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     

Combining trastuzumab (Herceptin) with hormonal therapy in breast cancer: what can be expected and why?

Hormonal therapy and the humanised anti-HER2 monoclonal antibody trastuzumab (Herceptin) represent one of the oldest and one of the newest treatment modalities for breast cancer, respectively. Recent data have suggested that HER2 overexpression is associated with resistance to hormonal therapy and there is considerable preclinical evidence to support the existence of interaction or 'cross talk' between HER2 and estrogen-receptor (ER) signalling pathways in breast cancer. Preclinical data also demonstrate that adding trastuzumab to hormonal therapy results in greater antitumour activity than either agent alone. The existence of an inverse relationship between ER expression and HER2 overexpression has also been well established clinically. Thus, a range of clinical trials are now ongoing to determine whether the addition of trastuzumab to hormonal therapy will provide breast cancer patients with benefits in clinical practice. This review describes the rationale for these trials and discusses the potential of therapeutic regimens combining trastuzumab with hormonal therapy.     

The estrogen receptor from a tamoxifen stimulated MCF-7 tumor variant contains a point mutation in the ligand binding domain

The nonsteroidal antiestrogen tamoxifen (TAM) is the most commonly used endocrine treatment for all stages of breast cancer in both pre- and postmenopausal women. However, the development of resistance to the drug is common, as most patients treated with TAM eventually experience a recurrence of tumor growth. One of the potential mechanisms of treatment failure is the acquisition by the tumor of the ability to respond to TAM as a stimulatory rather than inhibitory ligand. We (Gottardis and Jordan, Cancer Res 48: 5183-5187, 1988; Wolfet al., J Natl Cancer Inst 85: 806-812, 1993) and others (Osborneet al., Eur J Cancer Clin Oncol 23: 1189-1196, 1987; Osborneet al., J Natl Cancer Inst 83: 1477-1482, 1991) have extensively described the reproducible development of TAM stimulated growth in a laboratory model system using MCF-7 human breast cancer cells grown as solid tumors in athymic mice. In this paper we report on the isolation of an estrogen receptor (ER) from a TAM stimulated tumor (MCF-7/MT2) which contains a point mutation that causes a tyrosine for aspartate substitution at amino acid 351 in the ligand binding domain. The mutant appears to the major form of ER expressed by this tumor. We also report that only wild type ER was detected in three other TAM stimulated MCF-7 tumor variants, suggesting that multiple mechanisms are possible for the development of TAM stimulated growth. The implications of these findings are discussed.     

Adjuvant tamoxifen for pre- and postmenopausal women with estrogen receptor positive,node positive breast cancer: A randomized study

Summary 370 patients with operable, axillary node positive breast cancer, were randomized to receive tamoxifen (TAM) 20 mg/day for 2 years or no adjuvant hormone therapy. All patients had estrogen receptor (ER) positive (ER > 10 pmol/g) primary tumours. 350 patients, 93 younger than 50 years of age and 257 patients 50 years or older, were evaluable for the study. After a median follow up of 76 months, significantly (p = 0.0001) fewer loco-regional, but not distant (systemic), relapses have been recorded in the TAM group. Overall survival was also improved, but even though the study was designed to give maximum benefit from TAM statistically significant effect of TAM seemed to be limited to patients 50 years of age and older.     

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.     

乳腺癌内分泌治疗耐药相关机制的研究进展

内分泌治疗作为雌激素受体（estrogen receptor,ER）阳性乳腺癌的主要治疗方案被广泛应用。他莫西芬（tamoxifen,Tam）是乳腺癌内分泌治疗最常用的药物,它通过与雌激素竞争性结合ERα来降低雌激素的生物学活性,抑制细胞的增殖,从而治疗乳腺癌。然而,肿瘤细胞所表现出的原发性或获得性的他莫西芬耐药使得其临床应用受到了限制,寻找克服他莫西芬耐药的治疗策略已经刻不容缓。目前为止,他莫西芬耐药的相关机制已部分明确,但仍需进一步研究。有证据表明ERα、生长因子受体信号通路及microRNA的表达异常等多种机制均与他莫西芬耐药有关。本文对他莫西芬耐药的相关机制进行了具体分析,以期为ER阳性乳腺癌的治疗提供新思路。     

Changes in hormone receptors and proliferation markers in tamoxifen treated breast cancer patients and the relationship with response

Aim: To determine the effects of tamoxifen on the levels of hormone receptors and proliferation markers in the early phase of treatment and the relationship of the changes with tumor response in patients with primary breast cancer. Methods: Twenty-one women with primary, operable breast carcinomas were treated with tamoxifen 20 mg daily. Fine needle aspiration (FNA) was used to obtain samples prior to the start and at 14 days and 8-weeks post-treatment. From these samples estrogen receptor (ER), progesterone receptor (PgR), and Ki67 levels were determined using immunocytochemistry and ploidy and S-phase fraction (SPF) using flow cytometry. Tumor response was measured clinically according to UICC criteria. Results: There were 12 responders (2 CR, 10 PR) and 9 non-responders (2 NC, 7 PD). Responders were more likely to be ER + (p=0.002), PgR + (p=0.006), and low SPF (p=0.06). At 14 days post-tamoxifen, the median decrease in Ki67 (% cells staining) for responders was – 4.8 and for non-responders – 0.15 (p=0.005). This decrease was seen predominantly in ER + tumours. The difference in SPF was not significant. A decrease in ER was seen in 3/15 patients all of whom were responders. A rise in PgR was seen in 7/17 patients and all but one were responders. Similar changes for ER and PgR were seen at 8-weeks post-tamoxifen, although the reductions in Ki67 and SPF at that time point were not related to response. Conclusion: We have observed a decrease in Ki67 and ER and a rise in PgR after 14 days of treatment with tamoxifen that was related to subsequent response. This is the first study in which an early decrease in a proliferation marker has been shown to relate to subsequent clinical response.     

AIB1、HER - 2 表达与乳腺癌他莫西芬耐药的关系

目的：探讨HER-2和AIB1在ER阳性乳腺癌他莫西芬耐药中的作用.方法：选择复发转移后接受他莫西芬治疗的女性乳腺癌患者70例,采用免疫组化SP法检测的乳腺癌组织中HER-2和AIB1的表达,分析二者与他莫西芬疗效的关系.结果：他莫西芬治疗总有效率42.9%.HER-2（＋）组治疗有效率28.6%,HER-2（-）组治疗有效率52.4%,有统计学差异（P=0.041）.AIB1（＋）组治疗有效率28.6%,AIB1（-）组治疗有效率64.3%,有统计学差异（P=0.003）.他莫西芬在HER-2（＋）AIB1（＋）、HER-2（-）AIB1（＋）、HER-2（＋）AIB1（-）、HER-2（-）AIB1（-）四组中的治疗有效率分别为27.3%、30.0%、33.3%、72.7%,有显著差异（P=0.008）.结论：HER-2和AIB1的表达均与乳腺癌他莫西芬治疗疗效有关,二者共表达提示他莫西芬耐药.     

Randomized clinical trial of tamoxifen plus sequential CMF chemotherapy versus tamoxifen alone in postmenopausal women with advanced breast cancer

Summary Eighty-eight postmenopausal women with metastatic breast cancer, in whom estrogen receptors (ER) were positive or unknown, were treated on a controlled trial to determine the effectiveness of tamoxifen and to assess the therapeutic advantage of sequentially adding low-dose cyclophosphamide-methotrexate-5-fluorouracil (CMF) chemotherapy in tamoxifen responders. Patients with known ER negative status were not studied. After the initial 12-week treatment with tamoxifen alone, 60% of ER positive patients achieved complete or partial response as did 35% in whom ER were unknown. Response status further improved in 18% randomized to continue tamoxifen alone vs 31% in whom CMF was added to tamoxifen. There were no statistically significant differences in time to the development of progressive disease or survival between the ER positive and ER unknown patients or between the tamoxifen and tamoxifen plus CMF groups. We conclude that inability to determine ER status should not prejudice against the use of tamoxifen in postmenopausal patients with advanced breast cancer. No benefit has been demonstrated from the addition of CMF chemotherapy in tamoxifen responders. Address for reprints: J.H. Glick, M.D., Hospital of the University of Pennsylvania, 3400 Spruce St., Philadelphia, PA 19104.     

Drug resistance to tamoxifen during breast cancer therapy

Summary Breast cancer is the most common malignancy occurring in Western women, and is one of the leading causes of cancer mortality. The nonsteroidal antiestrogen tamoxifen has been shown to be an effective treatment for pre and postmenopausal women with all stages of the disease. Tamoxifen provides effective palliation when used to treat patients with advanced disease, and adjuvant tamoxifen therapy produces significant increases in both disease-free and overall survival (Early Breast Cancer Trialists Collaborative Group. Lancet 339:1-15, 71-85, 1992). Data from the laboratory have shown that the primary action of tamoxifen is tumoristatic rather than tumoricidal, and long-term therapy is therefore recommended. Unfortunately, many patients experience disease progression while taking tamoxifen. Some tamoxifen resistant tumors may remain sensitive to alternative endocrine therapies, while others may become refractory to any hormonal manipulation. Many models have been developedin vitro andin vivo to study the progression of breast cancer growth from tamoxifen sensitive to tamoxifen resistant. We and others have used long-term estrogen deprivation and long-term tamoxifen exposure to develop cell lines and tumors capable of growth in the presence of clinically relevant tamoxifen concentrations. Recently our laboratory has also shown that mutations in the estrogen receptor can cause an antiestrogen-occupied receptor to behave as though it were occupied by an estrogen. Breast cancer is a highly heterogeneous disease and it is likely that the mechanisms which cause tamoxifen resistant growth are equally heterogeneous. Several of the models from our laboratory and others which may contribute to an understanding of this complex phenomenon are discussed here.     

Late risk of relapse and mortality among postmenopausal women with estrogen responsive early breast cancer after 5 years of tamoxifen.

BACKGROUND: Letrozole after 5 years of adjuvant tamoxifen results in a significant reduction in risk of recurrence from estrogen receptor (ER) positive breast cancer. An individualized estimate of the risk of relapse and death after 5 years of tamoxifen could improve decisions regarding extended hormonal therapy. METHODS: The British Columbia Breast Cancer Outcomes database was used to identify women aged 45 years or older at the time of diagnosis with early-stage (I-IIIA) breast cancer who received tamoxifen and were disease free 5 years after diagnosis. Ten-year breast cancer event rates and mortality were calculated as well as annualized hazard rates of recurrence. RESULTS: A total of 1086 women were identified with a median age of 64 years and follow-up of 10.5 years. The relative risk (RR) of death was 3.1 (P=0.003) and for recurrence was 1.7 (P=0.037) for N1 (one to three positive nodes) versus N0 (zero nodes positive) disease. N2 (four to nine nodes positive) had a RR of 5.8 (P<0.001) for death and 3.0 (P=0.002) for recurrence. Low tumor grade and high ER level subgroups had a more favorable prognosis. Annual breast cancer risk between years 6 and 10 was, respectively, 2.2%, 3.5% and 7.6% for N0, N1 and N2 disease and 2.6% and 4.5% for T1 and T2 breast cancer. CONCLUSION: T and N stages predicted late relapse and death from breast cancer in a population-based cohort of postmenopausal women. Risk estimates reported herein may be used to optimize decision making regarding adjuvant therapy after 5 years of tamoxifen.     

三苯氧胺与来曲唑治疗ER阳性乳腺癌的临床疗效及对血清雌二醇水平和远期预后的影响

目的探讨三苯氧胺与来曲唑治疗雌激素受体(ER)阳性乳腺癌的临床疗效及对血清雌二醇(E2)水平和远期预后的影响。方法采用简单随机抽样法将110例ER阳性乳腺癌患者分为对照组(n=53)和研究组(n=57)。两组患者均接受长春瑞滨联合顺铂治疗,对照组患者在此基础上接受三苯氧胺治疗,研究组患者在此基础上接受来曲唑治疗,随访3年。比较两组患者的临床疗效、血清肿瘤标志物和E2水平、子宫内膜情况、不良反应发生率及生存情况。结果研究组患者的疾病控制率为92.98%,高于对照组的79.25%,差异有统计学意义(P<0.05)。治疗前,两组患者的血清糖类抗原153(CA153)、癌胚抗原(CEA)及E2水平比较,差异均无统计学意义(P>0.05)。治疗后3个月,两组患者的血清CEA和CA153水平均较本组治疗前降低,且研究组患者的血清CEA和CA153水平均低于对照组,差异均有统计学意义(P<0.05)。治疗后3、6、12个月,研究组患者的血清E2水平均低于治疗前,对照组患者的血清E2水平均高于治疗前,差异均有统计学意义(P<0.05)。病理结果提示,治疗后对照组中子宫内膜息肉2例,内膜不典型增生1例。两组患者恶心呕吐、便秘、肝肾功能不全、血小板减少、粒细胞减少及白细胞降低的发生率比较,差异均无统计学意义(P> 0.05)。研究组患者的3年生存情况优于对照组(P<0.05)。结论来曲唑治疗ER阳性乳腺癌的临床疗效优于三苯氧胺,且可降低血清肿瘤标志物和E2水平,改善远期预后。     

Cyclical use of tamoxifen and high-dose medroxyprogesterone acetate in advanced estrogen receptor positive breast cancer

Summary One-hundred and seventy patients with estrogen receptor positive (10 pmol/g protein) advanced breast cancer have been treated in a prospective randomized study either with continuous tamoxifen 30 mg × 1 daily (TAM), or with TAM 30 mg × 1 daily for 8 weeks alternating with medroxyprogesterone acetate 500 mg × 2 daily for 8 weeks (TAM/HD-MPA). The response rate was 62% in the group treated with cyclic TAM/HD-MPA versus 41% in the TAM alone group (p = 0.02). There was no significant difference in duration of remissions or survival.     

Gynaecologic effects of tamoxifen

Tamoxifen, an estrogen antagonist, is widely used as adjuvant therapy in patients with breast cancer. Its efficacy in increasing survival and reducing recurrence rates has been demonstrated in several European and American studies. However, its effects appear to be tissue specific. Tamoxifen exerts an estrogen effect (agonist) on the endometrium, myometrium and vagina. An increase in uterine cancer has been confirmed in several placebo-controlled clinical trials. Due to the widespread use of this drug, it is timely to review the gynecologic effects of tamoxifen.     

Antiestrogen resistance in ER positive breast cancer cells

Summary Acquisition of the antiestrogen resistance by breast cancer cellsin vivo may result from a variety of mechanisms. The main pathway appears to involve loss of estrogen receptor (ER) expression or selection for ER negative cells among heterogenous population of tumor cells. However, clinical data suggest that, in about 30% of the cases, antiestrogen resistance arises even in the presence of estrogen receptors. Postulated mechanisms leading to the latter phenotype include selection for variant receptor forms during treatment, development of novel metabolic pathways for the drug, loss of nuclear co-factors, or activation of signal transduction pathway that cross activate ER signals. We have used anin vitro experimental system utilizing LY-2 cell line, an ER positive and antiestrogen resistant MCF-7 cell variant, to study the mechanism of antiestrogen resistance in the presence of functional ER. Result from a complementation experiment suggests that LY-2 phenotype is a recessive trait. Cloning of the genetic defect in the LY-2 cells would provide further insight for the mechanism of antiestrogen resistance in ER positive breast cancer cells.     

乳腺癌患者应用三苯氧胺导致的妇科并发症及其监测

三苯氧胺具有抗雌激素和雌激素的双重特性,长期持续使用可导致子宫内膜发生多种病理改变。临床应予以重视,并加以监测。本文就妇科并发症的发生和临床监测方面做一综述,以早发现、并减少并发症的发生。     

Trastuzumab plus paclitaxel or docetaxel in HER-2-negative/HER-2 ECD-positive anthracycline- and taxane-refractory advanced breast cancer

Trastuzumab is considered effective against human epidermal growth factor receptor (HER)-2-positive breast cancer as assessed by immunohistochemistry (IHC) and fluorescence or chromogenic in situ hybridization (FISH/CISH) on biopsy material. Trastuzumab is now approved in both the adjuvant and metastatic settings for this patient population. Because HER-2 extracellular domain (ECD) levels have been correlated with disease progression in the metastatic setting, we considered trastuzumab salvage therapy plus a taxane in heavily pretreated trastuzumab-naive relapsed breast cancer patients with high serum levels of HER-2 ECD (> or =15 ng/ml). All patients had previously failed at least two lines of anthracycline- and taxane-based regimens and were HER-2 negative by IHC and FISH/CISH prior to a centralized reanalysis, and were serum positive for HER-2 ECD (> or =15 ng/ml) at baseline. Regular serum accounts of HER-2 ECD were recorded and compared with response and survival outcomes. Twenty-two patients were finally eligible for salvage therapy. Minor responses were observed in five (23%) and stable disease (SD) was observed in 11 patients, leading to a clinical benefit rate of 73% (16 of 22 patients). The median time to progression and overall survival time were 5 (6.5 months in minor responders and SD) and 12 months, respectively; 11 and eight patients remained progression free for >6 and >12 months, respectively. Eleven and seven patients were alive at 12 and 15 months, respectively, after treatment start. Furthermore, in total, 13 (59.1%) patients obtained a biochemical response. In our study, patients with conventionally HER-2-negative disease but with expression of HER-2 ECD above the normal limit (> or =15 ng/ml) displayed a rapid response, both biochemically and clinically, to the trastuzumab-taxane combination. This is the first study assessing anti-HER-2-based treatment in HER-2-negative advanced breast cancer according to HER-2 ECD positivity; if our results are confirmed, additional patients with "hidden" HER-2-positive breast cancer might benefit from anti-HER-2 treatment.     

Trastuzumab beyond progression in HER2-positive advanced breast cancer: the Royal Marsden experience

Background:

Recent UK clinical guidance advises against continuing trastuzumab (T) beyond disease progression (PD) in the absence of brain metastases in patients with HER-2 positive (+ve) advanced breast cancer .We have retrospectively evaluated the outcome of patients with HER-2+ve locally advanced (LA) or metastatic breast cancer (MBC) who continued T beyond PD, treated in our unit.

Methods:

All HER-2+ve patients on our prospectively maintained database with LA or MBC who received T beyond PD after adjuvant or one line of T for advanced disease were assessed for response and outcome. From the timepoint of T continuation beyond PD, we calculated the overall disease control rate, time to progression (TTP), and overall survival (OS).

Results:

One hundred and fourteen patients with HER-2+ve LA or MBC treated with T beyond PD were identified. The main site of disease was visceral_in 84 (74%) patients. Seventy-six (66%) had one line of chemotherapy before continuation of T beyond PD and 21 (19%) had two or more. Post-progression, 66 (58%) received T combined with chemotherapy. Of the 93 (82%) patients with documented clinical or radiological response evaluation, 67 (59%) were considered as having stable disease or better. The median TTP was 24 weeks (95% CI: 21–28) and the median OS was 19 months (95% CI: 12–24).

Conclusion:

Our results from an unselected group of patients provide additional evidence that continuation of T beyond PD is of clinical benefit.     

Incidence and risk factors for breast cancer subtypes in three distinct South-East Asian ethnic groups: Chinese,Malay and natives of Sarawak,Malaysia

We determined the incidences of the estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) subtypes among breast cancer cases in Sarawak, Malaysia and their correlation with various risk factors in the three ethnic groups: Chinese, Malay and native. Subtype status was ascertained for 1,034 cases of female breast cancer (93% of all cases diagnosed since 2003), and the age-standardized incidence rates (ASRs) of each subtype were inferred. Case–case comparisons across subtypes were performed for reproductive risk factors. We found 48% luminal A (ER+/PR+/HER2−), 29% triple-negative (ER−/PR−/HER2−), 12% triple-positive (ER+/PR+/HER2+) and 11% HER2-overexpressing (ER−/PR−/HER2+) subtypes, with ASRs of 10.6, 6.0, 2.8 and 2.8 per 100,000, respectively. The proportions of subtypes and ASRs differed significantly by ethnic groups: HER2-positive cases were more frequent in Malays (29%; 95% CI [23;35]) than Chinese (22%; [19;26] and natives (21%; [16;26]); triple-negative cases were less frequent among Chinese (23%; [20;27]) than Malays (33%; [27;39]) and natives (37%; [31;43]). The results of the case–case comparison were in accordance with those observed in western case series. Some uncommon associations, such as between triple-negative subtype and older age at menopause (OR, 1.59; p < 0.05), were found. The triple-negative and HER2+ subtypes predominate in our region, with significant differences among ethnic groups. Our results support the idea that the risk factors for different subtypes vary markedly. Westernized populations are more likely to have factors that increase the risk for the luminal A type, while risk factors for the triple-negative type are more frequent in local populations.     

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.