The determination of progesterone receptors in breast cancer and their relationship to estrogen receptors

A simple method for the assay of specific progesterone receptors in breast cancer tissue is described. Progesterone receptors were detected in 63 of 74 breast cancer specimens (85%). Estrogen receptor positive tumors had a wide range of progesterone receptor concentrations, but in 77% of cases the level was above 3 fmol/mg protein. The progesterone receptor level was generally low in tumors lacking estrogen receptors, 75% of the samples having concentrations between 0 and 3 fmol/mg protein. Unlike estrogen receptors, age had no influence on the number of progesterone receptors in breast cancer tissue.     

Relative importance of estrogen and progesterone receptor assays as prognostic indicators in primary breast cancer: a short-term study

This short-term study of the relative importance of estrogen and progesterone receptors shows that progesterone receptor correlates better than estrogen receptor with tumor recurrence regardless of lymph-node status. Life-table analysis has effectively identified only two groups of patients that may be classified by progesterone receptor status alone. Progesterone-receptor negativity correlated well with tumors of histological Grade III; estrogen-receptor positivity correlated with Grade I and II tumors. The earlier recurrence of Grade III breast tumors may explain why progesterone receptor is a better prognostic indicator than estrogen receptor in short-term studies.     

乳腺导管原位癌的X线影像特征及病理核分级与人表皮生长因子受体2、雌激素受体及孕激素受体表达的相关性

目的 探讨乳腺导管原位癌(DCIS)的X线影像特征及病理核分级与雌激素受体(ER)、孕激素受体(PR)及人表皮生长因子受体2(HER2)表达的相关性。方法 回顾经手术病理证实为DCIS的患者105例,共107个病灶,术前均接受乳腺X线摄影检查,系统描述病变的X线影像学特征。分析不同病理核分级及其影像特征与不同肿瘤因子表达(HER2阳性组、ER阳性组和三阴组)的相关性。结果 钙化为DCIS的主要影像学特征(74/107,69.15%),HER2阳性组、ER阳性组、三阴组间钙化形态及分布类型的差异均有统计学意义(P均<0.05),HER2阳性组以区段样分布(23/45,51.11%),线状分枝状钙化(18/45,40.00%)表现为主,主要为高级别DCIS(38/55,69.09%)。ER阳性组以区域性分布(23/45,51.11%)、多形性钙化(12/23,52.17%)表现为主,以非高级别为主(22/42,52.38%)。结论 DCIS患者的乳腺X线表现特征与肿瘤的一些分子生物学表达存在相关性,可以间接反映肿瘤的某些生物学行为。     

Taxonomy of breast cancer based on normal cell phenotype predicts outcome

Accurate classification is essential for understanding the pathophysiology of a disease and can inform therapeutic choices. For hematopoietic malignancies, a classification scheme based on the phenotypic similarity between tumor cells and normal cells has been successfully used to define tumor subtypes; however, use of normal cell types as a reference by which to classify solid tumors has not been widely emulated, in part due to more limited understanding of epithelial cell differentiation compared with hematopoiesis. To provide a better definition of the subtypes of epithelial cells comprising the breast epithelium, we performed a systematic analysis of a large set of breast epithelial markers in more than 15,000 normal breast cells, which identified 11 differentiation states for normal luminal cells. We then applied information from this analysis to classify human breast tumors based on normal cell types into 4 major subtypes, HR0–HR3, which were differentiated by vitamin D, androgen, and estrogen hormone receptor (HR) expression. Examination of 3,157 human breast tumors revealed that these HR subtypes were distinct from the current classification scheme, which is based on estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2. Patient outcomes were best when tumors expressed all 3 hormone receptors (subtype HR3) and worst when they expressed none of the receptors (subtype HR0). Together, these data provide an ontological classification scheme associated with patient survival differences and provides actionable insights for treating breast tumors.     

Serum cytokine levels and the expression of estrogen and progesterone receptors in breast cancer patients.

BACKGROUND: The aim of this study was to assess the correlation between serum concentrations of cytokines and soluble cytokine receptors in breast cancer patients and the expression of estrogen and progesterone receptors in tumor cells. METHODS: The study comprised 158 female breast cancer patients before treatment and 50 healthy individuals as a reference group. RESULTS: The study revealed significantly higher concentrations of most cytokines in breast cancer patients compared to the reference group. Assessment of the correlation between cytokine concentrations in serum and the expression of estrogen and progesterone receptors in tumor cells showed significantly higher interleukin-8 (IL-8) concentrations in patients lacking progesterone receptors in comparison to patients with these receptors. The concentrations of cytokines and their soluble receptors as a function of the expression of estrogen and progesterone receptors were also analyzed in two age groups. In younger patients, aged 50 years and below, no significant differences were found between serum cytokine concentrations and the expression of both estrogen and progesterone receptors. In patients older than 50 years, significantly higher IL-8 concentrations were observed in individuals lacking progesterone receptors, whereas IL-1ra was significantly higher in those lacking estrogen receptors. CONCLUSIONS: IL-1ra and IL-8 concentrations in serum, together with a lack of estrogen and progesterone receptors in tumor cells, in breast cancer patients older than 50 years could represent additional predictive factors for this disease.     

Characteristics and distribution of receptors for [D-TRP6]-luteinizing hormone-releasing hormone, somatostatin, epidermal growth factor, and sex steroids in 500 biopsy samples of human breast cancer

Binding capacities and apparent dissociation constants of receptors for [D-Trp6]-luteinizing hormone-releasing hormone [( D-Trp6]-LH-RH), somatostatin (SS-14), epidermal growth factor (EGF), and estrogen and progesterone were determined in 500 breast cancer specimens using multipoint assays. Specific binding sites greater than 10 fmol/mg cytosol protein for estrogen were found in 408 carcinomas (81.6%), and for progesterone in 340 specimens (68%). High affinity EGF receptors were present in membrane preparations from 335 samples (67%). In 260 of 500 samples (52%), two classes of [D-Trp6]-LH-RH membrane receptor sites were also detected, one class showing high affinity and low capacity, and the other class showing low affinity and high capacity; 178 biopsy samples (35.6%) exhibited binding sites for SS-14. Statistically significant inverse correlations were found between the binding capacities of estrogen and EGF receptors as well as between Bmax of progesterone and EGF receptors. Significant positive correlations were demonstrated between binding capacities of estrogen and progesterone and between Bmax of high affinity and low affinity binding sites of [D-Trp6]-LH-RH receptors. However, no correlation was found between the dissociation constants of different receptor sites in human breast cancer specimens. These results demonstrate that numerous human breast cancers, in addition to receptors for estrogen and progesterone, also show binding sites for EGF, [D-Trp6]-LH-RH and SS-14. The methods described herein permit a routine quantification of receptor sites for [D-Trp6]-LH-RH, SS-14, and EGF in membrane preparations of biopsy samples of breast cancer and can be used in conjunction with the determination of estrogen and progesterone receptors in nuclear-cytosolic extracts. The simultaneous measurements using a microanalytic approach allow the determination of peptide and steroid hormone receptors that might be involved in the response mechanisms of human breast cancer. It should be possible to correlate the levels of these receptors with clinical parameters to better identify endocrine-responsive neoplasms. This approach might be useful to guide a rational hormonal therapy in women with breast cancer.     

Lymphocyte reactivity to mitogens and tumor sex steroid receptors in breast cancer patients

In 60 breast cancer patients in stages I and II the blastogenic transformation of peripheral blood lymphocytes after phytohaemagglutinin (PHA) pokeweed mitogen (PWM) and concanavalin A (Con A) stimulation were assayed and estrogen (ER) and progesterone (PgR) receptor concentrations in tumor cytosol were measured. A negative correlation between lymphocyte reactivity to the mitogens and tumor steroid receptors concentration was found. The lymphocyte response to the mitogens in the patients with ER-PgR-tumors (R-) was significantly higher than in those with tumors either ER+PgR-or ER-PgR+ (R+) or ER+PgR+ (R++). There was also a negative correlation between lymphocyte response to PHA and either ER or PgR concentrations in the tumors. These results suggest that the presence of steroid receptors in tumor cells may be associated with the depression of immunological reactivity in breast cancer patients.     

人类表皮生长因子受体2在乳腺癌表达与临床的相关病理特征分析

目的 评估人类表皮生长因子受体2(HER2)预测价值,并分析其与常见的组织病理学参数的相关性。方法 收集陕西省人民医院2011年～2014年之间160例接受手术治疗的乳腺癌患者组织标本,通过免疫组织化学方法(IHC)和荧光原位杂交(FISH)检测 HER2水平,通过χ²检验用来评估HER2基因扩增状况及不同临床病理特性的相关性,临床参数包括:肿瘤大小、组织学分级、雌激素受体(ER)和孕激素受体(PR)表达,年龄、绝经情况和Ki-67指数。结果 HER-2表达与组织学分级、淋巴结转移、ER水平、PR,Ki-67指数差异存在统计学意义(均P<0.05)。相对于HER-2⁺组患者,HER-2^-病变多表现为雌激素ER阴性、孕激素阴性、ER阴性、淋巴结阴性、ki-67≥20%。结论 HER-2表达与多种临床病理因素存在相关性。     

子宫内膜不典型增生的保守治疗

目的：探讨孕激素治疗子宫内膜不典型增生（EAH）的疗效及治疗前后子宫内膜雌激素受体和孕激素受体（ER、PR）的变化情况。方法：对32例经诊刮病理确诊为EAH需保守治疗的患者采取孕激素治疗，每3个月为一疗程，疗程结束后了解其子宫内膜病变病检逆转情况和治疗前后ER、PR的变化。结果：一疗程结束后总治愈率为71．9％（23／32），其中轻度为100％（10／10），中度为61．50％（8／10），重度为55．6％（5／9）。延长疗程，治愈率为100％。治疗前后ER、PR表达下降非常显著（P〈0．01）。结论：对需保留生育功能的子宫内膜不典型增生的患者，在随诊条件下孕激素治疗有一定的效果。     

Corticosteroid sulfate excretion and estrogen receptors in breast cancer.

The urinary excretion of corticosteroid sulfates and free cortisol were determined in 150 breast cancer patients. Four of 60 cases of early breast cancer (7%) and 26 of 90 patients with advanced breast cancer (29%) showed an elevated urinary corticosteroid sulfate excretion. Urinary free cortisol was usually normal. Estrogen receptor assays were performed on tumor samples from 67 breast cancer patients; 24 were from primary lesions obtained at mastectomy, 3 from inoperable primaries in patients with systemic metastases, and 40 from metastases. Sixteen of the primary breast cancers (67%), 26 of the metastases (65%) and 1 of the 3 inoperable primaries contained estrogen receptors. With 2 exceptions, patients with an increased urinary corticosteroid sulfate excretion also had estrogen receptor-containing tumors.     

乳腺癌免疫组化表达与X线表现相关性的研究进展

人表皮生长因子受体2(HER-2)表达状态与乳腺癌预后有密切关系,同时又受雌激素受体(ER)、孕激素受体(PR)的影响。本文就上述免疫组化标记与乳腺癌X线表现相关性的研究进展作一综述。     

Application of estrogen receptor immunocytochemical assay to aspirates from mammographically guided fine needle biopsy of nonpalpable breast lesions.

The importance of hormone receptors in the management and prognosis of breast cancer is well established, but difficult to apply to the growing numbers of very small breast cancers being detected. To assess the feasibility of applying estrogen receptor immunocytochemical assay (ER-ICA) to cytologic specimens, we prospectively studied 100 patients who had fine needle aspiration biopsy (FNAB) of mammographically detected nonpalpable breast lesions. All 100 patients also had surgical excision of these nonpalpable lesions immediately after cytologic aspiration. Twenty malignancies were ultimately diagnosed by histology; 17 of them had been cytologically diagnosed. Using specific monoclonal antibody for estrogen receptor, we applied ER-ICA to cytologic preparation of 15 malignant neoplasms with sufficient cellular material available for the assay. Positive immunostaining was demonstrated in nine cases. No ER expression was seen in six cases. Immunocytochemical assay was also done on frozen tissue of the corresponding surgically removed tumors, with 86.6% concordance between the two results. This study is the first to demonstrate that ER-ICA can be effective in assessing hormone receptor content of mammographically directed cytologic aspirates.     

超声结合钼靶成像及Ki-67表达对乳腺癌新辅助化疗疗效的预测价值

目的 探讨常规超声、钼靶X线影像学特征及Ki-67阳性表达率对乳腺癌新辅助化疗后达到病理完全缓解(pCR)的预测价值.方法 回顾性选取2014年11月至2019年11月在常州市第二人民医院行新辅助化疗治疗的68例乳腺癌患者,患者行化疗前均接受乳腺超声和钼靶X线检查,且均经粗针穿刺取得病理和免疫组化结果.依据新辅助化疗疗...     

Molecular analysis of metaplastic breast carcinoma: high EGFR copy number via aneusomy

Metaplastic breast carcinoma, a rare tumor composed of adenocarcinomatous and nonglandular growth patterns, is characterized by a propensity for distant metastases and resistance to standard anticancer therapies. We sought confirmation that this tumor is a basal-like breast cancer, expressing epidermal growth factor receptor (EGFR) and stem cell factor receptor (KIT). EGFR activating mutations and high copy number (associated with response to tyrosine kinase inhibitor gefitinib) and KIT activating mutations (associated with imatinib sensitivity) were then investigated. Seventy-seven metaplastic cases were identified (1976-2006); 38 with tumor blocks available underwent pathologic confirmation before EGFR and KIT immunohistochemical analyses. A tissue microarray of malignant glandular and metaplastic elements was constructed and analyzed immunohistochemically for cytokeratin 5/6, estrogen receptor, progesterone receptor, and p63, and by fluorescence in situ hybridization for EGFR and HER-2/neu. DNA isolated from individual elements was assessed for EGFR and KIT activating mutations. All assessable cases were negative for estrogen receptor, progesterone receptor, and (except one) HER2. The majority were positive for cytokeratin 5/6 (58%), p63 (59%), and EGFR overexpression (66%); 24% were KIT positive. No EGFR or KIT activating mutations were present; 26% of the primary metaplastic breast carcinomas were fluorescence in situ hybridization-positive, displaying high EGFR copy number secondary to aneusomy (22%) and amplification (4%). We report here that metaplastic breast carcinoma is a basal-like breast cancer lacking EGFR and KIT activating mutations but exhibiting high EGFR copy number (primarily via aneusomy), suggesting that EGFR tyrosine kinase inhibitors should be evaluated in this molecular subset of breast carcinomas.     

Development of two ELISA for estrogen and progesterone receptor with sufficient sensitivity for fine needle aspirate and core biopsy

The quantitative determination of estrogen and progesterone receptors (PR and ER) in breast tumor cytosol has been routinely performed in clinical laboratories to aid in the selection between hormonal and chemotherapy and also to predict prognosis. However, the small amount of tissue available from the increasingly popular fine-needle aspiration and core biopsies from breast cancer patients requires more sensitive immunoassays for receptor quantification. We have developed two sensitive immuno-assays for ER and PR on microplate with the use of recently available anti-ER and anti-PR antibodies of higher affinity and a powerful signal magnification agent, namely Amdex. The calibrator was a pooled breast tumor cytosol used as calibrator and calibrated against Abbott kits. The protein concentration of the cytosol and the upper normal cutoffs for our assays were reduced to approximately 0.2 mg/mL and 3 fmol/0.2 mg/mL, respectively. Both assays have sensitivities close to 1 fmol/mL, which are sufficiently sensitive for the receptor quantification in fine-needle aspiration biopsies and cord biopsies of breast tumor.     

Determination of threshold values for determining the size of the fraction of steroid hormone receptor-positive tumor cells in paraffin-embedded breast carcinomas

BACKGROUND: For 4 years we used a multiparameter DNA flow cytometric (MP-FCM) technique to assess steroid hormone receptor expression in the diagnostic workup of routinely processed formalin-fixed, paraffin-embedded breast carcinomas as an alternative to immunohistochemistry (IHC) for the quantification of hormone receptor-positive cells. In all cases a positive fraction of hormone receptor-expressing epithelial cells was detected. This observation raised the question of what the cutoff value might be to distinguish receptor-negative from receptor-positive tumors. METHODS: In our search for a possible threshold value of positivity for estrogen receptor (ER) and progesterone receptor (PR) in MP-FCM, we developed four steps. First, we compared IHC results in our own laboratory with the results obtained by MP-FCM on a small series of breast tumors (n = 42). Second, after collecting our first 843 tumors, we made a comparison with the literature of the distribution of receptor positivity according to age classes. Third, using the most likely threshold that resulted from this comparison, we compared a subset of 340 node-negative tumors for their combined ER/PR profiles with the data from a similar group of node-negative tumor cases from the National Cancer Institute's Surveillance, Epidemiology and End-Result (SEER) study. Fourth, with the results of these comparisons, we prospectively collected IHC data and MP-FCM results of the same tumor samples for a period of 1 year. In this way, we collected data for an additional 180 tumors. RESULTS: The first step in this process resulted in an previous publication where 20% of steroid hormone receptor-positive cells seemed to be an acceptable cutoff point for positivity. However, the second step provided the best correlation at approximately 35% of ER reactive cells in the cytokeratin-positive cell population. With this cutoff, the distribution of combined ER/PR profiles in our patient population of node-negative breast cancers also showed a distribution similar to the data from the SEER study. The fourth step, using the 35% threshold value, resulted in a good correlation (r = 0.85, P < 0.0001) for ER and PR between IHC and MP-FCM in the 180 tumors investigated. CONCLUSION: By comparing in-house data with those from large external data collections in the literature, a threshold percentage can be defined that distinguishes steroid hormone receptor-negative from hormone receptor-positive tumors. As a result, information about DNA content and cell cycle distribution can be obtained. This observational study provides additional support to our opinion that MP-FCM is an alternative for IHC determination of ER and PR positivity. It is more objective and quantification can be done more appropriately. The additional value of this approach is that we generate continuous variables of ER/PR content instead of categorical classes, which can be used at different threshold levels for evaluation of clinical relevance.     

Management of primary breast cancer

During the past ten years, changes in the management of primary breast cancer—including mammographic screening, surgical alternatives to radical mastectomy, adjuvant chemotherapy for certain patients, and use of estrogen and progesterone receptor data to predict recurrence—have decreased mortality from this disease. Dr Rudolph proposes a logical approach to diagnosis and treatment of breast cancer, based on results of randomized controlled trials conducted over the past decade.     

绝经前后妇女子宫内膜癌临床病理分析

【目的】分析未绝经和绝经后妇女子宫内膜癌的临床病理特征。【方法】采用回顾性分析法,将53例内膜癌患者根据绝经与否分为未绝经组34例,绝经组19例,分析比较两组的发病因素、病程、临床表现、病理组织类型及雌、孕激素受体的表达。【结果】未绝经组与绝经组均以不规则阴道流血为主要表现,分别为88．2％、79．0％;未绝经组确诊时间（610．9±145．5）d,显著长于绝经组的（104．1±27．1）d（P〈0．05）;未绝经组子宫内膜样癌占97．1％,显著高于绝经组的78．8％,而非子宫内膜样癌占2．9％,低于绝经组的21．1％（P〈0．05）;两组在肿瘤病理组织学分级均差异无显著性（P〉0．05）;在临床分期间未绝经组Ⅱ期占5．9％,明显低于绝经组的42．1％,而Ⅲ期患者占32．4％,显著高于绝经组的5．3％（P〈0．05）;雌、孕激素受体表达在两组间差异无显著性（P〉0．05）;雌、孕激素受体阳性表达率I期高于Ⅱ～Ⅲ期（P〈0．05）;雌、孕激素受体表达呈正相关关系,雌、孕激素受体与临床分期分别呈负相关关系（P〈0．05）。【结论】子宫内膜癌绝经前、后妇女均以不规则阴道流血为主要的临床表现;I型内膜癌占绝经前、后妇女的绝大多数;雌、孕激素受体可作为内膜癌预后的监测指标;重视绝经前妇女不规则阴道流血是其早期诊断的关键。     

High detection rate of breast ductal carcinoma in situ calcifications on mammographically directed high-resolution sonography.

OBJECTIVE: To assess the high-frequency sonographic characteristics of ductal carcinoma in situ of the breast. METHODS: In a retrospective review, we identified 18 patients with biopsy-proven pure ductal carcinoma in situ who had received mammographic and high-frequency sonographic examinations at transducer frequencies of 8-15 MHz, 8-5 MHz and 5 to 13 MHz [corrected]. RESULTS: All 18 patients had mammographically identified calcifications. Four (22%) of the 18 had either asymmetric focal mammographically identified densities or masses with the calcifications. These calcifications were identified sonographically in 17 (94%) of the 18 patients. In 9 (50%) of 18 patients, the calcifications were associated with sonographically detected malignant masses, and in 3 (17%) of 18 patients the calcifications were within focally dilated ducts. Lesions that had masses or dilated ducts visible on sonography represented 9 (82%) of 11 of the grade 3 neoplasms and only 2 (28%) of 7 of the grade 1 and 2 tumors. This difference was statistically significant (P < .039). CONDUSIONS: Our study showed that ductal carcinoma in situ may appear on sonography as calcifications, masses, or focally dilated ducts. Those lesions that were associated with masses or dilated ducts on sonography were more likely high-grade histologic specimens.