Emerging data on the efficacy and safety of fulvestrant, a unique antiestrogen therapy for advanced breast cancer

INTRODUCTION: Fulvestrant is an antiestrogen therapy with a unique mechanism of action. Unlike the selective estrogen receptor modulator tamoxifen, fulvestrant has no known estrogen agonist activity and is considered a pure antiestrogen. Its primary mechanism of action is thought to result from downregulation of the estrogen receptor (ER). Considerable data have demonstrated the efficacy of fulvestrant in postmenopausal women with ER-positive advanced breast cancer, both in the first-line setting and following disease progression on tamoxifen or aromatase inhibitors. Recent studies report improved benefit with alternative dosing strategies. At all administration schedules, fulvestrant has an excellent safety profile with no significant adverse effects. AREAS COVERED: This article provides a review of the mechanism of action of fulvestrant and the preclinical and clinical data evaluating its use as a form of endocrine therapy. The reader will gain insight into the pharmacologic properties of the drug and its role in the treatment of advanced hormone receptor-positive breast cancer in postmenopausal women. EXPERT OPINION: Based on data demonstrating the efficacy of fulvestrant, including prolonged clinical benefit in many patients, this well-tolerated antiestrogen is an important therapy for breast cancer. The optimal position of fulvestrant in the sequence of endocrine therapies for postmenopausal women and its role in combination regimens are not yet resolved.     

Emerging data on the efficacy and safety of fulvestrant,a unique antiestrogen therapy for advanced breast cancer

Introduction: Fulvestrant is an antiestrogen therapy with a unique mechanism of action. Unlike the selective estrogen receptor modulator tamoxifen, fulvestrant has no known estrogen agonist activity and is considered a pure antiestrogen. Its primary mechanism of action is thought to result from downregulation of the estrogen receptor (ER). Considerable data have demonstrated the efficacy of fulvestrant in postmenopausal women with ER-positive advanced breast cancer, both in the first-line setting and following disease progression on tamoxifen or aromatase inhibitors. Recent studies report improved benefit with alternative dosing strategies. At all administration schedules, fulvestrant has an excellent safety profile with no significant adverse effects.

Areas covered: This article provides a review of the mechanism of action of fulvestrant and the preclinical and clinical data evaluating its use as a form of endocrine therapy. The reader will gain insight into the pharmacologic properties of the drug and its role in the treatment of advanced hormone receptor-positive breast cancer in postmenopausal women.

Expert opinion: Based on data demonstrating the efficacy of fulvestrant, including prolonged clinical benefit in many patients, this well-tolerated antiestrogen is an important therapy for breast cancer. The optimal position of fulvestrant in the sequence of endocrine therapies for postmenopausal women and its role in combination regimens are not yet resolved.     

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.     

Pure Antiestrogens and Breast Cancer

Summary

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. ICI182,780 (fulvestrant) (Faslodex) and ICI164,384 are competitive inhibitors of estrogen by binding to the estrogen receptor (ER). Preclinical and clinical studies show that fulvestrant and ICI164,384 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.     

氟维司群治疗乳腺癌的若干问题

氟维司群是一种新型甾体雌激素受体拮抗药,可在细胞水平下调雌激素受体和孕激素受体数量,且无激动效应。氟维司群对激素受体阳性的乳腺癌疗效确切,耐受性好,是一种新的内分泌治疗药物。本文回顾氟维司群治疗乳腺癌的临床研究进展,讨论若干临床应用关键问题。     

Fulvestrant

Fulvestrant, a novel oestrogen receptor (ER) downregulator, is a pure anti-oestrogen which completely blocks the trophic actions of oestrogens without exerting any partial agonist effects. It reduces expression of oestrogen receptor, progesterone receptor and proliferative and cell turnover indices. The drug is well-tolerated with minimal systemic side effects. Large randomised trials have demonstrated similar efficacy to anastrozole in the treatment of postmenopausal advanced breast cancer. While results of a Phase III trial comparing fulvestrant with tamoxifen as first-line endocrine therapy for postmenopausal advanced breast cancer are awaited, future studies on its role in adjuvant and neoadjuvant settings, as well as in premenopausal women are required. With the role of tamoxifen as the gold standard of first-line therapy being challenged by the third generation aromatase inhibitors, direct comparison of the latter with fulvestrant in the first-line setting may also be worthwhile.     

Fulvestrant

Fulvestrant, a novel oestrogen receptor (ER) downregulator, is a pure anti-oestrogen which completely blocks the trophic actions of oestrogens without exerting any partial agonist effects. It reduces expression of oestrogen receptor, progesterone receptor and proliferative and cell turnover indices. The drug is well-tolerated with minimal systemic side effects. Large randomised trials have demonstrated similar efficacy to anastrozole in the treatment of postmenopausal advanced breast cancer. While results of a Phase III trial comparing fulvestrant with tamoxifen as first-line endocrine therapy for postmenopausal advanced breast cancer are awaited, future studies on its role in adjuvant and neoadjuvant settings, as well as in premenopausal women are required. With the role of tamoxifen as the gold standard of first-line therapy being challenged by the third generation aromatase inhibitors, direct comparison of the latter with fulvestrant in the first-line setting may also be worthwhile.     

Fulvestrant: a review of its use in the management of hormone receptor-positive metastatic breast cancer in postmenopausal women

Fulvestrant (Faslodex?) is an intramuscularly administered steroidal estrogen receptor antagonist that is devoid of any known estrogen agonist effects. It is indicated as second-line therapy for the treatment of postmenopausal women with hormone receptor-positive advanced breast cancer who have progressed following prior endocrine therapy. In well designed, randomized clinical trials, regimens of fulvestrant 250 and 500 mg provided effective second-line therapy for postmenopausal women with advanced breast cancer who had progressed following prior endocrine therapy. Moreover, fulvestrant 250 mg monthly (with or without a loading dose) was as effective as aromatase inhibitor therapy. However, fulvestrant is absorbed slowly, and greater steady-state concentrations are achieved more rapidly when using a higher dosage with a loading dose regimen. Consequently, a regimen of fulvestrant 500 mg monthly with a loading dose was significantly more effective than a regimen of 250 mg monthly in postmenopausal women with disease progression. Limited data also indicate a potential role for the fulvestrant 500 mg regimen as first-line therapy. Fulvestrant is generally well tolerated with no additional adverse events noted with the high-dose regimen compared with the 250 mg regimens. Furthermore, the incidence of joint disorders was shown to be significantly lower with fulvestrant 250 mg monthly than with anastrozole. Treatment with fulvestrant is not associated with any clinically significant effects on endometrial thickening, bone-specific turnover markers or sex hormone levels. In conclusion, a monthly regimen of intramuscular fulvestrant 500 mg with a loading dose provides effective and well tolerated second-line therapy for postmenopausal women with advanced breast cancer who have progressed following prior endocrine therapy and is now the approved optimal dose.     

Identification of a novel, orally bioavailable estrogen receptor downregulator

Tamoxifen has been widely used for the treatment of estrogen receptor (ER)-positive breast cancer, but its partial agonist activity is considered to limit the efficacy, and cause tumor flare and endometrial cancer. Fulvestrant, on the other hand, binds and degrades ER, thereby acting as a pure anti-estrogen without partial agonist activity. However, due to its low oral bioavailability, fulvestrant has to be intramuscularly administered to patients, which limits the convenience of the drug, and causes pain and inflammation at the site of injection. In search of a patient- friendly pure anti-estrogen, we screened and identified an ER antagonist, CH4893237, which bound to ER with an IC50 value of 1.4 muM and, by oral administration, inhibited estrogen-stimulated uterine growth in ovariectomized mice. CH4893237 reduced the amount of ER at the protein level and impaired the nuclear accumulation of ER, indicating an orally active pure anti-estrogen. Furthermore, CH4893237 inhibited the estrogen-stimulated proliferation of MCF-7, ZR-75-1 and BT-474 cells, and caused a marked growth inhibition of the MCF-7 xenograft in vivo. Thus, CH4893237 will provide an additional option for second-line hormone treatment of breast cancer.     

Fulvestrant for the treatment of endometrial cancer

Introduction: About one third of patients with endometrial cancer (EC) relapse and face a limited prognosis, if surgery or radiotherapy are not feasible. The remaining therapeutic options are chemotherapy and endocrine therapy.

Areas covered: This review summarizes the development of the first selective estrogen receptor (ER) down-regulator fulvestrant. This article provides its mechanism of action, pharmacokinetics and the available preclinical and clinical data. Furthermore, this review provides an overview of the market of treatments for recurrent or metastatic EC (RMEC) while also taking into account studies of fulvestrant in metastatic breast cancer.

Expert opinion: Even if fulvestrant showed only marginal activity in two phase II trials, it shouldn’t be abandoned but instead further developed in EC. Firstly, the dose of fulvestrant used in these trials was too low from today’s point of view. Secondly, the available literature on other endocrine agents is full of limitations and does not provide a gold standard. Furthermore, given the activity of mTOR inhibitors in EC, there may also be synergistic effects, given the cross-regulation of ER and the PI3K/AKT/mTOR pathway. The authors suggest that a prospective, phase II trial in ER positive RMEC would help to further explore the efficacy and tolerability of fulvestrant together with a mTOR inhibitor.     

An evaluation of fulvestrant for the treatment of metastatic breast cancer

ABSTRACT

Introduction: Fulvestrant is currently the only selective estrogen receptor degrader (SERD) that is approved for clinical use in estrogen receptor (ER) positive advanced breast cancer (ABC). The drug is approved as single-agent therapy in the first and second-line setting of metastatic ER-positive breast cancer.

Areas covered: In this review, the authors review the preclinical studies that were pivotal in the development of fulvestrant, the pharmacologic properties of the drug, and the key clinical trials that resulted in its approval for clinical use. The authors discuss mechanisms of endocrine resistance and potential targets for endocrine refractory disease while highlighting ongoing studies that assess fulvestrant use with novel agents.

Expert opinion: While fulvestrant has limited use in the first-line setting in advanced breast cancer, it is most frequently used in the second line after progression with aromatase inhibitors. The combination of fulvestrant with CDK4/6 inhibitors has shown a clear benefit over monotherapy in patients who progress on prior endocrine therapy. Further study is necessary to assess if patient outcomes can be enhanced by optimizing the sequence of endocrine therapies, targeting resistance pathways with novel agents, and development of new agents in the SERD class.     

Fulvestrant: a new type of estrogen receptor antagonist for the treatment of advanced breast cancer

Postmenopausal women with hormone receptor- positive tumors are candidates for endocrine treatment. Current treatment options include the selective estrogen receptor modulators (e.g., tamoxifen and toremifene), which inhibit estrogen receptor signaling, and the aromatase inhibitors (e.g., anastrozole and letrozole), which prevent the conversion of androgens into estrogen in postmenopausal women. As most patients eventually become resistant to endocrine agents, there is a need for new treatments that are effective, well tolerated and lack cross-resistance with currently available therapies. This review describes the development of fulvestrant (Faslodex), a new type of endocrine agent, which is an estrogen receptor antagonist with no agonist effects. Phase III clinical trials have found that fulvestrant is as effective and well tolerated as anastrozole for treating postmenopausal patients with advanced breast cancer who have progressed on one prior endocrine therapy. In addition, fulvestrant has first-line efficacy similar to that of tamoxifen in patients with estrogen receptor-positive and/or progesterone receptor-positive breast cancer. Moreover, in a compassionate-use program, it has become clear that fulvestrant is not cross-resistant with other therapies. Therefore, fulvestrant is a versatile new treatment option for postmenopausal women with advanced breast cancer who have progressed on prior endocrine therapy.     

依维莫司联合氟维司群用于激素受体阳性晚期乳腺癌的研究进展

乳腺癌是一种经典的激素依赖性肿瘤,内分泌治疗是激素受体阳性［HR（+）］/人表皮生长因子 2 阴性 ［HER-2（-）］晚期乳腺癌的主要治疗方法。传统的内分泌药物,如他莫昔芬、芳香化酶抑制剂（AI）和氟维司群已被 广泛应用于晚期（局部晚期或转移）绝经后患者。然而,对于这种亚型的乳腺癌患者,在引入靶向药物,如人哺乳动 物雷帕霉素位点（mTOR）抑制剂和细胞周期蛋白依赖性激酶4/6（CDK4/6）抑制剂后,内分泌治疗的选择已经扩大,出 现了各种靶向药物与内分泌治疗的组合。本文旨在探讨mTOR抑制剂依维莫司联合氟维司群在对AI耐药的雌激素 受体阳性［ER（+）］/HER-2（-）晚期乳腺癌中的应用。     

Estrogen receptors as therapeutic targets in breast cancer

The estrogen receptor alpha (ERalpha) has proven to be the single most important target in breast cancer over the last 30 years. The use of the selective ER modulator (SERM) tamoxifen for the treatment and prevention of breast cancer has changed therapeutics. The SERM raloxifene, approved for the treatment of osteoporosis, lacks tamoxifen's increased risk for endometrial cancer and is being evaluated for the prevention of breast cancer. Other SERMs approved or under development for use against breast cancer or osteoporosis include toremifene, GW5638, GW7604 (the active metabolite of GW5638), idoxifene, lasofoxifene, arzoxifene, bazedoxifene, EM-800 and acolbifene (the active metabolite of EM-800). Aromatase inhibitors (AIs) have recently proven to be more efficacious than tamoxifen as first-line therapy, efficacious for second-line therapy (e.g. against tamoxifen-resistant disease), and useful for extended adjuvant therapy after tamoxifen. The AIs include the non-steroidal agents letrozole and anastrole, and the steroidal agent exemestane. The pure antiestrogen fulvestrant has proven to be just as effective as AIs. Other pure antiestrogens, ZK-703, ZK-253, RU 58668 and TAS-108 show great promise. The development of resistance to endocrine therapy remains a clinically important problem, and laboratory models based on human breast cancer cells grown as tumors in immune-compromised mice have led to important insights into this problem. Progesterone receptor-negative status of ER-positive breast cancers may reflect altered growth factor receptor signaling, and helps to explain why this subclass of tumors exhibits lower response rates to tamoxifen compared to cancers typed progesterone receptor-positive. Crosstalk among plasma membrane-localized ER, growth factor receptor signaling, and nuclear-localized ER provide further insights into antihormonal-resistant breast cancer.     

Selective oestrogen receptor modulators,pure antioestrogens and related oestrogen receptor ligands

Oestrogen or hormone replacement therapy (HRT) is an effective treatment for postmenopausal women in alleviating disorders associated with lower circulating levels of oestrogens such as hot flushes and osteoporosis. Unfortunately, long-term HRT is associated with an increased risk of breast and endometrial cancers. Consequently, an alternative to traditional HRT has been the use of selective oestrogen receptor modulators (SERMs), which antagonise the oestrogen receptor (ER) in the breast and uterus but at the same time exert beneficial effects on bone. Initially, most of the SERMs had targeted ERα for HRT. After the identification of ERβ, however, speculation grew that ERβ would be an additional exciting target for HRT. This speculation was further fuelled since ERβ was not the dominant ER receptor in the uterus, the key organ to avoid stimulating in HRT. The aim of this review is to summarise the relevant patent literature from January 2000 to June 2003 on SERMs, pure antioestrogens and related ER modulatory ligands, mainly with respect to their chemical scaffolds and broad therapeutic relevance .     

Fulvestrant – a new treatment for postmenopausal women with hormone-sensitive advanced breast cancer

Approximately 75% of breast tumours in postmenopausal women are positive for the oestrogen receptor (ER) and/or the progesterone receptor (PgR) and are, therefore, potential candidates for endocrine treatment. Fulvestrant is a new type of ER antagonist with no agonist effects and a novel mode of action; it binds, blocks and degrades the ER, leading to a reduction in cellular ER and, consequently, in PgR levels. This novel mode of action results in a lack of cross-resistance with other commonly used endocrine treatments. In Phase III trials in postmenopausal women with advanced breast cancer progressing on prior anti-oestrogen therapy, fulvestrant was at least as effective as the third-generation aromatase inhibitor, anastrozole, in terms of time to progression and objective response, and was associated with similar overall survival. In the first-line setting, fulvestrant showed similar efficacy to tamoxifen in patients with ER-positive and/or PgR-positive disease. Efficacy in more heavily pretreated patients has also been demonstrated in the fulvestrant compassionate use programme. Fulvestrant is well tolerated, being associated with a significantly lower incidence of joint disorders compared with anastrozole, and a lower incidence of hot flushes compared with tamoxifen. Fulvestrant, therefore, provides clinicians with a useful additional treatment for hormone-sensitive advanced breast cancer in postmenopausal women. Ongoing trials will help to clarify the optimal position of fulvestrant in the endocrine treatment sequence for these patients.