Combining emerging agents in advanced breast cancer

Newer treatments have improved survival for patients with metastatic breast cancer over the last two decades, and a battery of new cytotoxic and targeted therapies is continuing to enhance this trend. This review outlines recent data and ongoing research in this area, by highlighting new developments (regarding approved but relatively new classes of cytotoxic and targeted agents) and also new classes of targeted therapy that are undergoing clinical evaluation. Mechanisms for synergy between agents are discussed where data are available, as is information on the rationale behind the development of agents that inhibit angiogenesis, DNA repair, histone deacetylases, heat shock proteins, or various signaling pathways in tumor proliferation. The abundance of clinical research surrounding anticancer agents, together with ongoing cancer biology research, is expected to further increase the available pool of therapeutic options for metastatic breast cancer. Concomitantly, in the absence of an effective targeted monotherapy, a better understanding of the interplay between biologic and cytotoxic anticancer agents will improve our ability to rationally design combination regimens with better efficacy and tolerability.     

来曲唑治疗绝经后晚期乳腺癌临床观察

目的观察来曲唑治疗绝经后晚期乳腺癌的疗效和不良反应。方法42例雌激素或孕激素受体阳性或不明的绝经后晚期乳腺癌患者口服来曲唑每日一次,每次2.5mg,28天一周期,至少2周期。结果42例患者中,可评价疗效者42例。完全缓解(CR)0例;部分缓解(PR)5例,占11.9%;稳定(SD)23例,占54.8%,其中SD≥6个月14例,占33.3%;临床获益CBR(CR PR SD≥6个月)19例,占45.2%;进展14例,占33.3%。肿瘤进展时间2月~58月,中位进展时间(TTP)10月。未出现严重不良反应。结论来曲唑治疗绝经后晚期乳腺癌疗效确切,不良反应轻微,耐受性好。     

Fulvestrant in postmenopausal women with advanced breast cancer.

PURPOSE: Patients with hormone-sensitive breast cancer who have responded to tamoxifen (TAM) may receive additional benefit from a second endocrine agent after progression or relapse after TAM therapy. Fulvestrant (FVT; Faslodex; i.m. injection, ICI 182,780; AstraZeneca Pharmaceuticals, Wilmington, DE) was developed as a selective antagonist of estrogen. In postmenopausal women, FVT is reported to inhibit the proliferative effects of estrogen on sensitive tissues and has no apparent measurable estrogenic activity. In this report, we describe the data and analyses supporting marketing approval for FVT by the United States Food and Drug Administration (FDA). EXPERIMENTAL DESIGN: The FDA review of 16 clinical trials and 6 pharmacokinetic trials, as well as preclinical pharmacology and chemistry data, are described. The bases for marketing approval are summarized. RESULTS: Toxicology studies in the mouse, rat, and dog showed minimal toxicity except for antiestrogenic effects. Because of FVT aqueous insolubility, an i.m. formulation, given at monthly intervals, was selected for clinical studies. Pharmacokinetic studies demonstrated sustained concentrations with monthly injection. In in vitro studies FVT was extensively metabolized, primarily by hepatic cytochrome P450 3A4. Phase I studies showed minimal toxicity, and the maximal dose (250 mg) was limited by FVT solubility. In two Phase III trials, 851 patients were randomized to either 250 mg FVT i.m. monthly or to anastrozole (ANZ) 1 mg p.o. daily. Ninety-six percent of patients had received TAM previously for early (adjuvant treatment) or advanced breast cancer. Response rates (RR) were 17% for both FVT and ANZ study arms in the North American trial, and were 20% versus 15% for FVT versus ANZ, respectively, in the European trial. There were no observed differences between study arms with respect to time to progression or survival. The most common FVT adverse events reported as potentially treatment-related were injection site reactions and hot flashes. CONCLUSIONS: FVT was approved on April 25, 2002 by the FDA for the treatment of hormone receptor-positive metastatic breast cancer in postmenopausal women with disease progression after antiestrogen therapy. The recommended dose is 250 mg i.m. monthly as a single 5 ml injection or as two concurrent 2.5 ml injections into the buttocks. Approval was based on results of two randomized trials comparing response rates and time to progression of FVT- and ANZ-treated patients. Complete prescribing information is available on the FDA website.     

晚期乳腺癌分子靶向药物治疗进展

分子靶向药物已经被临床广泛使用,其疗效显著,不良反应轻微,主要有表皮生长因子(EGF)抑制剂、血管内皮生长因子(VEGF)抑制剂、小分子酪氨酸激酶抑制剂、单克隆抗体等.与多种化疗药物联合可以进一步提高疗效.     

Role of epirubicin in advanced breast cancer

Anthracyclines were first introduced for the treatment of metastatic breast cancer in the 1970s and are still among the most active single agents for the treatment of this disease. Unfortunately, their clinical value is limited by late-onset ventricular dysfunction. Epirubicin, an anthracycline analogue, does not eliminate the risk of cardiotoxicity but is less cardiotoxic and myelotoxic than doxorubicin at equimolar doses, thereby allowing the safe administration of cumulative doses between 950 and 1000 mg/m2. The inclusion of epirubicin in combination regimens, such as fluorouracil/epirubicin/cyclophosphamide (FEC), has been shown to be safe and active as first-line treatment for metastatic breast cancer. In the past few years, new drugs, including taxanes, have shown a high level of activity as single agents in the treatment of advanced breast cancer. Doxorubicin/paclitaxel combinations have shown high overall response rates (90%) as first-line chemotherapy of advanced breast cancer; however, congestive heart failure has been reported in up to 20% of patients. Epirubicin/paclitaxel combinations have been associated with grade 3 cardiotoxicity (6%) in only one study. We report findings of a trial of combination epirubicin/paclitaxel as first-line treatment of advanced breast cancer, with overall response rates (ORRs) of 84% and a complete response (CR) rate of 19%. Achieving a CR to first-line chemotherapy for advanced breast cancer appears to predict survival, and adding an active drug with a different mechanism of action and nonoverlapping toxicity might increase the percentage of CRs. We therefore tested the feasibility and activity of 6 to 8 courses of first-line treatment with a three-drug combination (gemcitabine 1000 mg/m2 days 1 and 4, epirubicin 90 mg/m2 day 1, and paclitaxel 175 mg/ m2 over 3 hours on day 1) in a phase II study of 36 metastatic breast cancer patients. Treatment was well tolerated, with an ORR of 92% (95% confidence interval: 77.53%-98.25%) and a CR of 31%. In considering retreating patients who progress or relapse after receiving an anthracycline-/taxane-containing regimen with the same active drugs, epirubicin appears ideal in both the adjuvant and metastatic breast cancer settings.     

Role of bisphosphonates in postmenopausal women with breast cancer

Data suggest that bisphosphonates protect bone health and may have anticancer activity in postmenopausal women during adjuvant breast cancer therapy. However, key questions remain surrounding the role of adjuvant bisphosphonates in breast cancer, including patient populations deriving benefit, timing/scheduling of therapy, and specific clinical benefits. PubMed, Embase, and San Antonio Breast Cancer Symposium databases provide study results that address these issues in postmenopausal women. Review of these data would aid physicians in providing optimal management of breast cancer in postmenopausal women. For example, recent data reinforce use of intravenous bisphosphonates concurrently with adjuvant endocrine therapy to ameliorate bone loss in recently postmenopausal or osteopenic postmenopausal women with early breast cancer. In contrast, clinical data for oral bisphosphonates have not provided support for using anti-osteoporosis doses in this setting, and the optimal dose is unclear. Additionally, current clinical data show improvements in disease outcomes with bisphosphonates in many studies, although not in all patient subsets. Strong support for the potential adjuvant anticancer benefits from bisphosphonates has been demonstrated in women with established menopause (i.e., very low circulating estrogen levels). Initiating bisphosphonates early and concomitantly with adjuvant therapy generally provided the greatest benefits. However, questions remain such as schedule of treatment and relative potency among the intravenous bisphosphonates and elucidation of the role of oral bisphosphonates, as well as ongoing studies that might provide clarification. This review addresses these controversies in the context of translational research, which may provide the rationale for ongoing studies and evolving treatment paradigms in this area.     

Aminoglutethimide for the treatment of advanced postmenopausal breast cancer

Two hundred and thirteen unselected postmenopausal women with advanced breast cancer were treated with aminoglutethimide and hydrocortisone. There were 6 complete responses (CR), 47 partial responses (PR), 25 stable disease (SD) and 3 mixed response. Overall objective response rate was 28%, and with SD 41%. Median duration of objective response was 14 months. Years after menopause, age and tumour-free interval did not affect response rates. Main side-effects were drowsiness and lethargy (33%), rash (23%) and nausea (15%). Eleven patients (5%) stopped treatment because of toxicity. Median survival from start of treatment was 28 months and was the same for CRs, PRs and SD, compared with 10 months for progressive disease (P < 0.001). Median survival from first metastasis was 43 months for PR/CR, 40 months for SD (not significantly different) and 22 months for progressive disease (P < 0.001). Aminoglutethimide is an effective endocrine therapy in advanced postmenopausal breast cancer, particularly for bone deposits. Disease stabilization is associated with symptomatic and survival benefit similar to CR/PR.     

Role of fulvestrant in sequential hormonal therapy for advanced, hormone receptor-positive breast cancer in postmenopausal women

The introduction of antiendocrine agents with differing mechanisms of action now mandates the design of rational sequential hormonal regimens for breast cancer. The aromatase inhibitors (AIs), including the nonsteroidal compounds anastrozole and letrozole and the steroidal compound exemestane, are important alternatives or adjuncts to the antiestrogen agent tamoxifen in postmenopausal women with hormone receptor-positive breast cancer in the first-line management of advanced disease and in the adjuvant treatment of early-stage disease. These and other endocrine agents, including the newer estrogen receptor antagonist fulvestrant and also tamoxifen itself, have not been extensively evaluated within the context of hormonal sequencing. Based on a retrospective analysis of data from 3 phase III trials, patients treated with fulvestrant in the first- or second-line hormonal management of advanced breast cancer may derive further clinical benefit from subsequent treatment with an endocrine agent from another class. The need for prospective investigation of post-AI hormonal therapy is intensifying as a result of the increasing clinical use of the AIs. Sophisticated sequencing regimens designed to exploit different mechanisms of action have the potential to confer greater clinical benefit than the historical approach of selecting the agent with the next highest single-agent clinical activity upon disease progression.     

Role of fulvestrant in the management of postmenopausal breast cancer

Fulvestrant is a form of endocrine therapy used in the treatment of postmenopausal breast cancer. It has a unique mechanism of action in that it causes the degradation of estrogen receptor and therefore has been labeled a selective estrogen receptor downregulator. Unlike the selective estrogen receptor modulator tamoxifen, it has no agonistic properties and is therefore a pure anti-estrogen. Given its low level of bioavailability and presystemic metabolism, it has been formulated as an intramuscular injection. A number of dosing regimens have been utilized - these include a dose of 250 mg monthly ('approved dose'), an initial 500 mg followed by 250 mg on days 14 and 28, and thereafter 250 mg every 28 days ('loading dose'), or 500 mg on days 0, 14 and 28, and thereafter every 28 days ('high dose'). This article will review its unique mode of action and preclinical data, as well as clinical data for different dosing regimens and data for its combination with aromatase inhibitors. Fulvestrant is a well-tolerated drug and its toxicities will also be reviewed. The optimal position of fulvestrant in sequential endocrine therapy has yet to be defined.     

Treatment of advanced breast cancer in postmenopausal women with 4-hydroxyandrostenedione

4-Hydroxyandrostenedione (4-OHA), a new specific aromatase inhibitor, was used to treat 57 postmenopausal women with advanced breast cancer at a dose of 250 mg by i.m. injection every 2 weeks; 55 women were assessable for response. In all, 18 patients (33%) had objective evidence of a response to treatment, with a median duration of 12 months; the disease stabilised in 8 (14%) patients. Serum oestradiol levels, which were measured weekly in nine of the patients, were found to be suppressed to a mean of between 36% and 51% of pretreatment levels during the first 6 weeks of treatment. Three patients were withdrawn from treatment because of toxicity (pain at injection site, sterile abscess and rash). One patient had an isolated episode of anaphylaxis after 6 months of treatment. In comparison with our previous reports of 4-OHA treatment, a dose of 250 mg given i.m. fortnightly appears to be the optimal dose regimen. The efficacy of the drug seems to be similar to that of tamoxifen and aminoglutethimide.     

Fulvestrant in the treatment of postmenopausal women with advanced breast cancer

Fulvestrant is a new type of estrogen receptor antagonist with no agonist effects, and represents a valuable addition to the range of endocrine treatments available to treat postmenopausal women with advanced breast cancer. Fulvestrant binds, blocks and degrades the estrogen receptor, thereby retarding growth and progression of hormone-sensitive tumors. Two Phase III trials have demonstrated that fulvestrant is at least as effective as the third-generation aromatase inhibitor anastrozole in the treatment of advanced breast cancer following progression on antiestrogen therapy. In addition, a Phase III trial comparing fulvestrant with tamoxifen in postmenopausal women with advanced breast cancer showed similar efficacy and tolerability. Clinical trials are ongoing to evaluate different endocrine sequence options for postmenopausal women with breast cancer, and to evaluate the efficacy of fulvestrant in combination with anticancer agents that target other signaling pathways.     

Use of aromatase inhibitors in postmenopausal women with advanced breast cancer

Surgeons have been involved in the management of metastatic breast cancer since the technique of ovarian ablation was introduced in 1896. However, as newer hormonal and chemotherapeutic regimens were developed, drug therapy gradually replaced surgery as the preferred treatment for metastatic breast cancer. Thus, management of metastatic breast cancer has largely shifted from surgeons to medical oncologists. Advances in hormonal pharmacology have placed hormonal therapy alongside surgery and radiation therapy as a standard treatment option for women with advanced breast cancer. The purpose of this article is to update surgeons on the current use of hormonal agents for treatment of advanced breast cancer in postmenopausal women, and to review the aromatase inhibitors, a new line of hormonal agents for the treatment of advanced breast cancer. J. Surg. Oncol. 1997;66:215–220. © 1997 Wiley-Liss, Inc.     

Role of fulvestrant in the management of postmenopausal breast cancer

Fulvestrant is a form of endocrine therapy used in the treatment of postmenopausal breast cancer. It has a unique mechanism of action in that it causes the degradation of estrogen receptor and therefore has been labeled a selective estrogen receptor downregulator. Unlike the selective estrogen receptor modulator tamoxifen, it has no agonistic properties and is therefore a pure anti-estrogen. Given its low level of bioavailability and presystemic metabolism, it has been formulated as an intramuscular injection. A number of dosing regimens have been utilized – these include a dose of 250 mg monthly (‘approved dose’), an initial 500 mg followed by 250 mg on days 14 and 28, and thereafter 250 mg every 28 days (‘loading dose’), or 500 mg on days 0, 14 and 28, and thereafter every 28 days (‘high dose’). This article will review its unique mode of action and preclinical data, as well as clinical data for different dosing regimens and data for its combination with aromatase inhibitors. Fulvestrant is a well-tolerated drug and its toxicities will also be reviewed. The optimal position of fulvestrant in sequential endocrine therapy has yet to be defined.     

法乐通治疗晚期乳腺癌临床总结

目的 考察法乐通治疗晚期绝经后乳腺癌的放疗及其不良反应。方法：法乐通一线治疗每日一次６０ｍｇ口服,二线治疗每日一次１２０ｍｇ口服。结果：共６０例,有效率１８．３％,一线治疗１８例,有效率３３．３％,二线治疗４２例,有效率１１．９％,淋巴结和骨转移疗效较好,肝转移,肺转移及胸壁转移也有一定疗效。一线治疗较二线治疗,未用内分泌治疗较曾用内分泌治疗,绝经时间长（≥１０年）较经时间短（〈１０年）以及疗后无     

Pros and cons of aminoglutethimide for advanced postmenopausal breast cancer

Summary In a phase II clinical trial, 38 postmenopausal women with advanced breast cancer were treated with aminoglutethimide and replacement hydrocortisone. All women had previously received up to 4 modalities of endocrine therapy. Seventeen patients had also been treated with cytostatic drugs. Twenty-five percent of the 29 evaluable patients experienced objective tumor regression, lasting from 11 to more than 18 months. In 29% the disease was stabilized for 3 to more than 15 months. Toxicity was significant, necessitating drug withdrawal in 3 patients. One patient died within 3 weeks of therapy from multiple perforated gastric ulcers. Two patients developed herpes zoster within 4 weeks of treatment. Many side effects were minor and transient. However, treatment resulted in overt primary hypothyroidism in 25% of the evaluable patients and in a strongly increased need of acenocoumarin in all 3 patients on anticoagulant therapy.     

Fulvestrant in the treatment of postmenopausal women with advanced breast cancer

Fulvestrant is a new type of estrogen receptor antagonist with no agonist effects, and represents a valuable addition to the range of endocrine treatments available to treat postmenopausal women with advanced breast cancer. Fulvestrant binds, blocks and degrades the estrogen receptor, thereby retarding growth and progression of hormone-sensitive tumors. Two Phase III trials have demonstrated that fulvestrant is at least as effective as the third-generation aromatase inhibitor anastrozole in the treatment of advanced breast cancer following progression on antiestrogen therapy. In addition, a Phase III trial comparing fulvestrant with tamoxifen in postmenopausal women with advanced breast cancer showed similar efficacy and tolerability. Clinical trials are ongoing to evaluate different endocrine sequence options for postmenopausal women with breast cancer, and to evaluate the efficacy of fulvestrant in combination with anticancer agents that target other signaling pathways.     

Endocrine effects of low dose aminoglutethimide alone in advanced postmenopausal breast cancer

The site of action of aminoglutethimide (AG) has been investigated. An initial study was performed on 10 postmenopausal patients with advanced breast cancer who had taken 1000 mg AG per day and 20 mg hydrocortisone (HC) twice daily (b.d.) for greater than 3 months. There was a 15.5 +/- 5.6 s.e.-fold rise in 17-OH progesterone and a 4.9 +/- 0.9 s.e.-fold rise in 4 delta androstenedione but no rise in cortisol or oestrone 30 min after short Synacthen tests. These results suggested that peripheral aromatisation was a more important site of AG action than adrenal desmolase, and that adrenal 11 beta hydroxylase was inhibited. Since aromatase is more sensitive than desmolase to AG in vitro, lower doses of AG alone (i.e. without HC) were assessed for endocrine effects in 13 further post-menopausal women with advanced breast cancer. All of these patients tolerated 125 mg AG b.d., but 3 could not tolerate the conventional maximum dose. Oestrone levels on 125 mg AG b.d. were suppressed below pretreatment levels and were not significantly different from those on 500 mg AG b.d. alone, or with the addition of HC. Oestradiol levels were suppressed to a similar extent. Dehydroepiandrosterone sulphate (DHA-S) levels were not suppressed by AG alone, but fell on addition of HC. The endocrine results show low dose AG alone is an effective and well tolerated inhibitor of the peripheral production of oestrogens in postmenopausal patients. Therapeutic trials are now possible. DHA-S is not a marker of AG effect.