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PubMed2005

Combined targeting of the estrogen receptor and the epidermal growth factor receptor in non-small cell lung cancer shows enhanced antiproliferative effects.

Identifying new effective therapeutic treatments for lung cancer is critical to improving overall patient survival. We have targeted both the estrogen receptor (ER) and the epidermal growth factor receptor (EGFR) pathways using an ER antagonist, fulvestrant ("Faslodex"), and the selective EGFR tyrosine kinase inhibitor, gefitinib ("Iressa"), in non-small cell lung cancer (NSCLC) cells. Rapid activation of phospho-EGFR and phospho-p44/p42 mitogen-activated protein kinase by estrogen was observed, indicating nonnuclear ER transactivation of EGFR. Additionally, EGFR protein expression was down-regulated in response to estrogen and up-regulated in response to fulvestrant in vitro, suggesting that the EGFR pathway is activated when estrogen is depleted in NSCLC cells. Cell growth and apoptosis were examined in several NSCLC lines that express varying amounts of ERbeta, EGFR, and Neu but no full-length ERalpha. One cell line contained an EGFR mutation. Cells were exposed to 10 nmol/L estrogen and 10 ng/mL EGF and either 1 mumol/L fulvestrant or 1 mumol/L gefitinib alone or in combination. In all cell lines, the drug combination decreased cell proliferation up to 90% and increased apoptosis 2-fold. The relative responses to gefitinib and fulvestrant were similar regardless of ER and EGFR expression and mutation status. In an in vivo lung tumor xenograft model, the drug combination decreased tumor volume in severe combined immunodeficient mice by approximately 60% compared with 49% and 32% for gefitinib and fulvestrant treatment alone, respectively. Antitumor effects of the combination therapy were accompanied by biochemical and histologic evidence of increased apoptosis, decreased phospho-p44/p42 mitogen-activated protein kinase expression, and increased Ki-67 expression compared with individual treatment. These studies provide evidence of a functional interaction between the ER and the EGFR pathways in NSCLC.

Animals↗

PubMed2006

Estrogens, selective estrogen receptor modulators, and a selective estrogen receptor down-regulator inhibit endothelial production of tissue factor pathway inhibitor 1.

BACKGROUND: Hormone therapy, oral contraceptives, and tamoxifen increase the risk of thrombotic disease. These compounds also reduce plasma content of tissue factor pathway inhibitor-1 (TFPI), which is the physiological inhibitor of the tissue factor pathway of coagulation. The current aim was to study if estrogens and estrogen receptor (ER) modulators may inhibit TFPI production in cultured endothelial cells and, if so, identify possible mechanisms involved. METHODS: Human endothelial cell cultures were treated with 17beta-estradiol (E2), 17alpha-ethinylestradiol (EE2), tamoxifen, raloxifene, or fulvestrant. Protein levels of TFPI in cell media and cell lysates were measured by an enzyme-linked immunosorbent assay, and TFPI mRNA levels were assessed by quantitative PCR. Expression of ERalpha was analysed by immunostaining. RESULTS: All compounds (each in a concentration of 10 nM) reduced TFPI in cell medium, by 34% (E2), 21% (EE2), 16% (tamoxifen), and 28% (raloxifene), respectively, with identical inhibitory effects on cellular TFPI levels. Expression of TFPI mRNA was principally unchanged. Treatment with fulvestrant, which was also associated with down-regulation of secreted TFPI (9% with 10 nM and 26% with 1000 nM), abolished the TFPI-inhibiting effect of raloxifene, but not of the other compounds. Notably, the combination of 1000 nM fulvestrant and 10 nM raloxifene increased TFPI secretion, and, conversely, 10 nM of either tamoxifen or raloxifene seemed to partly (tamoxifen) or fully (raloxifene) counteract the inhibitory effect of 1000 nM fulvestrant. The cells did not express the regular nuclear 66 kDa ERalpha, but instead a 45 kDa ERalpha, which was not regulated by estrogens or ER modulators. CONCLUSION: E2, EE2, tamoxifen, raloxifene, and fulvestrant inhibited endothelial production of TFPI by a mechanism apparently independent of TFPI transcription.

Cells, Cultured↗

PubMed2003

Oestrogen receptor-mediated modulation of the EGFR/MAPK pathway in tamoxifen-resistant MCF-7 cells.

Oestrogen receptor (ER) levels are usually maintained on acquisition of tamoxifen resistance in the clinic, however, tumour re-growth is associated with increased expression of epidermal growth factor receptor (EGFR) and activation of the mitogen activated protein kinase (MAPK) pathway. In the present study we have used the ER down-regulator fulvestrant ('Faslodex') to investigate the influence of the ER on growth of a tamoxifen-resistant (TAM-R) human breast cancer cell line. Expression levels of ER mRNA and protein were equivalent in parental wild-type MCF-7 (WT) and TAM-R cells. Fulvestrant eliminated ER protein expression and inhibited proliferation in both cell lines. The growth inhibitory effects of fulvestrant were associated with a decrease in basal EGFR, c-erbB2 and ERK1/2 activity in TAM-R but not WT cells. ER functionality as determined by oestrogen response element (ERE)-luciferase reporter activity and expression of PgR, pS2 and transforming growth factor alpha (TGFalpha) was significantly reduced in TAM-R compared to WT cells and was further decreased by fulvestrant treatment in both cell lines. Epidermal growth factor (EGF) and TGFalpha significantly increased EGFR/MAPK pathway activity in both cell lines. Ligand-induced EGFR/MAPK activation promoted TAM-R cell growth in both the absence and presence of fulvestrant, whereas no proliferative activity was observed under the same conditions in WT cells. These results suggest that the ER modulates EGFR/MAPK signalling efficiency in TAM-R cells possibly through the regulation of TGFalpha availability. This effect may be overcome by the action of exogenous EGFR ligands, which strengthen EGFR/MAPK signalling activity to generate endocrine-insensitive cell growth.

Antineoplastic Agents, Hormonal↗

PubMed2001

Preliminary experience with pure antiestrogens.

Endocrine therapy plays an important role in the management of all stages of breast cancer, and the development of effective endocrine therapies has focused on modifying the response of hormone-sensitive tumors to estrogen. The most widely used agents are the nonsteroidal antiestrogens or selective estrogen receptor (ER) modulators, the class to which tamoxifen, the standard in terms of antiestrogen therapy, belongs. Tamoxifen is effective in both adjuvant and first-line settings and is now used as prophylactic therapy in high-risk individuals. However, the partial agonist activity of tamoxifen on the uterus, coupled with "tumor flare" and the development of tamoxifen resistance, has limited its therapeutic utility. Attempts to eliminate the partial agonist activity of tamoxifen and increase its potency have led to the development of fulvestrant (Faslodex), the first in a new class of pure antiestrogens, the ER down-regulators. Fulvestrant has a high affinity for the ER compared with tamoxifen but has none of the agonist activities of tamoxifen. This new agent is showing promising clinical activity in the treatment of advanced breast cancer after tamoxifen therapy. Fulvestrant's lack of ER agonist activity may provide a longer duration of response compared with tamoxifen, as it did in a preclinical setting. Fulvestrant has demonstrated that it is at least as effective as the third-generation aromatase inhibitor anastrozole in patients whose disease has relapsed or recurred on prior endocrine therapy and is currently being evaluated in Phase III trials versus tamoxifen for the first-line therapy of advanced breast cancer. Future clinical studies will evaluate fulvestrant in adjuvant and neoadjuvant settings, together with its optimal sequencing in relation to tamoxifen and other endocrine therapies.

Animals↗

PubMed2001

Pure antiestrogens and breast cancer.

Tamoxifen, which is the most commonly used drug for treatment of breast cancer, has both estrogen agonist and antagonist actions. Pure antiestrogens are devoid of any estrogen agonist effects. ICI 182,780 (fulvestrant) (Faslodex) and ICI 164,384 are competitive inhibitors of estrogen by binding to the estrogen receptor (ER). Preclinical and clinical studies show that fulvestrant and ICI 164,384 are more potent than tamoxifen in inhibiting the growth of breast cancer cells. They are devoid of any estrogen-agonist action on the uterus and vagina but lack the beneficial effects of tamoxifen on the bone and serum lipid profile. Fulvestrant is the first pure antiestrogen to complete phase III clinical trials. Such studies have shown that fulvestrant is at least as good as anastrozole in the treatment of post-menopausal women with advanced breast cancer who had relapsed or progressed on prior endocrine therapy. The drug was well tolerated and only minor side-effects were reported. Its potential role in the adjuvant setting will be determined by its adverse effects on bone mass and serum lipids. EM-800 and EM-652 are the most potent pure antiestrogens and EM-652 has the highest affinity of all antiestrogens to ER. They have no stimulatory effects on the uterus or vagina. It seems reasonable to expect that pure antiestrogens will be good alternatives to tamoxifen and aromatase inhibitors in the treatment of breast cancer.

Antineoplastic Agents, Hormonal↗

PubMed2005

Reversal of tamoxifen resistant breast cancer by low dose estrogen therapy.

Currently, the standard of care for estrogen receptor (ER)-positive breast cancer is 5 years of tamoxifen (TAM) or an aromatase inhibitor (AI) such as anastrozole. New studies indicate that extending antiestrogen therapy beyond 5 years with sequential regimens will improve disease-free survival. Based on the emerging concept that longer therapies are better, we have developed sequential models of tamoxifen-resistant breast cancer in vivo to mimic the clinical scenario of long-term antiestrogen therapy. The goal of the current study was to investigate the consequences of long-term treatment with tamoxifen on the growth of breast tumors in athymic mice. The results demonstrate that there are distinct phases of resistance to tamoxifen that correlate with time of treatment and expression of HER2/neu mRNA. In the treatment phase, 17beta-estradiol (E2) stimulated growth, while TAM inhibited growth of MCF-7 tumors (MCF-7E2). The withdrawal of treatment, mimicking the use of an AI, completely prevented growth. In Phase I resistance, the tumors (MCF-7TAMST) were growth-stimulated by either E2 or TAM, but inhibited by no treatment, fulvestrant, or E2 + fulvestrant. Phase II-resistant tumors (MCF-7TAMLT) were treated for more than 5 years and growth-stimulated by TAM. However, no treatment, fulvestrant, or E2 completely inhibited growth. Interestingly, the few tumors (MCF-7TAMLT) that survived in response to E2 were robustly re-stimulated by E2 after transplantation into new generations of athymic mice. These E2-stimulated tumors (MCF-7TAME) were inhibited by TAM in a dose-dependent similar to their parental tumors (MCF-7E2). In addition, the MCF-7TAME tumors were inhibited by either no treatment or fulvestrant. HER2/neu and HER3 mRNAs were over-expressed in TAM-stimulated MCF-7TAMLT tumors and remained high in E2-stimulated MCF-7TAME tumors. The data indicate that complete reversal of resistance to TAM can be achieved with the use of low dose E2 therapy. Also, these data suggest that over-expression of HER2/neu alone is insufficient to predict resistance to TAM. Based on the results, we suggest using an alternating treatment regimen, cycling antiestrogen with estrogen therapy to avoid drug-resistance.

Animals↗

PubMed2002

Sequencing of hormonal therapy in postmenopausal women with metastatic breast cancer.

BACKGROUND: Hormonal therapy (HT) is an important consideration in the management of postmenopausal women with metastatic breast cancer. Despite the fact that the advanced-stage disease is virtually incurable, HTs can offer patients disease control equivalent to that of chemotherapy, but with improved quality of life (QOL). Knowledge of the estrogen and progesterone receptor status, as well as other clinical factors, allows for selection of patients who are most likely to benefit from HT. Disease that becomes refractory to an initial HT may respond to another agent or class of HTs. Thus, HTs are generally administered sequentially, delaying the need for cytotoxic chemotherapy, which often reduces QOL. Optimal sequencing is thus one of the more important facets of HT. Prior to the release of a number of newer agents, tamoxifen had been considered as initial HT. At present, more agents exist, including the aromatase inhibitors, progestins, and the estrogen receptor antagonist fulvestrant. OBJECTIVE: This article reviews key trials evaluating the use of sequential HTs. METHODS: Articles were identified for inclusion in this manuscript through the following searches, limited to English-language publications: MEDLINE (mid 1960s to January 2002), American Society of Oncology abstracts (1997-2001), and San Antonio Breast Cancer Symposium abstracts (2001 and 2002). The following search terms were used: breast cancer, hormonal therapies, tamoxifen, toremifene, letrozole, anastrozole, exemestane, megestrol acetate, fulvestrant, and ICI 182,780. RESULTS: Results of Phase III studies have shown many of these agents to be equivalent or superior to tamoxifen and can be used initially to treat patients who either have failed tamoxifen therapy or may be unable to tolerate some of the toxicities associated with tamoxifen. For example, the aromatase inhibitors have been shown to be highly active and tolerable in postmenopausal women with breast cancer who have failed tamoxifen therapy or who are naive to HT. Other clinical trials have demonstrated the efficacy of fulvestrant in patients with metastatic breast cancer who are tamoxifen-resistant, and have shown fulvestrant to be at least as effective as anastrozole in tamoxifen-resistant patients. CONCLUSIONS: Although the optimum sequence of HTs remains controversial, using the newer agents as initial or subsequent therapy should improve QOL and may improve overall survival.

Antineoplastic Agents, Hormonal↗

PubMed2005

Selective oestrogen receptor modulators, aromatase inhibitors and the female breast.

PURPOSE OF REVIEW: Tamoxifen has been available for over 20 years and remains the most commonly recognized endocrine therapy. This review was prompted by a wealth of new data on several newer endocrine agents, including selective oestrogen receptor modulators, aromatase inhibitors and a new oestrogen receptor antagonist, fulvestrant, which unlike the selective oestrogen receptor modulators has no oestrogen agonist effects. RECENT FINDINGS: Completed analysis of the 'Arimidex', Tamoxifen, Alone or in Combination trial demonstrated that anastrozole as initial adjuvant therapy significantly improved disease-free survival and time to recurrence compared with tamoxifen, as well as reducing the incidence of contralateral breast cancer deaths. The Italian Tamoxifen Anastrozole trial and the Austrian Breast and Colorectal Cancer Study Group 8/Arimidex Nolvadex 95 trial have indicated that anastrozole may also be beneficial in women who have already received 2-3 years of tamoxifen. Similarly, the Intergroup Exemestane Study demonstrated the efficacy of exemestane in this setting. Women who have completed a full 5-year course of tamoxifen may also benefit from aromatase inhibitor treatment as indicated by the MA 17 trial, which investigated letrozole as extended adjuvant therapy. Fulvestrant is effective in tamoxifen-resistant disease, and phase II trial data suggest that fulvestrant may also be effective following aromatase inhibitor failure. SUMMARY: The introduction of the third-generation aromatase inhibitors has caused a paradigm shift in adjuvant endocrine treatment. Research into the optimal use of selective oestrogen receptor modulators continues and the evidence base for fulvestrant, the first in a new class of endocrine agents, continues to grow, confirming its value in the treatment of hormone-responsive breast cancer.

Aromatase Inhibitors↗

PubMed2006

Postmenopausal advanced breast cancer: options for therapy after tamoxifen and aromatase inhibitors.

All patients receiving endocrine treatment for advanced breast cancer (ABC) eventually progress, resulting in a need for new therapies that lack cross-resistance with existing agents. Oestrogen receptor (ER) modulators such as toremifene and raloxifene have poor efficacy following tamoxifen failure, whereas the non-steroidal aromatase inhibitors (AIs), anastrozole and letrozole and the steroidal AI exemestane are effective. Fulvestrant is a new ER antagonist with no agonist effects that is as effective as anastrozole in treating patients who have progressed on tamoxifen. AIs are replacing tamoxifen as first-line treatments for ABC and in the adjuvant setting, necessitating a re-evaluation of optimal sequencing. Preliminary data suggest that tamoxifen, exemestane and fulvestrant have activity in patients who have progressed on non-steroidal AIs and hence could be considered for use in this setting. Due to the apparent lack of cross-resistance between non-steroidal and steroidal AIs, non-steroidal AIs could also be effective following steroidal AI failure. Clinical trials are underway to assess the most appropriate treatment sequence following non-steroidal AI failure, with comparisons of fulvestrant and exemestane of major interest.

Aromatase Inhibitors↗

PubMed2005

Model systems: mechanisms involved in the loss of sensitivity to letrozole.

A number of models have been used to study the development and treatment of breast cancer. Since most breast cancer patients are postmenopausal and treated with hormone therapy, we developed a model to simulate this type of patient. Tumors of human estrogen receptor (ER)-positive breast cancer cells transfected with aromatase (MCF-7Ca) are grown in immune suppressed mice. In this model, we have explored a number of strategies to optimize the antitumor efficacy of treatment such as combining the non-steroidal aromatase inhibitor letrozole with the antiestrogens, tamoxifen. This combination resulted in tumor suppression similar to the antiestrogen alone, but was less effective than letrozole alone. Clinical findings with the non-steroidal inhibitor anastrozole in combination with tamoxifen (ATAC trial) were consistent with our results. Although letrozole was the most effective single agent tested in the model, tumors ultimately began to grow during continued treatment. To investigate the mechanisms by which tumors adapt to growth during letrozole treatment, we determined the expression of signaling proteins in tumors during the course of letrozole treatment compared to the tumors of control mice. We found that tumors initially up regulated the ER, but subsequently receptor levels decreased in tumors unresponsive to letrozole. Adapter proteins (p-Shc and Grb-2) as well as all of the signaling proteins in the MAPK cascade (p-Raf, p-Mek1/2, and p-MAPK), but not Akt, were increased in tumors no longer responsive to letrozole. The results suggest that tumor cells adapt to estrogen deprivation during letrozole treatment by activation of alternate signaling pathways to increase transcription. When letrozole was combined with the pure antiestrogen fulvestrant, to down regulate ER, the combination was more effective than either letrozole or fulvestrant alone. Tumors regressed by 45% and were maintained without growth for the duration of the experiment (29 weeks). Down regulation of ER by fulvestrant may prevent cross talk between these signaling pathways. The results suggest that achieving more complete estrogen blockade may delay development of hormone-independent signaling pathways regulating proliferation.

Adaptor Proteins, Signal Transducing↗

PubMed2005

No estrogen-like effects of an isopropanolic extract of Rhizoma Cimicifugae racemosae on uterus and vena cava of rats after 17 day treatment.

The effects of black cohosh extracts (Rhizoma Cimicifugae racemosae) on primary estrogen target organs, like mammary gland and endometrium are better described then those on other estrogen-sensitive systems e.g. the vasculature. We therefore treated ovariectomized DA/Han rats for 17 days with an isopropanolic Cimicifuga racemosa rhizoma extract (iCR) alone and in combination with the pure antiestrogen fulvestrant. As control groups vehicle, estradiol, fulvestrant, and estradiol fulvestrant cotreatment were used. Effects of all substances were investigated by vena cava and uterine gene expression analysis using real-time-PCR. Uterus wet weight was increased after estradiol treatment compared to the negative controls but none of the other treatments including the treatment with iCR had a uterotrophic effect. While estradiol-induced changes in uterine gene expression were mainly analogous to those detectable in shorter term experiments, iCR showed no or slightly antiestrogenic effects on gene expression in the uterus. This is mirrored in the vena cava where iCR had a very minor impact on the expression of the genes analyzed. While C. racemosa is effectively used for treatment of peri- and post-menopausal symptoms for a long time its mechanism of action remains unresolved. Contrary to earlier suggestions C. racemosa does not seem to act as an estrogen agonist, but possibly as a weak antiestrogen.

2-Propanol↗

PubMed2003

Oestrogen receptor downregulation: an opportunity for extending the window of endocrine therapy in advanced breast cancer.

BACKGROUND: Advanced breast cancer is largely incurable and current treatment modalities are aimed towards restricting tumour growth, prolonging survival, palliating symptoms and maintaining quality of life (QoL). The development of breast cancer is strongly influenced by endogenous oestrogens (and other growth factors), leading to a strong focus on the development of antioestrogenic compounds for the treatment of hormone-sensitive advanced disease. DESIGN: This is a review of current endocrine therapies available for postmenopausal women with advanced breast cancer, examining the likely impact of newer agents on treatment strategies. RESULTS: In postmenopausal women, current treatment options include tamoxifen, aromatase inhibitors (AIs) and megestrol acetate. Fulvestrant ('Faslodex') is a new, well-tolerated, oestrogen receptor antagonist that has no known agonist effect and is at least as effective as the AI anastrozole for the treatment of postmenopausal patients with metastatic or advanced breast cancer who have progressed on prior endocrine therapy. Fulvestrant maintains QoL throughout successful treatment. CONCLUSIONS: Fulvestrant represents a new treatment option for postmenopausal women with advanced disease. New agents that appear to lack cross-resistance with existing treatments may be used to extend the time period during which endocrine therapy may be employed before the need for cytotoxic chemotherapy.

Aged↗

PubMed2006

Ligand-selective interdomain conformations of estrogen receptor-alpha.

Selective estrogen receptor modulators (SERMs) inhibit estrogen activation of the estrogen receptor (ER) in some tissues but activate ER in other tissues. These tissue-selective actions suggest that SERMs may be identified with tissue specificities that would improve the safety of breast cancer and hormone replacement therapies. The identification of an improved SERM would be aided by understanding the effects of each SERM on the structure and interactions of ER. To date, the inability to obtain structures of the full-length ER has limited our structural characterization of SERM action to their antiestrogenic effects on the isolated ER ligand binding domain. We studied the effects of estradiol and the clinically useful SERMs 4-hydroxytamoxifen and fulvestrant on the conformation of the full-length ERalpha dimer complex by comparing, in living human breast cancer cells, the amounts of energy transfer between fluorophores attached to different domains of ERalpha. Estradiol, 4-hydroxytamoxifen, and fulvestrant all promoted the rapid formation of ERalpha dimers with equivalent interaction kinetics. The amino- and carboxyl-terminal ERalpha domains both contain activation functions differentially affected by these ligands, but the positions of only the carboxyl termini differed upon binding with estradiol, 4-hydroxytamoxifen, or fulvestrant. The association of a specific ERalpha dimer conformation with the binding of ligands of different clinical effect will assist the identification of a SERM with optimal tissue-selective estrogenic and antiestrogenic activities. These studies also provide a roadmap for dissecting important structural and kinetic details for any protein complex from the quantitative analysis of energy transfer.

Cell Line, Tumor↗

PubMed2004

Selective oestrogen receptor modulators/new antioestrogens: a clinical perspective.

Following tamoxifen, the first selective oestrogen receptor modulator (SERM), a number of other antioestrogens have been developed. The first-generation SERMs exhibit cross-resistance with tamoxifen and have agonist effects on the uterus. Toremifene has equal efficacy to tamoxifen and may be useful as a tamoxifen alternative. Efficacy results for droloxifene and idoxifene were disappointing and their clinical development ceased. Response rates for second-generation SERMs such as raloxifene and arzoxifene are also not high, although raloxifene shows promise in the chemoprevention of breast cancer. Paradoxically, high-dose oestrogens are proving to be effective breast cancer treatment with similar responses to tamoxifen in postmenopausal women with advanced disease, although these drugs are not well tolerated. Fulvestrant is a new type of oestrogen receptor (ER) antagonist with no agonist effects, which binds, blocks and degrades the ER. Fulvestrant produces high response rates compared with the SERMs, is not cross-resistant with SERMs or aromatase inhibitors (AIs) and is equally as effective as the AI anastrozole in the treatment of postmenopausal women with advanced breast cancer who have progressed after prior antioestrogen therapy. Pure antioestrogens such as the ER antagonist fulvestrant provide opportunities for therapeutic sequencing with tamoxifen and AIs and offer exciting possibilities for the future treatment of breast cancer.

Antineoplastic Agents, Hormonal↗

PubMed2003

A review of the efficacy of anastrozole in postmenopausal women with advanced breast cancer with visceral metastases.

Tumors that have spread to the liver or lungs (visceral metastases) are associated with a worse prognosis than tumors in soft tissue and bone only. Here we review available efficacy data to address whether or not anastrozole, a non-steroidal aromatase inhibitor (AI), is effective in postmenopausal patients with advanced breast cancer (ABC) and visceral metastases. We include data from Phase III clinical trials, comparing clinical benefit (CB) with anastrozole versus tamoxifen as a first-line treatment, and versus megestrol acetate (MA) or fulvestrant as a second-line therapy. Patients in these trials had adequate organ function and the volume of disease had to be minimal or moderate for them to be eligible for inclusion. First-line treatment of patients with or without visceral metastases in the overall population resulted in CB rates of 49.5 and 62.3%, respectively, for anastrozole and 46.9 and 55.9%, respectively, for tamoxifen. In patients with confirmed hormone receptor (HR)-positive tumors, the CB rate was 51.9 and 65.7%, respectively, for anastrozole and 41.6 and 58.7%, respectively, for tamoxifen. In patients with or without visceral metastases, second-line treatment with anastrozole resulted in a CB rate of 31.4 and 51.8%, respectively, compared with 31.9 and 47.1%, respectively, for those treated with MA. Patients in the overall population with and without visceral metastases treated with anastrozole obtained a CB rate of 37.4 and 43.8%, respectively, while those treated with fulvestrant obtained a CB rate of 38.2 and 47.6%, respectively. In patients with confirmed HR-positive tumors, CB was seen in 37.6 and 41.5%, respectively, of patients treated with anastrozole and in 37.3 and 47.0%, respectively, of patients treated with fulvestrant. The results reveal anastrozole to be an effective and valuable first- and second-line therapy in postmenopausal women with ABC and visceral metastases, showing similar CB to other endocrine therapies.

Anastrozole↗

PubMed2004

Characterization of new estrogen receptor destabilizing compounds: effects on estrogen-sensitive and tamoxifen-resistant breast cancer.

BACKGROUND: Antiestrogens of the selective estrogen receptor modulator (SERM) type, such as tamoxifen, have two major limitations: their mixed agonist and antagonist profile and the development of tumor resistance. We characterized two new pure antiestrogens-ZK-703 and ZK-253-that belong to the class of specific estrogen receptor destabilizers (SERDs), which includes fulvestrant, and compared their activity with that of fulvestrant and tamoxifen. METHODS: Effects of antiestrogens on the growth of estrogen-dependent breast tumors in vivo were determined using several mouse xenograft models (including the tamoxifen-sensitive tumors MCF7, T47D, and MV3366 and the tamoxifen-resistant tumors ZR75-1 and MCF7/TAM) and chemically induced (nitrosomethyl urea [NMU] and dimethylbenzanthracene [DMBA]) rat breast cancer models (groups of 10 animals). We determined the initial response and effects on hormone receptor levels and the time to relapse after treatment (i.e., time to reach a predetermined tumor size threshold). Estrogen receptor (ER) levels were determined by immunoassay. RESULTS: ZK-703 (administered subcutaneously) and ZK-253 (administered orally) were more effective than tamoxifen or fulvestrant at inhibiting the growth of ER-positive breast cancer in all xenograft models. For example, MCF7 tumors relapsed (i.e., reached the size threshold) in 10 weeks in mice treated with tamoxifen but in 30 weeks in mice treated with ZK-703. ZK-703 and ZK-253 also prevented further tumor progression in tamoxifen-resistant breast cancer models to a similar extent (more than 30 weeks in mice with ZR75-1 and MCF7/TAM tumors). In the chemically induced rat breast cancer models, orally administered ZK-703 and ZK-253 caused a nearly complete (>80%) inhibition of tumor growth. ER levels were dramatically reduced in MCF7 tumors after 5 weeks of ZK-703 treatment compared with ER levels in vehicle-treated tumors; by contrast, ER levels in tamoxifen-treated tumors were higher than those in control tumors. CONCLUSION: ZK-703 and ZK-253 are potent, long-term inhibitors of growth in both tamoxifen-sensitive and tamoxifen-resistant breast cancer models.

9,10-Dimethyl-1,2-benzanthracene↗

PubMed2002

Existing and emerging endocrine therapies for breast cancer.

Endocrine therapy is first-line therapy for patients with estrogen receptor-positive or progesterone receptor-positive metastatic breast cancer. Commonly used endocrine therapies are tamoxifen, megestrol acetate, and aromatase inhibitors. Although tamoxifen and megestrol acetate have a favorable therapeutic profile, there are risks associated with these agents. With tamoxifen, the partial agonist property can lead to thromboembolic events. An important adverse event of megestrol acetate is weight gain and fluid retention in some patients. The aromatase inhibitors are currently used as second-line therapy after tamoxifen failure. A recent study showed that anastrozole, an aromatase inhibitor, is as effective or even superior to tamoxifen when used as a first-line therapy. However, not all patients will respond to currently available therapies. A new class of drug, the estrogen receptor downregulators, has been developed. Fulvestrant, the first agent in this new class, not only induces the degradation of the estrogen receptor but also is an estrogen antagonist; further, its lack of agonist activity provides a better safety profile. Two phase III trials have proven that fulvestrant is at least as effective as anastrozole in postmenopausal women with advanced breast cancer. Fulvestrant is an effective and safe endocrine therapy for postmenopausal women who have failed prior endocrine therapy.

Antineoplastic Agents, Hormonal↗

PubMed2004

Inhibition of HER1 signaling pathway enhances antitumor effect of endocrine therapy in breast cancer.

Epidermal growth factor receptor (EGFR)/HER1 is expressed at high levels in at least 20% of breast cancers. This high expression correlates with a poor prognosis in patients with breast cancer. Experimental and clinical findings suggest that aberrant activation of tyrosine receptor kinases, such as HER1 pathway, play a causal role in the development of antiestrogen resistance in breast cancer. Recent preclinical and clinical evidence shows that inhibition of growth factor signaling pathways suppresses the growth of malignant cells without serious toxicities. To test the hypothesis that inhibition of the HER1 signaling pathway enhances the antitumor effect of endocrine therapy, a promising signal transduction inhibitor (STI) of HER1 tyrosine kinase, gefitinib, and an estrogen receptor (ER) antagonist, fulvestrant, were administered to human breast cancer cells. Our experimental results have revealed that gefitinib additively enhances the antitumor effect of fulvestrant in estrogen receptor (ER)-positive breast cancer cells under estrogen-supplemented conditions. An additive increase in the protein expression level of a cyclin-dependent kinase inhibitor, p21 may play a key role of this additive cytostatic effect. The rationale and future perspectives of the combined use of STIs with endocrine therapy in breast cancer are discussed.

Antineoplastic Agents↗