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

M. Piccart1,+, L. M. Parker2 and K. I. Pritchard3

1 Jules Bordet Institute, Brussels, Belgium; 2 Dana-Farber Cancer Institute, Boston, MA, USA; 3 Toronto-Sunnybrook Regional Cancer Centre, Toronto, Canada

Received 16 August 2002; revised 3 January 2003; accepted 25 February 2003

Abstract

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.

Key words: advanced breast cancer, estrogen receptor downregulation, ‘Faslodex’, fulvestrant, postmenopausal, sequencing

Introduction

Over the past 25 years, the prevalence of breast cancer has been increasing steadily in almost all populations. In the USA, the incidence has been rising by ~1% per year, with an accelerated period of increase seen in the 1980s and early 1990s, mainly due to the introduction of early detection measures during this time [1]. In Western countries, breast cancer is now the most common cancer in women and accounts for 18% of all female cancer deaths [2]. However, the mortality rate in many Western countries has been in decline since 1989 (particularly amongst Caucasian women), largely as a result of the introduction of new diagnostic techniques and improved therapeutic regimens [3, 4]. For Canada, the USA, and England and Wales, the 1989 age-standardized mortality rates for breast cancer per 100 000 women were approximately 31, 27 and 40, respectively. By 1999, the rates for these countries had declined to around 27, 22 and 31, respectively [57]. The most prominent rise in the incidence of breast cancer over the past 20 years has been in women >50 years of age, although the prognosis for women in this age group has been steadily improving. However, for women with advanced breast cancer, the prognosis remains poor; the 5-year relative survival rate for women >50 years of age with advanced stage disease is ~20% [8].

Advanced breast cancer (usually defined as metastatic or inoperable disease) is essentially incurable and the optimal management of the disease remains a significant therapeutic challenge. Restricting tumour growth, providing effective palliative treatment and maintaining quality of life (QoL) remain the objectives of therapy. For patients with widespread disease or aggressive visceral metastases, chemotherapy may be the most appropriate treatment. However, in patients with hormone-sensitive disease, a long disease-free interval, soft tissue or bony metastases and co-morbid conditions, hormonal therapy may be more appropriate [9]. Hormonal therapy is well tolerated and is the obvious option to be explored upon diagnosis of non-life-threatening hormone-sensitive breast cancer. This paper reviews the current status of endocrine therapy options in advanced stage disease in postmenopausal women. The role of newer therapies will be highlighted, and the opportunity of extending the window of endocrine therapy before the requirement for cytotoxic chemotherapy will be discussed.

Hormonal dependence of breast cancer

Since the late 19th century, a substantial amount of evidence has accumulated to demonstrate that oestrogens play a major role in the aetiology and progression of breast cancer [10, 11]. Oestrogens are essential for the normal growth and proliferation of target cells, such as breast epithelial cells [12]. These hormones exert their normal physiological effects by binding to specific nuclear proteins, known as oestrogen receptors (ERs), located mainly in the breast, liver and uterus in the female [12]. However, oestrogens also stimulate the growth of breast carcinoma, and it has been estimated that ~60–70% of breast cancers in postmenopausal women are ER-positive [13].

Breast cancer is more common in postmenopausal women [14]. However, postmenopausal women possess lower circulating levels of estrogen than premenopausal women [15]. This is rather paradoxical but may be explained by the fact that oestrogen levels in breast tissue are actually higher in postmenopausal women, possibly due to selective uptake of oestrogens from plasma and/or in situ synthesis [16, 17]. In addition, two large studies have shown that postmenopausal women, in whom breast cancer subsequently developed, had higher serum concentrations of free oestradiol than women who did not develop breast cancer [18, 19]. The high level of oestrogens found in the breast tissue of postmenopausal women may explain why about two-thirds of postmenopausal women who are diagnosed with breast cancer have oestrogen-dependent tumours, whereas only one-half of tumours found in premenopausal women are oestrogen-sensitive [20].

Current status of endocrine therapy

Breast cancer is characterised by great clinical and biological diversity. In some women with advanced disease, chemotherapy may restrict disease progression, while in others, the side-effects of this therapy do not warrant continuation of treatment. As endocrine therapy is generally well tolerated, hormonal agents have become the mainstay treatment for women with hormone-sensitive non-life-threatening advanced breast cancer. In addition to agents that directly affect oestrogen action, indirect methods of disrupting the effect of oestrogen on its target receptor have also been developed. These include inhibition of the biological pathways involved in the synthesis of oestrogen, and downregulation of the ER and the ER-regulated progesterone receptor (PgR).

Hormonal agents
The hypothalamic luteinising hormone-releasing hormone (LHRH) plays a key role in the control of ovarian oestrogen production. LHRH agonists may be used as an alternative to oophorectomy and have been used as treatment for disseminated breast cancer in premenopausal women. In these women, LHRH agonists have been successful, with response rates of between 31% and 63% [21]. In a recent trial, the addition of an LHRH agonist to standard adjuvant therapy (surgery ± radiotherapy ± chemotherapy ± tamoxifen) has been shown to significantly prolong relapse-free survival [relative risk (RR) 0.77; P = 0.001] and prolong overall survival (RR 0.84; P = 0.12) compared with patients who did not receive an LHRH agonist [22].

Progestins have an antioestrogenic action and thus a number of progestational agents have been assessed for their antitumour activity in women with advanced breast cancer. Megestrol acetate, a synthetic progestin, is the most widely used progestin and generally produces response rates of around 15–20% [23]. In some early trials, megestrol acetate demonstrated equivalent response rates to tamoxifen [24, 25] and, until the advent of the third-generation aromatase inhibitors (AIs: anastrozole, letrozole and exemestane), megestrol acetate was often used as second- or third-line treatment (depending upon menopausal status) after better-tolerated therapies. However, because of its unwelcome side-effect profile, characteristically associated with undesirable effects such as weight gain, it is now relegated to third- or fourth-line use.

Selective ER modulators (SERMs)
Tamoxifen was the first antioestrogen to be used in the treatment of hormone-responsive breast cancer and, with its good tolerability profile, has been the mainstay of hormonal therapy for postmenopausal breast cancer for many years [26, 27]. Tamoxifen exerts its antioestrogenic effect by competing with oestrogen for its binding site on the ER; binding is with a low affinity compared with that of oestrogen, causing attenuated transcription of oestrogen-responsive genes that are involved in the development and growth of breast malignancies (Figure 1).



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Figure 1. Comparison of the differing modes of action of (A) oestradiol, (B) tamoxifen and (C) fulvestrant. AF, activation factors; E, oestrogen; ER, oestrogen receptor; ERE, oestrogen response element; F, fulvestrant; HSP90, heat shock protein 90; T, tamoxifen; TC, transcription cofactors. Reprinted by permission of Wiley–Liss, Inc., a subsidiary of John Wiley & Sons Inc. from Howell et al. Cancer 2000; 89 (4): 817–825 [69]. Copyright 2000 American Cancer Society.

 
In some tissues, such as the breast tumour, tamoxifen exerts an oestrogen-antagonist effect [28]. However, in other tissues, tamoxifen has an oestrogen-agonist effect, which may be beneficial; in blood, tamoxifen appears to reduce serum cholesterol levels [29], and in bone it can offer some protection against osteoporosis [30, 31]. Tamoxifen also exerts an oestrogenic effect on the uterus. Evidence suggests that these effects are responsible for an increased risk of developing endometrial cancer in women treated with long-term tamoxifen. In an analysis of all trials comparing tamoxifen with no tamoxifen that began before 1990, the Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) analysed data from 37 000 women (comprising about 87% of the worldwide evidence). The incidence of endometrial cancer was found to be approximately two-fold greater in trials of women receiving 1 or 2 years of tamoxifen and approximately four-fold greater in trials of women receiving 5 years of tamoxifen [32]. There are also data suggesting that the intrinsic agonist activity of tamoxifen may eventually stimulate breast tumour growth and is a mechanism contributing to some treatment failures [33]. Tumours can develop resistance to tamoxifen via mechanisms that remain to be fully elucidated, although, interestingly, it is thought that this is not due to loss of ER status [34]. This, in turn, provides a rationale for continued hormone treatment after tamoxifen resistance has developed. In a preclinical model, it has been shown that various markers of the non-ER growth pathway [erbB1/2, extracellular signal-related kinase and epidermal growth factor receptor (EGFR)] are increased in tamoxifen-resistant breast cancer cell lines [35].

In the search to develop compounds lacking agonist properties, analogues of tamoxifen, such as toremifene and other triphenylethylenes, have been developed. In three phase III studies (serving as the basis for the 1997 FDA approval of toremifene for the treatment of metastatic breast cancer in postmenopausal women) tamoxifen and toremifene demonstrated equivalent efficacy [3638]. However, in patients treated with toremifene, stimulatory effects upon the uterus do not appear to be very different from those exerted by tamoxifen [39]. Significant cross-resistance has also been reported for both toremifene and tamoxifen [40, 41].

Another strategy for overcoming agonist-induced side-effects has been the development of compounds that retain the beneficial estrogenic effects on bone and lipids, while attempting to eliminate these effects on the uterus. Additional compounds such as raloxifene, LY353381, EM800 and CP336156 have been developed in an attempt to fulfill these criteria [42]. None of these agents has yet been approved for the treatment of breast cancer although, in studies examining efficacy in the prevention of osteoporosis, fewer breast cancers occurred in patients treated with raloxifene than placebo [43]. Trials to assess the efficacy of LY353381 in patients with advanced breast cancer are underway, whilst EM800 is no longer in development for this disease.

Aromatase inhibitors
At menopause, the synthesis of ovarian hormones ceases. However, oestrogen continues to be converted from androgen (produced by the adrenal glands) by the cytochrome P-450-dependent enzyme, aromatase [20]. This biological pathway served as the basis for the development of the anti-aromatase class of compounds. Both non-steroidal and steroidal anti-aromatase compounds have been developed. Both types suppress the final step in the conversion of androgen to oestrogen [44], and as such, are now widely used as breast cancer therapy in postmenopausal women.

Aminoglutethimide, a first-generation non-steroidal AI, was developed >30 years ago. A number of studies confirmed the efficacy of this agent in the treatment of metastatic breast cancer in postmenopausal women [45], with response rates equal to those of tamoxifen [46] and megestrol acetate [47]. However, side-effects with this agent are significant and include suppression of corticosteroid production (necessitating cortisol supplementation), drug-induced skin rash, fever, hypothyroidism, nausea, lethargy and dizziness [45]. Because of these effects, about 35% of patients discontinued treatment [48]. Additional problems including lack of specificity, low therapeutic index, and the demonstration that aromatase activity may actually increase following treatment with aminoglutethimide [49] led to the development of second-generation agents (e.g. formestane and fadrozole).

Second-generation AIs produce both partial and complete responses [50], although time to treatment failure (TTF) and time to progression (TTP) are significantly shorter in patients treated with formestane than in patients treated with tamoxifen [51]. In addition, undesirable side-effects (similar to those seen with first-generation AIs) and non-selective enzyme inhibition remain [52, 53].

The most recent non-steroidal AIs to be developed and marketed are anastrozole and letrozole. Since 1996 these third-generation AIs have been widely used in the treatment of advanced breast cancer in postmenopausal women with disease progression following tamoxifen.

Both anastrozole and letrozole have been shown to achieve similar TTP to megestrol acetate [5456]. As second-line therapy, anastrozole has also demonstrated an overall survival advantage over megestrol acetate [57]. In a pooled analysis of two phase III studies comparing two doses of anastrozole (1 mg/day and 10 mg/day) with megestrol acetate, 10.3% of patients who received anastrozole (1 mg/day) and 8.9% of those treated with anastrozole (10 mg/day) achieved a complete or partial response, compared with 7.9% of patients treated with megestrol acetate [53]. Two phase III studies have compared two doses of letrozole (2.5 mg/day and 0.5 mg/day) with megestrol acetate as second-line therapy in postmenopausal women with advanced breast cancer. In the first study letrozole 2.5 mg produced an objective response (OR) rate (complete response + partial response) of 24% compared with 13% for letrozole 0.5 mg (P = 0.004) and 16% for megestrol acetate (P = 0.04) [55]. However, in the second study there were no statistically significant differences in response rates between the three treatments, while the lower letrozole dose led to improved TTP and TTF [56].

Two large randomised phase III trials (North America and Europe) comparing anastrozole with tamoxifen as first-line treatment for postmenopausal women with advanced breast cancer have been conducted and were prospectively designed to allow combination of results. In the North American trial, TTP was 11.1 months and 5.6 months for anastrozole and tamoxifen, respectively (P = 0.005) [58]. In the European trial, median TTP was similar for both treatments (8.2 months versus 8.3 months for anastrozole and tamoxifen, respectively). Although no statistical analysis of subgroups was performed for this trial, for ER-positive patients a benefit was suggested in favour of anastrozole (median TTP 8.9 months versus 7.8 months for anastrozole and tamoxifen, respectively) [59]. Analysis of the combined data, carried out at a median follow-up of 18.2 months, demonstrated anastrozole to be at least equivalent to tamoxifen for median TTP (8.5 and 7.0 months, respectively), although this difference was not statistically significant [60]. In a Spanish trial comparing anastrozole and tamoxifen as first-line treatment of advanced breast cancer, a survival advantage was reported for anastrozole [61]. A similar phase III randomised trial in postmenopausal women with advanced stage disease has been performed to compare letrozole with tamoxifen. In this trial, TTP was significantly longer for patients receiving letrozole (median TTP 41 weeks versus 26 weeks; P = 0.0001). The OR rate was significantly higher for letrozole compared with tamoxifen (30% versus 20%; odds ratio 1.71; P = 0.0006) as was the rate of clinical benefit (49% versus 38%; P = 0.001) [62]. Letrozole has recently followed anastrozole in gaining FDA approval as first-line therapy for advanced breast cancer in postmenopausal women.

The third-generation steroidal AI exemestane, which irreversibly inhibits the aromatase enzyme, has also been developed. The minimum dose of exemestane that produces the maximum suppression of plasma estrogen levels is 25 mg/day [63]. In patients failing on tamoxifen, a phase III trial has demonstrated that exemestane (25 mg/day) significantly prolongs TTP and TTF when compared with megestrol acetate (median TTP 20.3 weeks versus 16.6 weeks, P = 0.042; median TTF 16.3 weeks versus 15.7 weeks, P = 0.042). Median survival time was also significantly longer with exemestane compared with tamoxifen (123.4 weeks; P = 0.039) and, at the time of analysis, median survival had not yet been reached in the exemestane-treated group [64]. Exemestane (25 mg/day) has also shown efficacy in patients who are refractory to megestrol acetate [65] and has demonstrated activity after treatment with non-steroidal AIs (mainly aminoglutethimide), leading to the assumption that there may be incomplete cross-resistance between steroidal and non-steroidal AIs [66]. Data comparing exemestane and tamoxifen as first-line agents are limited to reports of a small, randomised phase II trial and so accurate comparisons for these agents cannot be made.

Oestrogen receptor downregulation: a new mode of action in endocrine therapy
Fulvestrant (‘Faslodex’ is a trademark of the AstraZeneca group of companies) is a new ER antagonist that downregulates the ER and has no known agonist effect. Fulvestrant has undergone clinical evaluation for the treatment of metastatic or advanced breast cancer in postmenopausal women. Like tamoxifen, fulvestrant competitively binds to the ER, but with a much stronger affinity; ~89% that of oestradiol, compared with 2.5% for tamoxifen [67, 68], thus preventing endogenous oestrogen from exerting its effect in target cells. However, in contrast to tamoxifen, fulvestrant causes complete abrogation of transcription of oestrogen-sensitive genes and produces no demonstrable agonist effect [67, 69] (Figure 1). The reduced levels of ER in patients treated with fulvestrant are due to ER downregulation, accompanied by a reduction in the rate of receptor dimerisation [70] and/or to reduced shuttling of the ER from the cytoplasm [71].

Recently, a study compared the short-term biological effects of tamoxifen with fulvestrant in previously untreated postmenopausal women with primary breast cancer. Short-term exposure to fulvestrant reduced both ER and PgR protein concentrations in a dose-dependent manner, whereas tumours treated with tamoxifen developed increased PgR expression (attributed to the partial agonist effects of tamoxifen) [72]. In a trial involving 19 postmenopausal patients with advanced tamoxifen-resistant breast cancer, a clinical benefit rate (complete response + partial response + stable disease for a duration of >=24 weeks) of 69% was obtained in patients treated with fulvestrant, with a median duration of response of 26 months. Of note, there was no change in endometrial thickness during the first 15 months of fulvestrant therapy [73]. These data confirm that fulvestrant possesses a mechanism of action distinct from that of tamoxifen and that there is no cross-resistance between these two agents. These trials led to the initiation of the phase III clinical trial programme.

In two randomised, phase III trials [trial 0021: North American, double-blind, double-dummy trial in which fulvestrant was delivered in two 2.5 ml intramuscular (i.m.) injections; and trial 0020: conducted in Europe, South Africa and Australia, which had an open-label design and where fulvestrant was delivered in a single 5 ml i.m. injection] fulvestrant was compared with anastrozole in postmenopausal women with advanced breast cancer who had progressed after prior endocrine therapy. In both trials, fulvestrant was at least as effective as anastrozole for TTP (the primary efficacy end point) [74, 75]. In trial 0020, the OR rate was greater in the fulvestrant arm than in the anastrozole arm, although this was not statistically significant (20.7 versus 15.7%, respectively; P = 0.20). In trial 0021, the OR rate was similar in both treatment arms as was the clinical benefit rate (42.0% versus 36.0% for fulvestrant and anastrozole, respectively) [74]. Fulvestrant was well tolerated, with minor gastrointestinal disturbances being the most commonly described adverse event.

The maintenance of QoL is of the utmost importance in the consideration of treatment options for patients with advanced breast cancer. The monthly parenteral mode of administration of fulvestrant is novel for endocrine therapy and offers the potential benefit of enhanced patient compliance. The Functional Assessment of Cancer Therapy—Breast (FACT-B) questionnaire [76] is a sensitive measure for evaluating physical, functional, social and emotional well-being. Studies using the FACT-B questionnaire have demonstrated that disease progression, in particular, leads to a perceived deterioration in QoL, whereas treatment response is associated with an improvement in QoL. In the fulvestrant pivotal trials, use of the FACT-B questionnaire demonstrated that the mode of monthly administration, be it either two 2.5 ml i.m. injections or one 5 ml i.m. injection, did not adversely affect QoL [74, 75].

Extending the prospects for endocrine therapy

In hormone-responsive patients, endocrine therapy represents the mainstay of effective, well-tolerated treatment for advanced breast cancer before cytotoxic chemotherapy is required. Over the past 20 years, tamoxifen has been the most widely used treatment for advanced disease, with other endocrine therapies providing further treatment options after disease progression. Since the introduction of tamoxifen in 1971, a number of new endocrine agents have been developed with different modes of action, leading to the possibility of sequential administration in order to extend the window of palliative treatment. However, the most effective sequence of endocrine therapies has yet to be established. In fact, the individual nature of advanced malignancy emphasises the necessity for flexibility and the tailoring of the sequence of therapies to suit individual patients.

A proviso for the success of any new endocrine therapy must be a lack of cross-resistance with prior treatments. Of the SERMs that have been developed, none have shown clinically relevant activity following development of resistance to tamoxifen [40, 7780].

In contrast, it is well established that AIs are effective in patients progressing on tamoxifen therapy. As second-line treatment for postmenopausal women progressing on tamoxifen, the third-generation AIs offer a significant efficacy and safety advantage over older agents in this class and also megestrol acetate, and have therefore been widely used as second-line therapy [54, 55, 77]. Exemestane has been shown to have activity after failure with the non-steroidal AIs and may therefore be used as third-line treatment in patients progressing on tamoxifen and a non-steroidal AI [66].

The recent evidence demonstrating that AIs are more effective than tamoxifen in postmenopausal women with advanced breast cancer will likely bring changes to current first-line treatment practice. As the number of clinicians who choose AIs as first-choice treatment increases, the optimal position of subsequent endocrine therapies requires further investigation. In a recent study, the efficacy of tamoxifen as second-line therapy to anastrozole (and vice versa) was assessed in postmenopausal women with advanced breast cancer. Preliminary data from 98 patients who received tamoxifen subsequent to anastrozole showed that 56 patients had a clinical benefit of >=24 weeks. Preliminary data from 61 patients who received anastrozole second-line to tamoxifen showed that 41 had clinical benefit for a similar duration of time. Of the patients who showed a clinical benefit to either second-line therapy, >=50% maintained this benefit for 12 months or longer [81].

The introduction of fulvestrant provides a further therapeutic option for the treatment of women with hormone-sensitive disease and may increase the overall period during which hormonal agents may be used. The mechanism of action of fulvestrant is different from that of both tamoxifen and AIs, reducing the risk of cross-resistance, which should allow this drug to have an important role in the hormonal treatment of breast cancer. For patients who have progressed on tamoxifen, fulvestrant produces good response rates [73]; moreover, in tamoxifen-resistant patients, fulvestrant is as effective as anastrozole. A retrospective analysis showed that women with advanced breast cancer progressing on fulvestrant remained sensitive to subsequent treatment with anastrozole and letrozole [82]. These data suggest that in patients who have progressed on tamoxifen, fulvestrant represents an additional treatment choice and, importantly, allows the option of further endocrine therapy with AIs. As AIs move to more widespread use as first-line treatment for advanced disease, and eventually adjuvant therapy, data on the efficacy of fulvestrant after AIs are essential to determine the most appropriate sequence. In the 1980s, the standard sequence of therapy was tamoxifen followed by either megestrol acetate or aminoglutethimide. The introduction of new therapies has allowed this sequence to evolve considerably. In the current treatment environment, the choice of fulvestrant after tamoxifen may be reasonable, and when tamoxifen is used first-line, a possible sequence choice may be tamoxifen–fulvestrant–AI. When AIs are used as first-line treatment, fulvestrant may also be an appropriate second-line treatment, although, as yet, there are few data available to support the use of fulvestrant after AIs. A schematic illustrating the possible positioning of fulvestrant in the endocrine cascade for the treatment of postmenopausal women with metastatic or advanced disease is shown in Figure 2 [83].



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Figure 2. Possible positions for fulvestrant in the endocrine cascade for postmenopausal women with metastatic or advanced breast cancer [83]. Reprinted by permission of I.C. Henderson from A rose is no longer a rose. J Clin Oncol 2002; 20: 3365–3368. Copyright 2002 American Society of Clinical Oncology.

 
At present, AIs and fulvestrant look set to provide a significant contribution to the treatment of hormone-sensitive breast cancer in postmenopausal women. Hormonal agents such as megestrol acetate still have a role to play but have now been relegated to fourth- or even fifth-line. Although advanced breast cancer remains incurable, these new endocrine therapies that lack cross-resistance with existing agents and possess favourable toxicity profiles represent significant steps forward and may provide valuable opportunities to extend the treatment window of endocrine therapy before the requirement for chemotherapy. It is uncertain whether or not an additional link in the chain of endocrine therapies will prolong overall survival. Will the response rate, duration of response and survival improve with this new sequence of treatments, or will it be the same, with reduced toxicity? In either case, these well-tolerated agents will allow QoL to be maintained for as long as possible.

A promising addition to the future of hormonal therapy is the combination of antiestrogens with a number of biological antitumour agents. Herceptin, a monoclonal antibody specific for erbB2 [part of the EGFR-tyrosine kinase (EGFR-TK) family] has shown promising results in the treatment of women with metastatic breast cancer [84]; a randomised phase II/III trial is now underway to compare the effectiveness of anastrozole plus herceptin in postmenopausal women with advanced disease. The EGFR-TK inhibitor ZD1839 (‘Iressa’) is also an effective inhibitor of cell proliferation [85] and when used in combination with tamoxifen, this agent has been shown to be more effective at inhibiting proliferation of breast carcinoma cell lines than either drug alone [86]. Although the concept of combination biologic/hormonal therapy is still in its infancy, the future of biological therapies and their potential role in extending the window of effective endocrine therapies is an area of exciting possibilities.

Footnotes

+ Correspondence to: Dr M. Piccart, Chemotherapy Unit, Internal Medicine and Oncology, Jules Bordet Institute, 1 Rue Heger-Bordet, Boulevard de Waterloo 125, B-1000 Brussels, Belgium. Tel: +32-2-541-3206; Fax: +32-2-538-0858; E-mail: martine.piccart{at}bordet.be Back

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