| Abstract|| |
Aim: We aimed to determine the hormone receptor status in breast cancers and to investigate the relationship between single hormone receptor-positive, double hormone receptor-positive, double hormone receptor negativity, and human epidermal growth factor receptor 2 (HER2) status and some clinicopathological features. Materials and Methods: The study includes 85 patients who were diagnosed in our center between 2018 and 2019 and having surgical specimens were included in the study. Data of the cases, such as estrogen receptor (ER), progesterone receptor (PR), HER2 status, silver in situ hybridization (SISH) evaluation results, age distribution, histopathological findings were recorded. Results and Conclusions: We investigated the relationship between age, grade, tumor size, lymph node metastases and ER, PR, and HER2. However, there was not a significant association between ER, PR, and HER2 and age, tumor size, lymph node metastases (P > 0.05). On the other hand, we found a significant association between grades and ER (P = 0.02) and PR (P = 0.004), but not between grades and HER2 (P > 0.05). High-grade tumors were tumors with the lowest ER, PR positivity rate. Considering the four subtypes, cases aged above 45 years were at most double hormone receptor-positive (75%) and ER-positive/PR-negative (56%), respectively (P < 0.001). High-grade tumors were mostly double hormone receptor-negative and at least double hormone receptor positive. The ER-positive/PR-negative subtype was between these two groups (P < 0.001). The increased tumor size (T3) and increased metastatic lymph node number (N2 and N3) were observed at least in the ER-positive/PR-negative subtype. The majority of cases are in the older age group and invasive ductal carcinoma (IDC) is the most common tumor type. Older cases are most frequently double hormone receptor-positive and ER-positive/PR-negative, respectively. The ER, PR positivity rate is low in high-grade tumors. ER-positive/PR-negative tumors are of a higher grade than double hormone receptor-positive tumors, but they are of a lower grade than double hormone receptor-negative tumors. The increased tumor size and increased lymph node metastasis number are at most in the double hormone negative subtype and at least in the ER-positive/PR-negative subtype. The ER-negative/PR-positive subtype is observed very rarely, which raises the question of whether ER-negative/PR-positive tumors really exist. Further studies are needed to investigate this subtype and its properties.
Keywords: Breast, carcinoma, clinicopathological characteristics, ER, HER2, PR, subtype
|How to cite this article:|
Senel F. The hormone receptor status in breast cancer and the relationship of subtypes with clinicopathological features. Indian J Pathol Microbiol 2021;64:671-6
|How to cite this URL:|
Senel F. The hormone receptor status in breast cancer and the relationship of subtypes with clinicopathological features. Indian J Pathol Microbiol [serial online] 2021 [cited 2021 Dec 1];64:671-6. Available from: https://www.ijpmonline.org/text.asp?2021/64/4/671/328566
| Introduction|| |
Breast cancer is the most common type of cancer in women and is the second most common cause of death after lung cancer. The estrogen receptor (ER) and progesterone receptor (PR), which are the hormone receptors, are vital biomarkers in the prognosis and endocrine treatment of breast cancer. The molecular biomarkers of ER, PR, and human epidermal growth factor receptor 2 (HER2) are used in the routine clinical treatment of patients with invasive breast carcinoma. These receptors are targets for the treatment of breast cancer.
Some breast tumors are single hormone receptor-positive (ER-positive/PR-negative or ER-negative/PR-positive) and biologically and clinically different from ER-positive/PR-positive (double hormonereceptor-positive) and ER-negative/PR-negative (double hormone receptor-negative) subtypes.,
Compared to hormone receptor-negative breast cancers, hormone receptor-positive breast cancers have less aggressive clinicopathological features and have a better prognosis since they benefit from endocrine treatment.
| Materials and Methods|| |
Our research is a retrospective study, and 85 female patients who were diagnosed in our center in approximately 1 year between 2018 and 2019 and had surgical specimens were included in the study. The data of the cases, such as ER, PR, HER2 status, SISH evaluation results, age distribution, the histopathological type of the tumor, histopathological grade, tumor size, and lymph node metastasis status, were recorded.
The age of the cases was scored as 0--30 (1 point), 31--45 (2 points), and above 45 years (3 points). The tumor size was scored as ≤2 or T1 (1 point), 2--5 or T2 (2 points), ≥5 or T3 (3 points). The lymph node metastasis status was scored as 0 or N0 (1 point), 1--3 or N1 (2 points), 4--9 or N2 (3 points), and 10 and above or N3 (4 points). The tumor size and lymph node metastasis status were evaluated according to the TNM classification of breast tumors. The histological grade was scored as I (1 point), II (2 points), and III (3 points). The histological grade was evaluated according to the World Health Organization classification (according to Scarff-Bloom Richardson).
ER was scored as PR negative (0 points) and positive (1 point) [Figure 1]a and [Figure 1]b. HER2 was evaluated as negative (1+), weak (2+) [Figure 2]a, and positive (3+) [Figure 2]b. SISH was studied in cases with the weak HER2 result (2+). SISH was evaluated as negative (0 points) and positive (1 point) [Figure 2]c. After cases with suspected HER2 results were confirmed with SISH, the final HER2 status was scored as negative (0 points) and positive (1 point). Routine biomarker assessment and scoring were performed according to national guidelines.
|Figure 1: (a) Nuclear positivity in tumor cells with ER (IHC,200X). (b) Nuclear positivity in tumor cells with PR (IHC,200X)|
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|Figure 2: (a) Weak membranous staining (+2) in tumor cells with HER2 (IHC,400X). (b) Strong membranous staining (+3) in tumor cells with HER2 (IHC,400X). (c) Positive staining of tumor cells with SISH (IHC,400X)|
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For biomarker concordance analysis, we applied a cut off value of ≥10% for ER positivity, ≥10% for PR positivity. Negative HER2 protein expression was defined as score 1+, and positive as 3+. Equivocal tumors, scored 2+, had in most cases been subjected to additional in situ hibridizasyon (ISH). After ISH assessment, a HER2 copy/C17 control ratio >2.0 or an average HER2 copy number >4.0 signals/cell were classified as HER2 positivity. Negative HER2 status was defined as IHC score 0 or 1+, or ISH HER2/C17 ratio <2.0 and HER2 copy number <4.0 signals/cell. The reported overall HER2 status was based on combined results from immunohistochemical protein expression and gene amplification and included ISH HER2/chromosome 17 probe ratio and average number of HER2 copy numbers.
ER + / PR +, ER + / PR-, ER- / PR +, ER- / PR status were compared with HER2 status, age, grade, tumor size, lymph node metastasis status. The data were analyzed with SPSS 22.0 (Statistical Package for the Social Sciences, Armonk, NY) software.
| Results|| |
57 (67%) of the population were over 45 years old and 26 (%30.6) of them were between 31 and 45 years old while only 2 (%2.4) of them were younger than 30 years old [Table 1].
When we examine the frequency analysis of the diagnoses, it is seen that the diagnoses are distributed as IDC (65 cases, 76.5%), invasive lobular carcinoma (6 cases, 7.1%) and invasive ductal and lobular carcinoma (6 cases, 7.1%), other invasive carcinoma (8 cases, 9.4%) [Table 2].
The distribution of diagnoses in terms of population's age indicate that women under 30 years old were diagnosed with IDC (2 cases, 100%) and women between 31 and 45 years old were diagnosed with IDC (22 cases, 84.6%), invasive ductal and lobular carcinoma (2 cases, 7.7%) and other invasive carcinomas (2 cases, 7.7%), and women over 45 years old were diagnosed with other invasive carcinomas (6 cases, 10.5%), IDC (41 cases, 72%), invasive lobular carcinoma (6 cases, 10.5%), and invasive ductal and lobular carcinoma (4 cases, 7%) [Table 3].
In our study, 84.7% of the cases were ER-positive, 60% were PR-positive, and 22.4% were HER2-positive. Of the cases, 62.3% were ER-positive/PR-positive (double hormone receptor-positive), 15.3% were ER-negative/PR-negative (double hormone receptor-negative), 21.2% were ER-positive/PR-negative, and 1.2% were ER-negative/PR-positive.
We investigated the relationship between age, grade, tumor size, lymph node metastases and ER, PR, and HER2. However, there was not a significant association between ER, PR, and HER2 and age, tumor size, lymph node metastases (P > 0.05). On the other hand, we found a significant association between grades and ER (P = 0.02) and PR (P = 0.004), but not between grades and HER2 (P > 0.05) [Table 4]. High-grade tumors were tumors with the lowest ER, PR positivity rate.
The relationship of four subtypes with clinicopathological variables was examined. In the double hormone receptor-positive subtype, cases aged above 45 years were the most common (75%), while they were the least common in the double hormone receptor-negative subtype (53.9%). The most common cases in the ER-positive/PR-negative subtype were cases above 45 years (56%)(P < 0.001). Grade 3 cases were the most common in the double hormone receptor-negative subtype (46%), while they were the least common in the double hormone receptor-positive subtype (11%). The ratio of grade 3 cases in the ER-positive/PR-negative subtype was 33%, and it was between these two subtypes (P < 0.001). Considering the tumor size, tumors of ≥5 cm (T3) were the most common (16%) in the double hormone receptor-negative subtype, while they were the least common in the ER-positive/PR-negative subtype (6%)(P < .001). Considering the lymph node metastasis status, the increased metastatic lymph node number (N2 and N3) was observed most frequently in the double hormone receptor-negative subtype (21.4%), whereas it was observed least frequently in the ER-positive/PR-negative subtype (5.6%) [Table 5].
|Table 5: Comparison of the four groups in relation to other clinicopathologic variables|
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| Discussion|| |
Until approximately 20 years, breast cancers were classified according to their histopathological features as ductal, lobular, and medullary-like. Nowadays, with the help of the molecular techniques developed, it has been understood that tumors exhibit different behaviors, treatment responses, and prognosis, even if their histopathological appearance is the same, because of the loss of different oncogene/pro-oncogene activation and/or tumor suppressor gene functions. Nowadays, determinants such as ER, PR, and HER2 have been understood to be guiding in predicting the prognosis of breast cancer and determining the treatment modality.
Breast cancer is observed most frequently between the ages of 50--64 years, and there are fewer cases under the age of 40. In our study, the majority of cases (67.1%) are above 45 years. The most common type of breast cancer is IDC, and its rate is 40--75%. The prevalence of invasive lobular carcinoma (ILC) is 5--15%. The prevalence rate of IDC in our study is 76.5%, and the prevalence rate of ILC is 7.1%, which is consistent with the literature. ILC patients were older at diagnosis than IDC patients (>60 years of age, 63.4% and 52.3%, respectively). In our study, IDC is the most common in all age groups, and we do not have ILC cases in the age group below 30 years.
The steroid hormone receptors ER and PR are two critical molecules for assessing the heterogeneity of breast cancer and the benefit of therapy. The clinical significance of the hormone receptor status, especially in single hormone receptor-positive breast cancers, has not been fully understood to date and has not been investigated adequately because of the limited sample sizes.
ER and PR expressions are prognostic factors showing a good prognosis in breast cancers. HER2 expression is associated with poor prognosis.
The expression of ER is seen in 50--85% cases and PR in 60--70% cases of invasive breast carcinoma., In our study, 84.7% ER, PR 60% positive and are consistent with the literature.
In the literature, approximately 50% of breast cancers are double hormone receptor positive, 25% are double negative, 20% are ER-positive/PR-negative, and 5% are ER-negative/PR-positive. In our study, 62.3% of the cases are ER-positive/PR-positive, 15.3% are ER-negative/PR-negative, 21.2% are ER-positive/PR-negative, and 1.2% are ER-negative/PR-positive. In comparison with the literature, our double hormone receptor-positive cases are more, and our double hormone receptor-negative and ER-negative/PR-positive cases are fewer.
Double hormone receptor-positive tumors are most common in patients aged 60 years and above, whereas ER-negative/PR-positive tumors are most common in patients aged 30--49 years. In our study, the majority of double hormone receptor-positive tumors (75.1%) are in the advanced age group. We have only one ER-negative/PR-positive case, which is present in the group under the age of 30 years.
Tumors of young women differ from those of older women and are biologically more aggressive. The majority of tumors in young women are PR-positive, and ER positivity in young women is low. In our study, PR positivity was found to be higher than ER positivity in young women (below 45 years), and again, in our study, ER, PR positivity in young women was lower compared to women of advanced age, which was consistent with the literature. The grade of tumor in our study was significantly correlated to the expression of both ER and PR (P value of 0.02 and 0.004, respectively). The lower grade tumors showed high ER and PR positivity, similar to other studies.,
In their study, Rakha et al. reported that single hormone receptor-positive patients had more advanced clinicopathological features than patients with the double hormone receptor-positive subtype and had better clinicopathological features than patients with the double hormone receptor-negative subtype. In our study, statistically significant differences were observed between survival rates of single hormone receptor-positive/single hormone receptor negative breast carcinoma and double hormone receptor-positive/double hormone receptor-negative breast carcinoma patients. In our study, while single hormone receptor-positive patients (ER-positive/PR-negative group) were of a higher grade than double hormone receptor-positive patients, they were of a lower grade than double hormone receptor-negative patients. Considering the tumor size in our study, tumors of ≥5 cm (T3) are observed most frequently in the double hormone receptor-negative subtype (16%) and at least in the ER-positive/PR-negative subtype (6%). Considering the lymph node metastasis status, the increased metastatic lymph node number (N2 and N3) is observed most frequently in the double hormone receptor-negative subtype (21.4%) and at least in the ER-positive/PR-negative subtype (5.6%). Similarly, in the study of Jagtab et al., the increased number of metastatic lymph nodes is highest in the ER negative/PR negative subtype.
The ER-negative/PR-positive subtype constitutes a small part (2--5%) of breast cancers. It is reported that the clinical behaviors of these tumors are different from the double hormone receptor-positive subtype, and ER-negative/PR-positive tumors benefit less from endocrine treatment than ER-positive/PR-negative tumors. However, a 2011 meta-analysis of 20 randomized trials demonstrated that only ER status, but not PR status, was statistically significantly associated with tamoxifen response. The effectiveness of tamoxifen is lower in ER-positive/PR-negative tumors than in ER-positive/PR-positive tumors. Additional hormone therapy is not beneficial in patients with the ER-negative/PR-negative subtype. Another question is whether the ER-negative/PR-positive subtype really exists or is derived from a technical artifact. Some researchers maintain that ER-negative/PR-positive tumors do not exist and believe that the ER-negative/PR-positive subtype is caused by inadequate tissue fixation or technical failure of immunohistochemical assay in ER-positive/PR-positive tumors., It is undeniable that the frequency of ER-negative/PR-positive tumors has decreased with the optimization of immunohistochemical techniques.,
In our study, the ER-negative/PR-positive subtype is also the least common subtype and contains only 1 case (1.2%), which raises the question of whether ER-negative/PR-positive tumors really exist.
The HER2 gene is 15% positive. The HER2 positivity rate in our study is 22.3%. High-grade tumors are reported to exhibit a high rate of HER2 overexpression., Unlike these studies, our study supports the study of Arafah, and no significant relationship was detected between HER2 and grade.
In conclusion, the majority of cases are in the older age group and IDC is the most common tumor type. Older cases are most frequently double hormone receptor-positive and ER-positive/PR-negative, respectively. ER positivity in breast cancer is higher than PR positivity. The lower grade tumors show high ER and PR positivity. ER-positive/PR-negative tumors are of a higher grade than double hormone receptor-positive tumors, but they are of a lower grade than double hormone receptor-negative tumors. The increased tumor size and increased lymph node metastasis number are at most in the double hormone negative subtype and at least in the ER-positive/PR-negative subtype. Different strategies may be required for patients with single hormone receptor–positive tumors to ensure optimal treatment and maximum benefits from therapies. The ER-negative/PR-positive subtype is observed very rarely, which raises the question of whether ER-negative/PR-positive tumors really exist. Further studies are needed to investigate this subtype and its properties.
Author thank to Hatice Karaman for valuable help in preparing manuscript.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin 2011;61:69-90.
Bardou VJ, Arpino G, Elledge RM, Osborne CK, Clark GM. Progesterone receptor status significantly improves outcome prediction over estrogen receptor status alone for adjuvant endocrine therapy in two large breast cancer databases. J Clin Oncol 2003;21:1973-9.
Allred DC. Issues and updates: Evaluating estrogen receptor-alpha, progesterone receptor, and HER2 in breast cancer. Mod Pathol 2010;23:52-9.
Cui X, Schiff R, Arpino G, Osborne CK, Lee AV. Biology of progesterone receptor loss in breast cancer and its implications for endocrine therapy. J Clin Oncol 2005;23:7721-35.
Rakha EA, El-Sayed ME, Green AR, Paish EC, Powe DG, Gee J, et al
. Biologic and clinical characteristics of breast cancer with single hormone receptor positive phenotype. J Clin Oncol 2007;25:4772-8.
Early Breast Cancer Trialists' Collaborative Group. Tamoxifen for early breast cancer: An overview of the randomised trials. Lancet 1998;351:1451-67.
Sobin LH, Gospodarowicz MK, Wittekind Ch, editors. International Union against Cancer: TNM Classification of Malignant Tumors. 7th
ed. Oxford: Wiley-Blackwell; 2009.
Bloom HJ, Richardson WW. Histological grading and prognosis in breast cancer; A study of 1409 cases of which 359 have been followed for 15 years. Br J Cancer 1957;11:359-77.
Regional cancer center. Stockholm Gotland. National care program Breast cancer. Regional cancer centers. 2018.
Wolff AC, Hammond ME, Hicks DG, Dowsett M, McShane LM, Allison KH, et al
. Recommendations for human epidermal growth factor receptor 2 testing in breast cancer: American Society of Clinical Oncology College of American Pathologists clinical practice guideline update. J Clin Oncol 2013;31:3997-4013.
Slamon DJ, Clark GM, Wong SG, Levin WJ, Ullrich A, McGuire WL. Human breast cancer: Correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science 1987;235:177-82.
Yersal O, Barutca S. Biological subtypes of breast cancer: Prognostic and therapeutic implications. World J Clin Oncol 2014;5:412-24.
Gutierrez C, Schiff R. HER2: Biology, detection, and clinical implications. Arch Pathol Lab Med 2011;135:55-62.
American Cancer Society. Cancer Facts & Figures. Atlanta: American Cancer Society; 2012.
Ellis IO, Galea M, Broughton N, Locker A, Blamey RW, Elston CW. Pathological prognostics factors in breast cancer. II. Histological type. Relationship with survival in a large study with long-term follow-up. Histopathology 1992;20:479-89.
Zheling C, Jiao Y, Li S, Lv M, Yanwei S, Biyuan W, et al
. Invasive lobular carcinoma of the breast: A special histological type compared with invasive ductal carcinoma. PLoS One 2017;12:e0182397.
Coates AS, Winer EP, Goldhirsch A, Gelber RD, Gnant M, Piccart-Gebhart M, et al
.; Panel Members. Tailoring therapies: Improving the management of early breast cancer: St Gallen International Expert Consensus on the primary therapy of early breast cancer. Ann Oncol 2015;26:1533-46.
Li CI, Daling JR, Malone KE. Incidence of invasive breast cancer by hormone receptor status from 1992 to 1998. J Clin Oncol 2003;21:28-34.
Donegan WL. Tumor-related prognostic factors for breast cancer. CA Cancer J Clin 1997;47:28-51.
Noguchi M, Ohta N, Koyasaki N, Taniya T, Miyazaki I, Mizukami Y. Reappriasal of internal mammary node metastases as a prognostic factor in patients with breast cancer. Cancer 1991;68:1918-25.
Mohsin SK, Weiss H, Havighurst T, Clark GM, Berardo M, Roanh ID, et al
. Progesterone receptor by immunohistochemistry and clinical outcome in breast cancer: A validation study. Mod Pathol 2004;17:1545-54.
Barnes DM, Millis RR. Oestrogen receptors: The history, the relevance and the methods of evaluation. In: Kirkham N, Lemoine NR, editors. Progress in Pathology. Edinburgh: Churchill Livingstone; 1995. p. 89-114.
Li Y, Yang D, Yin X, Zhang X, Huang J, Wu Y, et al
. Clinicopathological characteristics and breast cancer–specific survival of patients with single hormone receptor–positive breast cancer. JAMA 2020;3:e1918160.
Anders CK, Hsu DS, Broadwater G, Acharya CR, Foekens JA, Yi Z, et al
. Young age at diagnosis correlates with worse prognosis and defines a subset of breast cancers with shared patterns of gene expression. J Clin Oncol 2008;26:3324-30.
Ratnatunga N, Liyanapathirana LV. Hormone receptor expression and Her/2neu amplification in breast carcinoma in a cohort of Sri Lankans. Ceylon Med J 2007;52:133-6.
Thoresen S, Thorsen T, Tangen M, Hartveit F. Oestrogen and progesterone receptor content and the distribution of histological grade in breast cancer. Breast Cancer Res Treat 1982;2:251-5.
Jagtap SV, Beniwal A, Chougule PG, Shah HP, Jagtap SS. Invasive lobular carcinoma of breast histopathological subtypes: Clinicopathological study. Int J Health Sci Res 2016;6:105-11.
Colomer R, Beltran M, Dorcas J, Cortes-Funes H, Hornedo J, Valentin V, et al
. It is not time to stop progesterone receptor testing in breast cancer. J Clin Oncol 2005;23:3868-9.
Davies C, Godwin J, Gray R, Clarke M, Cutter D, Darby D, et al
.; Early Breast Cancer Trialists' Collaborative Group (EBCTCG). Relevance of breast cancer hormone receptors and other factors to the efficacy of adjuvant tamoxifen: Patient-level metaanalysis of randomised trials. Lancet 2011;378:771-84.
Nadji M, Gomez-Fernandez C, Ganjei-Azar P, Morales AR. Immunohistochemistry of estrogen and progesterone receptors reconsidered: Experience with 5,993 breast cancers. Am J Clin Pathol 2005;123:21-7.
De Maeyer L, Van Limbergen E, De Nys K, Moerman P, Pochet N, Hendrickx W, et al
. Does estrogen receptor negative/progesterone receptor positive breast carcinoma exist? J Clin Oncol 2008;26:335-6.
Hammond ME, Hayes DF, Dowsett M, Allred DC, Hagerty KL, Badve S, 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;28:2784-95.
Kunc M, BiernatW, Senkus-Konefka E. Estrogen receptor–negative progesterone receptor–positive breast cancer: “Nobody's land” or just an artifact? Cancer Treat Rev 2018;67:78-87.
Epstein M, Ma Y, Press MF. ERBB2 testing: Assesment of status for targeted therapies. In: Harris JR, Lippman ME, Morrow M, Osbourne CK, editors. Diseases of the Breast. 4th
ed. Philadelphia: Wolters Kluwer Lippincott Williams Wilkins; 2010. p. 431-42.
Ivkovic-Kapicl T, Knezevic-Usaj S, Djilas-Ivanovic D, Panjkovic M. Correlation of HER-2/neu protein overexpression with other prognostic and predictive factors in invasive ductal breast cancer. In Vivo
Huang HJ, Neven P, Drijkoningen M, Paridaens R, Wildiers H, Van Limbergen E, et al.
Association between tumour characteristics and HER-2/neu by immunohistochemistry in 1362 women with primary operable breast cancer. J Clin Pathol 2005;58:611-6.
Arafah M. Correlation of hormone receptors with Her-2/neu protein expression and the histological grade in invasive breast cancers in a cohort of Saudi Arabia. Turk J Pathol 2012;28:38-43.
Department of Pathology, Kayseri City Hospital
Source of Support: None, Conflict of Interest: None
[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]