Steroid hormone receptor levels and adjuvant tamoxifen in early breast cancer

Summary Ten year disease-free survival (DFS) results of the Naples randomized trial of adjuvant tamoxifen (TM), 30 mg per day for 2 years versus no therapy according to receptor levels, are reported. From Feb. 1, 1978, through Dec. 31, 1983, 308 pre- and postmenopausal patients with early breast cancer entered the trial. Estrogen receptor (ER) data were available on 239 (77.6%) patients, progesterone receptor (PgR) data on 194 (63.0%), and both receptor data on 181 (58.8%).ER and PgR were assayed by dextran-coated charcoal technique in a single laboratory. The effect of adjuvant TM was significantly related to ER and PgR concentration of the primary tumor. The greatest TM benefit on DFS was evident in patients with the highest levels of receptors. The interaction between the treatment effect and receptor concentration was found whether ER and PgR were considered separately or together. Address for reprints: A. Raffaele Bianco, Division of Medical Oncology, University of Naples Medical School II, via S. Pansini, 5-80131 Naples, Italy     

乳腺癌组织PS2与雌激素和孕激素受体的关系及预后意义

目的 :探讨PS2在乳腺癌中的表达及其与雌激素受体 (ER)、孕激素受体 (PR)关系和预后意义。方法 :采用链亲和素(LSAB)法检测 110例乳腺癌中PS2的表达。结果 :PS2在乳腺癌组织中的阳性表达率为3 9 0 9% ( 4 3 / 110 ) ,其表达与患者年龄无关 ,P >0 0 5 ;与乳腺癌瘤体大小、腋淋巴结转移呈负相关 ,P <0 0 5。在ER阳性组和阴性组 ,PS2阳性率分别为 48 5 3 % ( 3 3 / 68)和2 3 81% ( 10 / 42 ) ,P =0 0 1;在PR阳性组和阴性组 ,PS2阳性率分别为 49 15 % ( 2 9/ 5 9)和2 7 45 % ( 14 / 5 1) ,P =0 0 2 ,PS2表达与ER、PR呈正相关关系。结论 :PS2可作为判断乳腺癌预后及预测术后抗雌激素治疗效果的重要指标     

乳腺癌内科治疗的现状及展望

本文对近年来可手术乳腺癌辅助治疗以及晚期转移性乳腺癌的内科治疗进展进行了回顾,认为规范化、个体化和靶向治疗是乳腺癌的治疗方向.     

乳腺增生病雌、孕激素受体表达及临床意义

目的:探讨乳腺增生病变组织中雌、孕激素受体表达情况,及其临床意义。方法:将乳腺增生病患者手术切除标本,常规福尔马林固定,石蜡包埋,采用免疫组化S-P法,测定ER、PR表达。结果ER和PR总阳性率74.36%(27/39)和87.18%(34/39),ER、PR同时阳性为66.67%(26/39)。本组不典型增生6例ER和PR阳性率均为100%,其表达强度最强,其次为腺病伴腺瘤形成,最弱为小叶增生。结论:乳腺增生病变组织中ER、PR虽然呈高表达,是三苯氧胺(TAM)治疗的适应症,但仍有25.64%的患者ER呈阴性表达,因此,用TAM治疗乳腺增生病前应检测患者的ER和PR,阳性者可用TAM治疗。     

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。     

mTOR表达与雌激素受体阳性乳腺癌辅助内分泌治疗预后的关系

目的探讨雌激素受体（estrogen receptor,ER）阳性乳腺癌中mTOR蛋白的表达与乳腺癌辅助内分泌治疗预后间的关系。方法采用免疫组化方法检测60例ER阳性且接受内分泌辅助治疗患者的原发乳腺癌组织中p-mTOR蛋白的表达情况,观察mTOR蛋白的表达特点.并分析其与临床特征间的关系及对无病生存的影响。结果 mTOR蛋白强阳性表达的乳腺癌细胞具有更多的组织学恶性特征,mTOR阴性组中位无病生存（56.4个月）显著优于阳性组（33.5个月）（P=0.015）,多因素回归分析中mTOR为阳性者发生肿瘤复发转移的风险比例（HR）是mTOR阴性者的3.212倍,其95%CI为1.291～7.992。结论 mTOR表达状态为ER阳性是乳腺癌复发转移的独立预后因素,提示辅助内分泌治疗联合mTOR抑制剂可为ER阳性乳腺癌患者带来生存获益。     

乳腺癌雌、孕激素受体与cerbB-2基因表达及相关分析

目的　观察乳腺癌组织中雌、孕激素受体 (ER、PR)与cerbB 2基因表达及相互关系 ,乳腺癌淋巴结转移 ,病理组织分型、临床分期与癌基因表达的关系。方法　应用免疫组织化学法对 2 10例原发性乳腺癌进行了ER、PR与cerbB 2检测。结果　ER的阳性表达率 5 9 0 5 % ,PR的阳性表达率 4 7 6 2 % ,cerbB 2的阳性表达率 33 81% ,cerbB 2的阳性表达与ER、PR的阳性表达 ,与临床分期、病理组织分型有显著相关性 (P <0 0 1) ,与腋淋巴结转移无相关性 (P >0 0 5 )。结论　ER、PR与cerbB 2在乳腺癌组织中有一定的内在联系 ,其检测结果对于临床治疗 ,辅助判断患者的预后有重要意义。     

Insights on adjuvant endocrine therapy for premenopausal and postmenopausal breast cancer

In 2005, cancer accounted for 13% of all deaths worldwide. Breast cancer is the number-one cause of cancer-related death among women in the USA, affecting 178,480 of them in 2007. As 75% of tumors in postmenopausal women and half in premenopausal women express estrogen receptor, endocrine therapy plays a significant role as a systemic treatment. Robust datasets have demonstrated the impact of tamoxifen in reducing breast cancer recurrence and mortality, regardless of the age of the patient. Other estrogen-deprivation strategies, such as aromatase inhibitors in postmenopausal women and luteinizing hormone-releasing hormone agonists in premenopausal women, are being increasingly used for estrogen receptor-positive breast cancer. This review discusses basic principles regarding endocrine therapy, the need for accurate estrogen receptor testing and the role of menopause in therapy selection.     

乳腺癌内分泌治疗耐药机制的研究进展

内分泌治疗是雌激素受体阳性乳腺癌的重要系统治疗手段,但原发性与继发性耐药是当前内分泌治疗面临的难题。耐药机制主要包括:ER表达缺失或表观遗传修饰;共调因子表达失衡;雌激素受体通路与生长因子受体（growth factor receptor,GFR）通路的交叉效应;特异性miRNA表达改变;乳腺癌上皮间质转化（EMT）等。根据PubMed检索获取相关资料,就近年来雌激素受体阳性乳腺癌内分泌耐药机制及治疗策略研究进展进行综述。     

Tumor nuclear grade,estrogen receptor,and progesterone receptor: Their value alone or in combination as indicators of outcome following adjuvant therapy for breast cancer

Summary Previous reports by us have shown that the outcome of breast cancer patients who have received systemic adjuvant therapy is influenced by tumor estrogen or progesterone receptor (ER or PR) content or by nuclear grade. This publication provides information regarding the relative merit of those three markers. Findings from patients receiving L-PAM plus 5-FU (PF) or PF plus tamoxifen (PFT) indicate that the disease-free survival and survival within each regimen was almost identical when related to either ER, PR, or nuclear grade. Those having tumors with either of the receptors 10 fmol or a good nuclear grade had a better outcome through five postoperative years than did those with ER or PR 0–9 fmol or poor nuclear grade. The magnitude of the difference was similar for each of the three discriminants. Since they were found to be of equal predictive value, one marker might well serve as a substitute for another. Cox regression analyses, however, clearly indicate that ER, PR, and nuclear grade have an independent influence on outcome and that a more accurate assessment of outcome is obtained when more than one marker is employed. Thus, information should be obtained on as many markers as possible. This conclusion is supported by observations presented which indicate that nuclear grade in combination with either or both of the receptors is a better predictor than either marker alone and that, as indicated by life table probability values and relative odds ratios, an increasing number of favorable tumor prognostic indicators results in a better patient outcome particularly in PFT-treated patients. A possible explanation is considered for why the separation of receptor/nuclear grade categories is more orderly and pronounced in PF-treated patients receiving tamoxifen than in those given PF alone. See Appendix I     

哌柏西利联合内分泌治疗对78例激素受体阳性HER-2阴性晚期乳腺癌的疗效观察

  目的  分析哌柏西利联合内分泌治疗的激素受体（hormone receptor,HR）阳性、HER-2阴性晚期乳腺癌临床疗效。  方法  回顾性分析2018年9月至2019年12月78例于天津医科大学肿瘤医院行哌柏西利联合内分泌治疗HR阳性、HER-2阴性晚期乳腺癌患者的临床资料,并对其疗效与安全性进行分析。  结果  78例患者的中位年龄为58岁,中位无进展生存期（progression-free sur?vival,PFS）为7个月,总体客观缓解率（objective response rate,ORR）为36.7%（22/60）,临床获益率（clinical benefit rate,CBR）为73.3%（44/60）。既往使用解救治疗 < 2线和≥2线的ORR分别为71.4%（20/28）和6.3%（2/32）,两者比较差异具有统计学意义（P < 0.001）。采用Cox比例风险回归模型多因素分析显示,转移部位数目、既往解救治疗线数和是否行解救化疗是哌柏西利联合内分泌治疗疗效的独立影响因素。不良事件中的中性粒细胞减少为96.2%（75/78）最常见,3~4级占62.8%（49/78）,14.1%（11/78）患者因3~4级的白细胞减少/中性粒细胞减少而调整用药剂量。最常见的非血液学不良事件是乏力,占23.1%（18/78）。不良事件引起的停药发生率为7.7%（6/78）。  结论  哌柏西利联合内分泌治疗更适合既往解救治疗线数少、未行解救化疗的患者,较后线使用有更好的疗效,且不良事件可控。      

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.     

The optimal duration of adjuvant endocrine therapy in early luminal breast cancer: A concise review

Patients with luminal early breast cancer are at risk of relapse, even after five years of adjuvant endocrine therapy. To date, no biomarkers have been clinically validated to identify those patients at risk of late recurrence, who might benefit from extended adjuvant endocrine therapy. In recent decades, multiple clinical trials have tested the role of extending adjuvant endocrine therapies in patients with luminal disease. However, the data currently at our disposal are conflicting. This article reviews all the major trials concerning extended adjuvant endocrine regimens, and formulates some general conclusions and hypotheses of future study.     

Direct comparisons of adjuvant endocrine therapy, chemotherapy, and chemoendocrine therapy for operable breast cancer patients stratified by estrogen receptor and menopausal status

Based on estrogen receptor (ER) and menopausal status, operable breast cancer (UICC stage I, II, III-a) patients were randomized for adjuvant endocrine therapy, chemotherapy, and chemoendocrine therapy, and the effects on the relapse-free survival (RFS) and overall survival (OS) were compared. Tamoxifen (TAM) 20 mg/day was administered orally for 2 years after mastectomy as an adjuvant endocrine therapy in postmenopausal patients. In premenopausal patients, oophorectomy (OVEX) was performed before TAM administration. In the chemotherapy arm (CHEM), patients were given 0.06 mg/kg of body weight of mitomycin C (MMC) intravenously, followed by an oral administration of cyclophosphamide (CPA) 100 mg/day in an administration of a 3-month period and a 3-month intermission. This 6-month schedule was repeated 4 times in 2 years. The chemoendocrine arm (CHEM + TAM) was composed of TAM with MMC + CPA chemotherapy. The patients were randomized according to ER and menopausal status. ER-positive patients were randomized to three arms: OVEX ± TAM, CHEM, and CHEM + TAM. For ER-negative patients there were two arms: CHEM and CHEM + TAM. 1579 patients entered the trial between September 1978 and December 1991, with median follow-up of 8.2 years. In ER-positive, premenopausal patients, there were no significant differences in RFS or OS among OVEX ± TAM, MMC + CPA, TAM + MMC + CPA arms. On the contrary, in ER-positive, postmenopausal patients, the chemoendocrine therapy showed a significantly higher RFS (p = 0.0400) and OS (p=0.0187) as compared with TAM to chemotherapy alone. There were no significant differences in RFS or OS by addition of TAM on the chemotherapy, in both pre- and post-menopausal ER-negative patients. It was concluded that in ER-positive premenopausal breast cancer, endocrine therapy alone may be equivalent in prolonging RFS and OS to chemotherapy or chemoendocrine therapy, and that ER-positive postmenopausal breast cancer may be better controlled with the combination of TAM and chemotherapy, as compared to TAM or chemotherapy alone. The importance of stratification of operable breast cancer by ER and menopausal status, as well as the direct comparisons of different treatments, were stressed.This revised version was published online in October 2005 with corrections to the Cover Date.     

雌孕激素受体与女性原发乳腺癌术后复发转移关系的临床研究

目的:分析乳腺癌患者雌激素受体(es-trogen receptor,ER)和孕激素受体(progesteronereceptor,PR)状态与术后复发、转移部位的关系。方法:1989~1994年经天津医科大学附属肿瘤医院收治乳腺癌病例且雌、孕激素受体明确、术后随访完整的病例1372例。根据ER和PR状态分组,总结ER和PR状态与首次治疗后发生复发、转移部位的关系。结果:ER /PR 组患者皮肤、骨骼转移率为10·91%,明显高于ER-/PR-组(5·56%),P=0·0053;ER-/PR-组内脏转移率为15·56%,高于ER /PR 组(3·64%),P=0·0000。激素依赖性组5年总生存率和无瘤生存率(82·31%,80·04%)高于非激素依赖性组(77·22%,73·89%),P<0·05。两组10年总生存率、无瘤生存率并无区别。结论:乳腺癌在晚期转移部位与ER、PR受体状态有关,ER /PR 组5年总生存率、无瘤生存率高于ER-/PR-组,进行综合治疗是提高总生存率、无瘤生存率的关键。     

早期乳腺癌辅助内分泌治疗的原则与临床应用策略

辅助内分泌治疗早期乳腺癌大大提高了患者的长期生存率，业已成为激素受体阳性乳腺癌患者最重要的治疗手段。本文结合近年来的文献，对乳腺癌辅助内分泌的原则和策略作一介绍和评述。     

延长辅助内分泌治疗在激素受体阳性早期乳腺癌治疗中的价值

雌激素受体（estrogen receptor,ER）阳性早期乳腺癌的复发风险一直存在。MA.17试验证明,在淋巴结阳性、雌激素受体阳性的乳腺癌患者中,常规应用5年来曲唑治疗后继续应用他莫昔芬治疗,其无病生存期（disease-free survival,DFS）和整体生存期（overall survival,OS）都得到了明显改善。MA.17R试验证明,完成5年芳香化酶抑制剂治疗的患者,继续随机应用来曲唑或安慰剂,来曲唑组的DFS明显改善。在这些研究中,延长内分泌治疗能减少远期复发的绝对益处是适度的,然而其耐受性和依从性的挑战依然存在。对于完成5年常规内分泌治疗的患者,最终是选择他莫昔芬还是来曲唑来延长治疗,主要应该考虑患者的绝经状态、淋巴结情况、耐受性和潜在的利益大小这些因素。     

ER(-)PR(+)乳腺癌辅助内分泌治疗的疗效

背景与目的：孕激素受体（PR）状态是雌激素受体（ER）状态预测乳腺癌辅助内分泌治疗的补充，临床上推荐ER阳性（＋）或PR（＋）患者均可接受内分泌治疗。ER阴性（-）PR（＋）肿瘤应用辅助内分泌治疗的疗效如何还存在争议。本研究将探讨辅助内分泌治疗对ER（＋）PR（＋）与ER（-）PR（＋）乳腺癌的疗效，并研究ER（-）PR（＋）患者的临床病理特性及预后。方法：回顾了1991年1月-2001年12月间的1863位ER／PR资料可用的可手术乳腺癌患者资料，ER、PR均采用免疫组化法检测。中位随访48个月，比较ER（-）PR（＋）组（205例）和ER（＋）PR（＋）组（798例）接受或不接受辅助内分泌治疗（3～5年的他莫昔芬）的无病生存（DFS）和总生存（0s）的差异。结果：ER（-）PR（＋）患者占全部乳腺癌患者的11．0％，中位年龄49岁，肿块中值大小3．0cm，其中未绝经者比例高达63．9％。ER（-）PR（＋）组较ER（＋）PR（＋）组而言，腋淋巴结转移数高、肿块大、分期晚。ER（＋）PR（＋）组和ER（-）PR（＋）组未行内分泌治疗时，组间生存差异无显著性；内分泌治疗后，两组的生存率均有所提高，但ER（＋）PR（＋）组的预后比ER（-）PR（＋）组更好（DFS：P=0．016，OS：P=0．007）。多因素分析显示对ER（-）PR（＋）患者，仅有腋淋巴结状态是独立的预后指标。结论：辅助内分泌治疗对ER（＋）PR（＋）乳腺癌的疗效优于对ER（-）PR（＋）乳腺癌的疗效，ER（-）PR（＋）患者能从内分泌治疗中得到一定收益，但较有限。     

乳腺癌原发灶与复发转移灶间ER、PR、HER-2、COX-2表达差异分析

[目的]回顾性分析乳腺癌原发灶与转移灶中ER、PR、HER-2、COX-2表达的情况及临床意义。[方法]应用免疫组化的方法,检测了50例乳腺癌转移患者的ER、PR、HER-2、COX-2在原发灶与复发转移灶中的表达。[结果]乳腺癌原发灶与复发转移灶中ER阳性表达分别为70%和38%,有显著性差异(P=0.002)。PR、HER-2、COX-2在乳腺癌原发灶与复发转移灶中的表达差异无统计学意义(P>0.05)。原发灶与转移灶中HER-2与COX-2表达呈相关性(P<0.05)。[结论]乳腺癌原发灶和转移灶中ER、PR、HER-2、COX-2表达不一致,需根据转移灶受体的表达情况决定治疗方案。     

Influence of obesity on breast cancer receptor status and prognosis

Pre-existing obesity and postoperative weight gain are related to a poor prognosis in breast cancer regardless of menopausal status. Delayed diagnosis may be one cause, but of more biological significance, especially in younger women, is the association of adiposity with estrogen receptor-negative tumors with a propensity for distant metastasis. After the menopause, the major mechanism for the relationship is the elevated estrogen synthesis by adipose tissue; these hormone-dependent tumors are estrogen receptor-positive. Insulin and some adipokines also stimulate breast cancer growth and metastasis, both directly and most probably by enhanced angiogenesis. Weight control is important, not only to target breast cancer progression, but also to reduce the risk of nonbreast cancer mortality risk associated with excess adiposity.