Progesterone receptor quantification as a strong prognostic determinant in postmenopausal breast cancer women under tamoxifen therapy

There is now an emerging body of evidence that shows there is a relationship between the survival of breast cancer patients and the expression level of steroid receptors. The aim of this study was to determine the relationship existing between estrogen receptors (ER) and progesterone receptors (PR) cytosolic content and the prognosis of postmenopausal breast cancer women under tamoxifen therapy. Two hundred and nineteen postmenopausal patients, without neoadjuvant chemotherapy and treated postoperatively with tamoxifen for at least 2 years, were followed up in our Cancer Center. We used flexible regression modeling and log likelihood methods for determining optimum cut-off values for steroid receptors, which allows the separation of patients into significantly different categories in term of survival. For PR, 3 categories were defined (category 1: PR < 10, category 2: 10 PR < 60 and category 3: PR 60 fmol/mg P). Univariate analysis at 8 years indicated that significant differences in event-free survival (EFS) were found for tumor size (T) (p = 0.005), lymph node status (N) (p = 0.003), histological Scarff, Bloom and Richardson grade (p = 0.003), ER values divided into 5 categories (p = 0.02) and PR values divided into 3 categories (p = 1 · 10^–5). Eight-year EFS rate for the 3 PR categories, adjusted for N, were 39, 66 and 81%, respectively. Multivariate Cox analysis indicated that only T, N and PR values were significant variables for EFS. Patients with PR values 60 present significantly greater EFS rates than patients with PR < 60 (p < 0.001). Our results show that the PR level in ER positive postmenopausal women is a strong prognostic marker in postmenopausal breast cancer women under tamoxifen therapy.     

Estradiol stimulates synthesis of a major intracellular protein in a human breast cancer cell line (MCF-7)

Summary Previous studies have shown that synthesis of a 24,000 molecular weight (24k) protein (7) and the mRNA activity coding for a 24k protein (8) are selectively stimulated by estradiol in MCF-7 human breast cancer cells. Utilizing a double-label electrophoresis technique to measure the relative rates of specific protein synthesis, the present study relates further characterization of this estrogen response. The 24k protein was found to be stimulated by estradiol provided cells were preincubated with antiestrogen. Under these conditions, antiestrogens inhibit cell growth and addition of estradiol reverses growth inhibition (estrogen growth rescue). As a control experiment, specific protein synthesis was measured in another growth rescue model produced by withdrawing serum from the medium to inhibit growth and then stimulating cells by readdition of serum (serum growth rescue). This failed to stimulate synthesis of a 24k protein, implying that the effect observed following estrogen rescue was not a non-specific result of growth stimulation. Increased 24k synthesis was found to be both time and estrogen-dose dependent and required specifically those steroid hormones which interact with the estrogen receptor. Moreover, the dose response curve for 24k stimulation paralleled closely the dose response for estrogen stimulation of nuclear estrogen receptor processing, an event correlated with another estrogenic response in MCF-7 cells, induction of progesterone receptor. These findings suggest that estradiol itself directly stimulates synthesis of the 24k protein through interaction with the estrogen receptor system. Further separation of double-label cytosols by two-dimensional electrophoresis resolved the 24k protein into two isoelectric species with pI's in the range of 6.7–6.9 and 6.4–6.7, the latter being the most abundant or rapidly labeling protein. Based on the percentage of total cytosol incorporation contained in individual two-dimensional gel spots, the major species of 24k represented in the fully stimulated cell (³H-counts) about 1.6% of newly synthesized protein. It also represented about 0.7% of newly synthesized protein in the unstimulated (¹⁴C-counts) cell, which indicates that 24k is synthesized constitutively. Because of its relative abundance, the 24k protein may be a suitable end product for investigating the mechanisms of estrogen action in human breast cancer.Abbreviations used are PgR, progesterone receptor ER estrogen receptor - DHT dihydrotestosterone - Hepes N¹-2-hydroxyethylpiperazine-N¹-ethane sulfonic acid - MEM Eagle's minimum essential medium - TCA trichloroacetic acid - SDS sodium dodecylsulfate; nafoxidine, (1-(2-[p-(3,4-dihydro-6-methoxy-2phenyl-1-naphthyl) Phenoxy]ethyl) pyrrolidine hydrochloride; Upjohn); tamoxifen, (1-p--dimethylaminoethyoxyphenyl-trans-1,2-diphenylbut-1-ene; ICI-46474); CI-628,1-[2-[p[-(p-methoxyphenyl)--nitrostyryl]-phenoxy]ethyl]pyrrolidine monohydrate monocitrate Address for reprints: William L. McGuir, M.D., Department of Medicine, University of Texas Health Science Center 7703 Floyd Curl Drive. San Antonio, TX 78284.     

Steroid hormone receptor activity of primary human breast cancer and pattern of first metastasis

Summary A series of 258 breast cancer patients with known estrogen receptor (ER) status of the primary tumour who subsequently developed metastases were reviewed for site of first metastasis. In 188 cases progesterone receptor (PgR) data were also available.Univariate analysis showed metastatic patterns to differ statistically significantly related to ER status and (less pronounced) PgR status of the primary tumour. Patients with ER-positive tumours had bone metastases three times more often than patients with ER-negative tumours. With respect to PgR-positive and PgR-negative tumours this frequency differed by a factor of two. With regard to visceral metastases ER and PgR status were equally potent prognosticators, patients with receptor negative tumours having a 50% higher frequency of visceral metastasis than patients with receptor positive tumours. Assessment of metastatic patterns in relation to combined receptor status did not substantially enhance the discriminatory value of ER and PgR when assessed separately.Multivariate analysis showed that the observed differences in metastatic patterns were all attributable to differences in the ER status of the primary tumour, and were not influenced by age, menopausal status, axillary lymph node involvement, duration of disease-free interval (DFI), mode of postoperative treatment, or the PgR status of the primary tumour.Including the Departments of Surgery (Th. Wobbes, R.F. v.d. Sluis), Radiotherapy (W.A.J. v. Daal), Pathology (R. Holland), Radiology (J.H.C.L. Hendriks), and Medical Oncology (D. Wagener)     

Steroid receptors in a group of Brazilian breast cancer patients

Two hundred and forty-two primary breast cancers were assayed for estrogen receptors (ER). Of these, 202 were analyzed for progesterone receptors (PR) and 155 for glucocorticoid receptors (GR). ER was positive in 58% of the specimens; PR and GR were positive in 57%. A positive association was found between ER but not PR or GR frequency and age. Frequency of ER, PR, and GR positivity was approximately the same in premenopausal and postmenopausal women but ER content was much higher in postmenopausal women. About 70% of ER+ patients were also PR+ and GR+. Both frequency of PR positivity as well as average concentration, and frequency of GR positivity as well as average concentration were positively correlated with ER.     

Association between estrogen receptors and weight in women with breast cancer

A significant association between body weight and estrogen receptor protein (ERP) was noted in 83 women with primary and metastatic breast cancer. Thirteen of 34 (54%) women with weight >150 lb had low or absent receptor protein (<10 femtomoles/mg of cytoplasmic protein) compared to 15 of 59 (25%) women with weight <150 lb (P <0.025). The observed association was stronger in the group of 62 postmenopausal women (P <0.01). The findings suggest that the endocrine and metabolic milieu in women with increased weight favors autonomous growth of breast cancer, and adjuvant treatment in this group should be planned accordingly.     

血小板活化和内皮细胞损害对恶性肿瘤影响的临床研究

目的 研究血小板活化和内皮细胞损害对恶性肿瘤病情和预后的影响。方法 采用放射免疫法和酶联免疫法测定78例恶性肿瘤和40例正常人血浆血栓烷B2(TXB2)，血小板α—颗粒膜蛋白(GMP—140)，血管性血友病因子(vWF)，环磷酸鸟苷(cGMP)和血清纤维结合蛋白(FN)含量。结果 1)肠癌、肺癌、肝癌组TXB2、GMP—140、vWF和cGMP升高、肠癌、肺癌FN下降。2)肿瘤组cGMF，与TXB2、GMP—40、vWF之间均呈正相关。3)肿瘤组合并感染FN下降；已转移FN下降，其余指标升高，手术后GMP—140、vWF和cGMP，下降，FN升高。结论 恶性肿瘤患者存在血小板活化和内皮细胞损害，二者影响恶性肿瘤的转移和预后。     

Tamoxifen response following no response to orchiectomy in metastatic male breast cancer: a case report

A male patient with advanced breast cancer had no response to orchiectomy but subsequently enjoyed a 17-month partial response to tamoxifen 10 mg B.I.D. His tumor estrogen receptor (ER) protein was 555 fmol protein/ml cytosol. The potential role of ER determinations in the selection of therapy for advanced male breast cancer is discussed.     

The effect of age on estrogen and progesterone receptor in primary breast cancer

We evaluated the estrogen receptors (Er) and progesterone receptors (Pr) in 228 female patients with primary breast cancer by Dextran-Charcol method. Their ages vary from 30 to 91 years. Mean age 60.7 years. (SD: 13.6 years). Er mean was 70.31. (SD:103); there exists a statistically significant correlation between age and Er at p less than .001; older patients have higher Er. Pr mean was 60.73, (SD:128). There is statistically significant correlation between age and Pr at .01 less than p less than .025; older patients have higher Pr. There is also very statistical significant correlation between Er and Pr at p less than 0.1; when Er is high Pr is high.     

Age-dependent changes in breast cancer hormone receptors and oxidant stress markers

Breast cancer incidence increases with age but this relationship has not been fully explored with regard to expression of estrogen receptor (ER) and ER-inducible genes (PR, pS2, Bcl2, cathepsin D), or the age-dependence of oxidant stress markers that also affect ER-inducible gene expression. In this three-part study, we first correlated age at diagnosis with expression of breast cancer markers ER, PR, pS2, Bcl2, and cathepsin D, quantitated by enzyme immunoassays from a European collective of 3000 cryobanked primary breast cancers and 300 adjacent non-malignant breast tissues. Results were then compared with ER and PR data reported to the SEER registry for 83,541 US cancers diagnosed during 1992–1997. Lastly, a homogeneous subset of 70 ER-positive tumors preselected from the European collective was blindly analyzed for age-specific changes in the DNA-binding content of redox-sensitive transcriprtion factors, AP1 and Sp1, and the oxidant stress-activated protein kinase, phosphorylated(P)-Erk5. Increases in breast tumor ER from patients aged <30 to >80 years mirrored 10-fold lower increases in non-malignant breast tissue ER content up to age 60, rising faster thereafter and reaching a near 25-fold differential between malignant and non-malignant breast tissue by age 80. ER-inducible markers PR, pS2, Bcl2, and cathepsin D were overexpressed in tumors relative to non-malignant breast tissue but, unlike ER, did not increase with patient age. While SEER data demonstrated that the increase in US breast cancer incidence rates after age 50 is confined to ER-positive tumors in patients of all ethnic subsets, these patients also showed a striking increase in the proportion of higher-risk ER-positive/PR-negative breast cancers arising after age 50. Mechanistically essential for ER-inducible PR expression, Sp1 DNA-binding function (but not Sp1 content) was lost with age in ER-positive tumors; and this functional defect correlated with increased tumor content of the oxidant stress marker, P-Erk5. Altogether these findings support two hypotheses: (i) dysregulated ER expression underlies the age-specific increase in breast cancer incidence after age 50; and (ii) oxidative stress and loss of Sp1 DNA-binding may contribute to an increasing incidence in higher-risk ER-positive/PR-negative breast cancers with aging.     

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.     

Human breast cancer: survival from first metastasis

Summary Survival from the detection of first metastasis (SAM) was analyzed in a single center series of 258 patients with advanced breast cancer. During the 15 year period covered by this study 230 patients died, 215 of their disease. The overall median SAM was 28 months.Univariate analysis of SAM stratified by first dominant site of metastasis, estrogen receptor status (ER), progesterone receptor status (PgR), tumor size, axillary lymph node status, patient age, menopausal status, and disease-free interval (DFI) showed the first dominant site of metastasis, ER, PgR, and axillary lymph node status to be significantly associated with SAM. Patients with visceral metastasis as first dominant site of metastasis had significantly shorter survival than those with either bone or soft tissue metastasis, median SAM 16 vs. 34 vs. 41 months respectively (P<0.001). SAM also differed according to the steroid hormone receptor status of the primary tumor: median SAM 34 and 33 months for patients with ER-positive or patients with PgR-positive tumors against 14 months for patients with ER-negative or with PgR-negative tumors (P<0.001). Patients with axillary lymph node involvement at primary disease had a shorter SAM than those without, median SAM 24 vs. 35 months (P=0.006). No association between SAM and either tumor size, patient age, menopausal status, or DFI could be observed.Multivariate analysis including first dominant site of metastasis, ER, PgR, and axillary lymph node status showed the first dominant site of metastasis, ER, and axillary lymph node status to be independently associated with SAM.including the Departments of Surgery (Th. Wobbes, R.F. v.d. Sluis), Radiotherapy (W.A.J. v. Daal), Pathology (R. Holland), Radiology (J.H.C.L. Hendriks) and Medical Oncology (D. Wagener)     

Factors influencing axillary lymph node metastasis in invasive breast cancer

Purpose: To explore the relationship between auxiliary lymph node metastasis and clinical features, andto identify the factors that affect metastasis occurrence. Methods: A total of 164 cases of primary breastcancer were selected to investigate features such as age, concomitant chronic disease and pathologic diagnosis.Immunohistochemistry was used to detect the expression of the estrogen receptor (ER) and CerbB-2. Logisticregression was employed to analyze the factors that affect the incidence of lymph node metastases. Results: Theincidence of lymph node metastases was 46.3% among elderly patients with breast cancer. Based on logisticregression, chronic disease, scale of tumor, age, and ER expression affected the occurrence of lymph nodemetastases; the ORs were 3.05, 2.18, 0.34, and 3.83, respectively. Between different pathologic diagnoses andthe risk factors, the OR scores were 12.7 and 8.02, respectively, for aggressive ductal carcinoma and aggressivelobular carcinoma auxiliary lymph node metastases. Conclusion: The incidence of lymph node metastases isaffected by chronic disease, scale of tumor, age, ER expression and pathologic diagnosis.     

Adjuvant tamoxifen in postmenopausal breast cancer: Preliminary results of a randomized trial

Summary Between May 1978 and March 1982, 179 postmenopausal women with operable breast cancer were randomized to receive either adjuvant tamoxifen, 40 mg daily for three years (TAM group), or no further treatment (controls).The difference in five-year survival rates (61% in the control group, 72% in the TAM group) was not statistically significant. However, there was a significant improvement in disease-free survival in the TAM group (61%) relative to the controls (44%) (p = 0.008). In estrogen receptor positive patients, tamoxifen improved both the disease-free rate (47% controls, 80% with tamoxifen) and the survival rate (63% to 83%). Similar results were observed in progesterone receptor positive patients. In patients that were estrogen receptor negative, tamoxifen modified neither the survival rate nor the disease-free interval.     

The Stockholm trial on adjuvant tamoxifen in early breast cancer

Summary The paper presents interim results of an on-going randomized trial of adjuvant tamoxifen (40 mg daily for 2 years) versus no endocrine adjuvant therapy in postmenopausal women with early breast cancer. A total of 1407 patients were included in the study between November 1976 through June 1984. Estrogen receptor (ER) data were available on 1184 patients (84%). The median follow-up was 53 months. Adjuvant tamoxifen increased the recurrence-free interval (P<0.01) but had no significant effect on overall survival. Treatment failures were reduced by 25% (P<0.01) and deaths by 7% (P>0.05). Tamoxifen mainly decreased the frequency of loco-regional recurrence whereas distant metastases were less affected. The treatment effect was independent of tumor stage but was significantly related to the estrogen receptor (ER) content of the primary tumor. Tamoxifen appeared ineffective among ER negative patients, and the greatest effect was seen among those with high levels of ER. The results indicate that the main mechanism of action of adjuvant tamoxifen is similar to that suggested in advanced disease, i.e. an interaction with the estrogen receptor.     

Estrogen alpha and progesterone receptor expression in the normal mammary epithelium in relation to breast cancer risk

Estrogens play a central role in the etiology of breast cancer, and results from observational studies and randomized trials have also implicated progestins. The effects of these hormones in the mammary tissue are exerted through binding with specific receptor proteins in the cell nucleus. It has been proposed that higher estrogen receptor alpha expression in the normal breast epithelium may increase breast cancer risk. In a study in Greece, we determined estrogen alpha and progesterone receptor expression in normal mammary tissue adjacent to the pathological tissue from 267 women with breast cancer and 299 women with benign breast disease. Mouse monoclonal antibodies specific for estrogen receptor alpha and progesterone receptor were applied. The H-index, which incorporates frequency and intensity of staining of the cells, and can range from 0 to 300, was deemed positive when it exceeded 9. Among premenopausal women, there was no evidence for an association with breast cancer risk for expression of either type of receptors. Among postmenopausal women, breast cancer risk was inversely associated with expression of both estrogen alpha (odds ratio (OR)=0.39; p=0.015) and progesterone (OR=0.40; p=0.008) receptors. The hypothesis that overexpression of estrogen receptors alpha or progesterone receptors in normal breast epithelium may increase the risk of breast cancer was not supported by our data. Instead, we found evidence that overexpression of these receptors may be associated with reduced risk for breast cancer in line with the well-known association of expression of these receptors in the malignant tissue and better breast cancer prognosis.     

成纤维细胞活化蛋白在乳腺癌组织的表达特征及临床意义

目的:观察基质成纤维细胞活化蛋白(fibroblast activation protein,FAP)在乳腺癌组织的分布特点、表达特征及其变化规律,探讨FAP在乳腺癌发生发展过程中的作用。方法:对术后病理证实为乳腺癌组织的82例病例进行回顾性分析,应用免疫组织化学法检测FAP的表达,探讨FAP在各临床病理参数组的表达分布特征。结果:免疫组化分析显示乳腺癌肿瘤细胞无FAP表达,FAP主要表达于肿瘤细胞周围基质成纤维细胞内。FAP表达与乳腺癌临床分期呈显著正相关(r=0.922,P=0.000)。非浸润性乳腺癌与浸润性乳腺癌FAP表达具有显著统计学差异(t=17.085P=0.000)。有淋巴结转移组较无淋巴结转移组FAP表达量高(t=11.003,P<0.01)。结论:FAP特异性表达于乳腺癌瘤周基质成纤维细胞,FAP在女性乳腺癌发生、发展、侵袭转移方面起到了重要的作用。     

成纤维细胞活化蛋白在乳腺癌组织的表达特征及临床意义

目的：观察基质成纤维细胞活化蛋白（fibroblast activation protein,FAP）在乳腺癌组织的分布特点、表达特征及其变化规律,探讨FAP在乳腺癌发生发展过程中的作用。方法：对术后病理证实为乳腺癌组织的82例病例进行回顾性分析,应用免疫组织化学法检测FAP的表达,探讨FAP在各临床病理参数组的表达分布特征。结果：免疫组化分析显示乳腺癌肿瘤细胞无FAP表达,FAP主要表达于肿瘤细胞周围基质成纤维细胞内。FAP表达与乳腺癌临床分期呈显著正相关（r=0．922,P=0．000）。非浸润性乳腺癌与浸润性乳腺癌FAP表达具有显著统计学差异（t=17．085P=0．000）。有淋巴结转移组较无淋巴结转移组FAP表达量高（t=11．003,P〈0．01）。结论：FAP特异性表达于乳腺癌瘤周基质成纤维细胞,FAP在女性乳腺癌发生、发展、侵袭转移方面起到了重要的作用。     

ER、PR在乳腺癌中的表达及临床意义

目的：检测并分析ER和PR在乳腺癌中的表达,探讨ER、PR在内分泌治疗中的作用。方法：选取137例有完整临床和病理资料的乳腺癌患者,采用免疫组化法检测其乳腺癌组织中的ER、PR表达。结果：ER,PR阳性率分别为55．47％,51．09％,PR（＋）患者,其ER大多数表达阳性;绝经后ER阳性患者较绝经前患者多;ER、PR阳性率表达与淋巴结是否转移无明显相关性。结论：ER和PR在乳腺癌组织中的存在可以预测肿瘤对激素治疗是否敏感,为临床指导辅助内分泌治疗提供有力的证据。