.004
PR expression 0.317 (0.110-0.910) 0.033
Age 0.305 (0.103-0.899) 0.031

PR=progesterone receptor; CI=confidence interval.

* 95% CI obtained from a multivariable COX proportional hazards regression model;

p-value is statistically significant.

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