pS2 in breast carcinoma: association with steroid hormone receptor status

AIMS AND BACKGROUND: Knowledge of the steroid hormone receptors has proved to be of significant value in breast cancer. In the present study the possible importance of estrogen-regulated pS2 protein was investigated. Our direct purpose was to answer the question whether the expression of pS2 may be a marker of functional heterogeneity with respect to the steroid hormone receptor status. METHODS AND STUDY DESIGN: The study included 152 patients with primary, operable, histologically confirmed breast carcinomas. Histology specimens were reviewed and classified according to type, nodal status, tumor size and grade. Steroid hormone receptors were assayed by biochemical methods according to the procedures recommended by the EORTC. pS2 protein measurement was performed in breast carcinoma cytosols using an immunoradiometric assay. The results were analyzed by non-parametric statistical methods. RESULTS: A statistically significant inverse correlation between pS2 protein expression and histological tumor grade was found. The expression of pS2 protein was confirmed to be correlated with steroid hormone receptor status. However, it is important to point out that in spite of these statistically significant findings there were no significant biological associations due to overlapping individual pS2 protein values. The baseline level of expression of pS2 protein was obtained in histological grade III carcinomas with a negative steroid hormone receptor status. It was shown that the distribution of carcinomas according to the baseline level of pS2 protein expression was heterogeneous among estrogen receptor-positive carcinomas, and strikingly homogeneous among estrogen and progesterone-negative carcinoma. CONCLUSION: Our study suggested that PR and pS2 protein may identify distinct subsets of estrogen receptor-positive breast carcinomas.     

Monoclonal antibodies applied to primary human breast carcinoma: Relationship to menopausal status,lymph node status,and steroid hormone receptor content

Summary Monoclonal antibodies were raised against purified human milk fat globule membranes. The binding of three of these (Mam-3, HMFG 1, and HMFG 2) to fixed histological sections of 100 primary breast carcinomas has been investigated. Tissue specificity was investigated by testing the binding of the antibodies to carcinomas from other organs and to benign proliferative breast lesions.In breast tissue, antigens were found only in the epithelial cells, while the stromal component, myoepithelium, and any inflammatory cells present were negative. The reaction was characterized by considerable heterogeneity, both with regard to the percent of cells positive and the intensity of the reaction. No relationship was observed between binding and histological type of breast carcinoma. However, in ductal infiltrating carcinomas, a tendency towards a greater proportion of tumors that bound the antibodies was observed among the highly differentiated compared to the low differentiated carcinomas.Data on estrogen and progesterone receptors were available in 53 and 22 of the 100 carcinomas, respectively. There were no apparent relationships between the presence of surface antigens and the menopausal status, lymph node status, or estrogen receptor status, but the tumors lacking progesterone receptor apparently lacked the antigens as well.The presence of surface antigens probably defines a differentiation in primary breast carcinoma. Whether this differentiation is of any prognostic significance remains to be established.     

Tumour steroid hormone synthesis and estrogen receptor status in breast cancer patients

Summary The capacity of breast cancer to synthesise active androgens and estrogens has been related to estrogen receptor (ER) status in 79 postmenopausal patients with breast cancer. Although there was no quantitative relationship between levels of ER and steroid metabolism in ER positive tumours, there was (a) a positive correlation between estrogen synthesis and ER positivity and (b) increased androgen synthesis and ER negativity. This may imply an inherent difference in the handling of hormones in ER positive and negative tumours. Address for reprints: R.C. Mason, University Department of Clinical Surgery, Royal Infirmary, Edinburgh EH39YW, United Kingdom.     

Sex steroid hormone levels in breast adipose tissue and serum in postmenopausal women

Elevated levels of circulating estrogens and androgens are linked to higher breast cancer risk among postmenopausal women; however, little is known about hormone levels within the breast. Hormone concentrations within the breast may not be reflected in the blood and are likely important contributors to breast carcinogenesis. We used a previously validated method to measure levels of estrone, estradiol, androstenedione, and testosterone in adipose tissue removed as part of breast excisions performed for cancer in 100 postmenopausal women (69 ER/PR +/+ and 31 ER/PR −/−) participating in a breast cancer case–control study. We also measured the same steroid hormones, as well as estrone sulfate, and sex hormone-binding globulin (SHBG) in serum from these patients and 100 controls matched on ages at blood collection and on menopause. Overall, concentrations of serum hormones did not vary significantly between controls and cases. However, women with ER−/PR− breast cancers had lower circulating levels of all measured sex steroid hormones and higher SHBG levels than women with ER+/PR+ breast cancers and controls. Similarly, hormone concentrations in breast adipose tissue were higher among women with ER+/PR+ compared to ER−/PR− breast cancer, although differences were only significant for testosterone. These data demonstrate that high sex steroid concentrations in both serum and adipose tissues are more strongly related to ER+/PR+ than ER−/PR− breast cancers. Measurement of sex hormones in serum and in the microenvironment may help in understanding the hormonal etiology of breast cancer, suggest methods for prevention, and have value in gauging treatment response and prognosis.     

Prognostic factors for survival in metastatic breast cancer by hormone receptor status

Hormone receptor (HR) status is an important prognostic factor for patients with metastatic breast cancer (MBC) and is also correlated with other prognostic factors, such as initial lymph node status, HER2-Neu status and age. The prognostic value of these other factors, however, is unknown when stratified by HR positive versus HR negative patients. The aim of this study was to evaluate prognostic factors for MBC survival in relation to HR status. Dutch women diagnosed with breast cancer in 2003–2006 treated with curative intent who developed MBC within 5 years of follow-up were selected from the Netherlands cancer registry (N = 2,001). Independent prognostic factors for survival after metastatic occurrence were determined by multivariable Cox survival analyses stratified by HR status. Interactions between HR status and prognostic factors were determined. Median survival for MBC patients with HR negative (HR?) tumours was 8 months, compared to 19 months for HR positive (HR+) patients. The prognostic value of lymph node status, HER2-Neu status, adjuvant endocrine treatment and first-line palliative chemotherapy was dependent on HR status. Initial lymph node status was independently associated with survival in HR? patients, but not in HR+ patients. HER2-Neu positive status was associated with better survival in both HR+ and HR? patients, although the association was stronger in HR? patients. Similarly, patients treated with first-line palliative chemotherapy fared better, especially HR? patients. HR+ patients had worse survival if they had received adjuvant endocrine treatment. This study shows that the prognostic value of various factors depends on HR status in MBC. This information may help physicians to determine individual prognostic profiles and therapeutic strategies for MBC patients.     

A correlation between estrogen sulfotransferase levels and estrogen receptor status in human primary breast carcinoma.

Estrogen sulfotransferase (EC 2.8.2.4) activity and estrogen receptor levels were measured in 32 human primary breast cancer cytosol preparations. Two types of tumors were identified: type 1, in which estrogen sulfotransferase levels were low (less than 40 pmol 17 beta-estradiol 3-sulfate formed per mg protein per 2 hr) and were independent of [35S]adenosine 3'-phosphate 5'-phosphosulfate production from [35S]sulfate and adenosine triphosphate, and type 2, in which estrogen sulfotransferase levels ranged from 50 to 200 pmol 17 beta-estradiol 3-sulfate per mg protein per 2 hr and were correlated with [35S]adenosine 3'-phosphate 5'-phosphosulfate formation (r = 0.70; p less than 0.005). In type 1 tumors, 11 of 16 were estrogen receptor negative; in type 2 tumors, 2 of 16 were receptor negative. Estrogen sulfotransferase levels in receptor-negative tumors were significantly lower than the levels in receptor-positive tumors (p = 0.025).     

Serum sex steroid and peptide hormone concentrations, and endometrial estrogen and progestin receptor levels during administration of human leukocyte interferon

Five normally cycling healthy women were given daily subcutaneous injections of human leukocyte interferon (3 X 10(6) units/day) from the 3rd through 23rd day of the menstrual cycle, and serum steroid and peptide hormone concentrations monitored at 3-day intervals during the treatment and the preceding control cycle. Concentrations of cytosol and nuclear estrogen receptors (ERC and ERN, respectively) and progestin receptors (PRC and PRN) were also measured from endometrial biopsies taken on the 24th day of the control and treatment cycle. In addition, an extensive monitoring of clinical chemical and hematological tests from the blood samples were performed. Serum estradiol and progesterone concentrations were significantly decreased during the treatment cycle, suggesting that interferon interacts in vivo with the function of both FSH and LH. No significant changes were observed in the serum peptide hormone concentrations measured (FSH, LH, prolactin, insulin, growth hormone and TSH); neither were the levels of endometrial ERC, ERN, PRC and PRN affected by interferon administration. As expected, interferon administration resulted in decreased leukocyte counts. Moreover, an increasing tendency in the activities of serum alkaline phosphatase and gamma-glutamyltransferase during the interferon therapy shows that interferon may slightly interfere with the liver function. These results suggest that one of the mechanisms by which interferon treatment may affect the growth of hormone-dependent neoplasms could be the interaction with production and/or function of circulating hormonal compounds.     

Variability in hormone and growth factor receptor expression in primary versus recurrent, metastatic, and post-neoadjuvant breast carcinoma

The introduction of selective molecular targeted therapy, specifically tamoxifen and trastuzumab, has significantly altered the clinical behavior of breast carcinoma. Several questions remain, however, regarding potential phenotypic drifts in estrogen receptor (ER), progesterone receptor (PR), and epidermal growth factor receptor (Her-2/neu) expression between the primary and metastatic site. Whether patients should be tested for ER, PR, and Her-2/neu expression in the nodal or distant metastatic site, local recurrence and following neoadjuvant therapy, and whether this has an effect on prognosis remains elusive. A review of 45 studies addressing ER, PR, and Her-2/neu expression in lymph node metastasis, distant metastasis, local recurrence, and post-neoadjuvant therapy revealed the following average phenotypic drift in ER, PR, and Her-2/neu expression, respectively: 13.1 % (median = 10.0 %), 13.8 % (median = 16.0 %), and 7.7 % (median = 5.0 %) for lymph node metastasis; 21.8 % (median = 19.5 %), 30.8 % (median = 33.5 %), and 7.6 % (median = 6.1 %) for distant metastasis; 19.8 % (median = 13.4 %), 27.1 % (median = 28.6 %), and 6.6 % (median = 1.6 %) for local recurrence; and 12.9 % (median = 8.0 %), 32.0 % (median = 20.0 %), and 8.9 % (median = 0 %) post-neoadjuvant therapy. The above findings support the notion of re-evaluating ER, PR, and Her-2/neu expression in distant metastasis, lymph node metastasis and to a lesser extent local recurrence. The effects of neoadjuvant therapy on receptor expression are more pronounced for PR, which may have a prognostic role in therapy efficacy.     

乳腺癌原发灶和转移灶激素受体与HER2表达差异及其影响因素

目的 乳腺癌的治疗已经进入分子分型时代,雌激素受体(estrogen receptor,ER)、孕激素受体(progesterone receptor,PR)和人类表皮生长因子受体-2(human epidermal growth factor receptor 2,HER2)的表达对指导制订乳腺癌治疗方案及评价患者预后等尤为重要.许多研究证实,部分乳腺癌患者原发灶及转移灶激素受体与HER2表达存在差异,影响术后辅助及解救治疗方案的制订,进而影响患者的治疗效果及预后.本研究探讨乳腺癌原发灶与腋窝及远处转移灶之间激素受体与HER2表达的差异及其临床意义,同时分析了造成差异的影响因素.方法 以乳腺癌、激素受体(ER和PR)、HER2、原发灶和转移灶为关键词,检索PubMed、CNKI数据库和万方数据库1995-01-2016-10的相关文献.共505篇文章被检索到.纳入标准:原发灶与腋窝转移灶激素受体及HER2表达差异情况,原发灶与远处转移灶激素受体及HER2表达差异情况,原发灶与转移灶激素受体及HER2表达差异情况的临床意义.根据纳入标准最终纳入分析38篇文献.结果 在部分乳腺癌患者中,原发灶与腋窝转移灶及远处转移灶激素受体及HER2表达情况存在差异,多数文献报道,乳腺癌原发灶与转移灶ER表达状况变化(阳性转阴性或阴性转阳性)比例约为20％,PR约为20％,HER2约为15％.“肿瘤异质性、抗肿瘤治疗和检测方法”等是影响其表达差异的影响因素.结论 推荐对于存在局部及远处转移的乳腺癌患者,同时检测并综合原发灶及转移灶的激素受体及HER2表达情况制订治疗方案.     

Relation of serum levels of estrogen and dehydroepiandrosterone sulfate to hormone receptor status among postmenopausal women with breast cancer

Background: It is hypothesized that breast cancer may consist of heterogeneous diseases with different hormonal environments classified by hormone receptor status. Epidemiologic studies evaluating risk factors for breast cancer by hormone receptor status have supported the hypothesis. However, there are inconsistencies in the risk factor profiles by estrogen receptor (ER) and progesterone receptor (PR) across the studies. To clarify the heterogeneity of the disease, it is necessary to understand not only risk factor profiles but also the biologic characteristics such as the relationships among endogenous sex hormone levels and hormone receptors. Methods: We measured serum levels of estrone (E1), estradiol (E2), dehydroepiandrosterone sulfate (DHEAS), and sex hormone-binding globulin (SHBG) in 142 postmenopausal women aged 50 and over with primary breast cancer who had undergone surgical treatment, and investigated the heterogeneity in the relations of endogenous sex hormone levels to hormone receptor status, using the case-series study method. Subjects were categorized into 3 classes based on tertiles of each hormone level in receptor-negative subjects, and odds ratios (ORs) for receptor-positive status compared with receptor-negative status were computed, taking the lowest category as a reference category. Results: There were clear trends toward higher serum levels of E1, E2, and DHEAS in women with PR+ cancer. The case-series approach revealed that PR+ status might be strongly associated with serum sex hormone levels. In particular, the OR of PR+ was large for a high DHEAS level (OR for the highest category = 4.28). No significant association between serum hormone levels and ER status was observed. Conclusion: The association of serum sex hormone levels with hormone receptor status may differ by PR status, but not by ER status. This finding suggests that PR status may be related to the heterogeneity in hormonal environments associated with breast cancer risk.     

Tumor hormone receptor status and recurrences in premenopausal node negative breast carcinoma

To ascertain the prognostic significance of tumor hormone receptor status in node negative, premenopausal patients with breast cancer, a retrospective view of 199 patients fitting these criteria was conducted. Of these 199 patients, 147 had estrogen receptor data available. There were 104 patients (71%) who were estrogen receptor negative, and 16 (15%) had developed local or distant recurrence with a median follow-up of 44 months. Five patients had died of breast cancer. Of the 43 patients who were estrogen receptor positive, there was one recurrence, and no breast cancer deaths. This difference in recurrence is statistically significant (P less than 0.01) by the log-rank probability test. Of the 17 patients with recurrent disease, 14 (82%) had primary tumors 2 cm or larger in size. If only those patients with tumors 2 cm or larger are considered, 23% (13/57) who were estrogen receptor negative and 5% (1/19) who were estrogen receptor positive recurred. This remains statistically significant (P less than 0.025). We conclude that tumor hormone receptor status and size of tumor are significant prognostic factors in identifying premenopausal, node negative women at risk for recurrent disease.     

原发性肺癌的性激素受体检测及其意义

目的　研究原发性肺癌与性激素受体的关系。方法　应用免疫组化SP法对47例患者进行雌激素受体（ER），孕激素受体（PR）及雄激素受体（AR）检测。结果　原发性肺癌的ER、PR及AR阳性率分别为65．95％、61．70％及61．70％。结论　本结果显示肺癌与性激素受体有一定关系，肺癌细胞分化程度越高，性激素受体阳性率越高。通过检测了解肺癌生物学特性，提示内分泌治疗对肺癌性激素受体阳性患者有效，并对预测其预后有一定意义。     

Risk of contralateral second primary breast cancer according to hormone receptor status in Germany

Introduction

Hormone receptor (HR) status has become an established target in treatment strategies of breast cancer. Population-based estimates of contralateral breast cancer (CBC) incidence by HR subtype in particular are limited. The aim of this study was to provide detailed data on CBC incidence for Germany.

Methods

Invasive breast cancer data were extracted on 49,804 women yielding 594 second primaries from the cancer registries of the Federal States of Brandenburg and Saarland and the area of Munich for the period from 1998 to 2007. Multiple imputation was used on missing values for HR status. We estimated standardized incidence ratios (SIRs) with 95% confidence intervals (95%CIs).

Results

SIR estimates of CBC among women diagnosed with an invasive first primary breast cancer (FBC) of any HR subtype ranged from 1.0 to 1.5 in the three registries. Pooling three registries’ data, the SIR of HR-positive CBC was 0.7 (95%CI: 0.6 to 0.8) among women with HR-positive FBC. For those women with HR-negative FBC, the SIR of HR-negative CBC was 8.9 (95%CI: 7.1 to 11.1). Among women with FBC diagnosed before the age of 50 years, incidence of CBC was increased, especially for HR-negative FBC (SIR: 9.2; 95%CI: 7.1 to 11.9).

Conclusions

HR status of the first primary and age at first diagnosis is relevant for predicting risk of CBC. Particularly, patients with HR-negative FBC had elevated risks.

Electronic supplementary material

The online version of this article (doi:10.1186/s13058-014-0452-4) contains supplementary material, which is available to authorized users.     

Significance of immunohistochemical assessment of steroid hormone receptor status for breast cancer patients

The assessment of steroid hormone receptors in resected breast cancer tissues is essential to decide whether endocrine therapy is indicated and to select the best treatment for each patient on the basis of receptor status. Both enzyme immunoassay (EIA) and immunohistochemistry (IHC) have been generally used as methods for examination of estrogen receptor (ER) and progesterone receptor (PgR). In some patients, receptor status cannot be examined for various reasons. A questionnaire survey in Japan clarified that ER status is not examined in approximately 40% of patients receiving breast conserving surgery. To eliminate "receptor unknown" cases, IHC examination on paraffin-embedded tissue is useful to assess the in situ receptor status. The concordance rate of ER and PgR status between EIA and IHC is very high and a study of 88 cases revealed a 97.7% concordance for ER and 92.0% for PgR at a cutoff point of 10%. The cutoff point of IHC is controversial and some studies demonstrated that patients showing 1% ER positive cancer cells would benefit from endocrine therapy. On the other hand, immunohistochemical expression of receptors is heterogeneous and some patients with ER negative invasive tumors have ER positive intraductal components. A study of 65 breast cancers demonstrated that ER positive intraductal components were detected in 3.1% cases of ER negative invasive lesions. According to these results and the recommendation of the St. Gallen International Conference, IHC is thought to be more useful than EIA in the assessment of steroid hormone receptor status for breast cancer patients.     

Immunohistochemical evaluation of hormone receptor status for predicting response to endocrine therapy in metastatic breast cancer

BACKGROUND: The importance of establishing hormone receptor status of tumors for the treatment of women with hormone receptor-positive breast cancer has been emphasized, however, there is no general agreement as to how immunohistochemical assays should be evaluated. It is critical to evaluate hormone receptor status when considering response to endocrine therapy. METHODS: Estrogen receptor (ER) and progesterone receptor (PgR) expression was examined by immunohistochemistry using Allred's score for primary breast tumors from 75 metastatic breast cancer patients who received first-line treatment with endocrine therapy (56 patients received tamoxifen, 11 patients received aromatase inhibitors, and 8 patients received LH-RH agonist or other endocrine reagents) on relapse. Correlation between hormone receptor status and response to endocrine therapy as well as post-relapse survival was analyzed. RESULTS: The most significant correlation between positive ER expression and response to any endocrine therapy (p = 0.011) or tamoxifen only (p = 0.030) occurred when the cutoff score was set at 10%. When the evaluation was based on Allred's score (TS), a cutoff point of TS>or=4 showed a more significant association between positive ER expression and response to all kinds of endocrine therapy (p = 0.020) or tamoxifen only (p = 0.047). When evaluated at a cutoff point of 1% positive cells, there were fifteen patients with both ER- and PgR-negative tumors, and three patients (20.0%) responded to the therapy. Patients with 1% or more ER or PgR positive cells had better survival after relapse (p = 0.0005 and p = 0.0008, respectively). CONCLUSIONS: The proportion score alone might be enough to predict hormone responsiveness and post-relapse survival in metastatic breast cancer. The cutoff might be set low, for example 1%, especially for metastatic disease.     

Association of hormone replacement therapy to estrogen and progesterone receptor status in invasive breast carcinoma

BACKGROUND: Observational studies and randomized trials have demonstrated that hormone replacement therapy (HRT) increases the recipient's risk of developing breast carcinoma. Because it is known that some breast malignancies are hormonally responsive and that others are not, it has been hypothesized that HRT may be associated with the development of estrogen receptor (ER)-positive/progesterone receptor (PR)-positive breast carcinoma more so than with the development of ER-negative/PR-negative breast carcinoma. METHODS: The Nurses' Health Study is a prospective cohort study that enrolled 121,700 female registered nurses ages 30-55 years in 1976. In the current study, the authors analyzed 2548 malignancies that developed among eligible postmenopausal women in that cohort between 1980 and 2000 and for which data on ER and PR status were available. RESULTS: Compared with women who had never used HRT, current long-term users of HRT were more likely to develop ER-positive/PR-positive breast carcinoma (multivariate risk ratio [RR], 1.80; 95% confidence interval [CI], 1.52-2.12) but were not any more likely to develop ER-negative/PR-negative disease (multivariate RR, 1.00; 95% CI, 0.72-1.39). This effect grew stronger with increasing duration of current HRT use and was also more pronounced among women with body mass index < 25 kg/m2. Furthermore, the association between HRT use and ER-positive/PR-positive disease was stronger among patients receiving combined HRT (CHRT) regimens, which included estrogen and progesterone, than among users of estrogen alone (ERT). In addition, tumors tended to develop more quickly in current users of CHRT than in ERT users. CONCLUSIONS: The finding that current users of HRT were more likely to develop ER-positive/PR-positive tumors than they were to develop ER-negative/PR-negative ones suggests that both endogenous and exogenous hormonal factors may influence breast tumor characteristics. In analyses of the effects of hormonal factors on breast tumor development, ER-positive/PR-positive tumors and ER-negative/PR-negative tumors should be considered separately from each other.