11.2.1 Endocrine treatment of breast cancer

Endocrine manipulation has been recognized as a treatment modality for breast cancer for over 100 years. Oestrogen is an important promoter in the pathogenesis of breast cancer and endocrine response, for the most part, is dependent on the presence of oestrogen receptor, a protein which can be detected in about 70% of primary breast cancers.

Historically, treatments 30–40 years ago involved surgical removal of endocrine glands such as the ovaries, adrenal glands, or hypophysis. However, a better understanding of the mechanisms that result in oestrogenic deprivation of breast cancer cells has enabled medical therapeutics to be developed which have largely replaced surgical ablative procedures (Box 11.2.1.1). Firstly, hormonal manipulation can be achieved at a cellular level by competing for oestrogen receptor in the breast tumour, using so-called antioestrogens, such as tamoxifen which, although antioestrogenic on breast cancer cells, can have oestrogenic effects in other tissues. More antioestrogenic agents known as selective oestrogen receptor modulators (SERMs), and ‘pure’ antioestrogens such as fulvestrant have now been developed that have little or no oestrogenic effects, and these are being clinically evaluated.

An alternative approach is to lower systemic oestrogen levels in premenopausal women by the use of luteinizing hormone releasing hormone (LHRH) agonists and in postmenopausal women by the use of aromatase inhibitors, which block oestrogen synthesis in nonovarian tissues. Additional, endocrine agents with more ill-defined mechanisms, such as progestogens, androgens, and corticosteroids, can also cause endocrine responses.

In patients with oestrogen receptor-positive advanced breast cancer, endocrine treatments in general achieve a response rate of between 20 and 40%, according to the type of therapy and prior exposure to endocrine treatment. Predictors of response to hormone therapy include a previous response to endocrine treatment, the site of metastases, coexpression of progesterone receptor, and the age of the patient. The median response duration to endocrine therapy in advanced disease is about 8–14 months and for some patients response duration can last several years.

In patients with early stage oestrogen receptor-positive breast cancer, adjuvant endocrine therapy given for 5 years after primary surgery delays local and distal relapse and prolongs survival. It also substantially reduces the incidence of contralateral breast cancer in patients with primary breast cancers, and similarly will reduce the incidence of breast cancer in healthy women by about 50%. As such, endocrine therapy can be used as chemoprevention of breast cancer.

Overall, the development of relatively low toxicity endocrine treatments for advanced and for operable breast cancer has had a substantial impact on the management of this disease, and the types of treatment will be reviewed in this chapter.

Approximately two-thirds of human breast carcinomas express oestrogen receptors and thus may be dependent on oestrogen for growth. Tamoxifen is a nonsteroidal oestrogen receptor antagonist which inhibits breast cancer growth by competitive antagonism of oestrogen at the receptor site. Its actions are complex due to partial oestrogenic agonist and antagonist effects depending on the specific end organ. It was first approved by the Food and Drug Administration (FDA) in 1978 for the treatment of advanced breast cancer and, although it is an effective treatment, the partial agonist effects may account for the development of tamoxifen resistance and disease progression after prolonged administration, in addition to specific adverse side effects on the gynaecological tract. Alternative therapies for endocrine-sensitive breast cancer following tamoxifen failure will be discussed elsewhere in the chapter.

The decrease in contralateral breast cancer in women receiving adjuvant tamoxifen, together with experimental data showing that the drug would prevent the development of rat mammary tumours, encouraged the development of trials in healthy women at increased risk of developing the disease. The National Surgical Adjuvant Breast and Bowel Project (NSABP) P1 trial (1) demonstrated that 5 years of tamoxifen reduced the risk of oestrogen receptor-positive tumours in women deemed to be at increased risk of developing the disease. This was, however, associated with an increased risk of thromboembolism and endometrial cancer. The International Breast Intervention Study (IBIS)-1 trial showed similar results with a reduction in the incidence of newly diagnosed breast cancer of 33% at a median follow-up of 50 months (2).

Finding agents which are more effective in chemoprevention with fewer side effects has been explored in several recent trials. The NSABP Study of Tamoxifen and Raloxifene (STAR) trial (3) compared the chemopreventive and tolerability/toxicity profiles of tamoxifen with raloxifene, a SERM originally developed for the prevention of osteoporosis. Raloxifene was found to be as effective as tamoxifen at reducing the risk of invasive breast cancer with a lower risk of thromboembolic events and cataracts. The risk of fractures and ischaemic heart disease was similar in both groups. The Postmenopausal Evaluation and Risk-reduction with Lasofoxifene (PEARL) trial (4) has evaluated the effects of the newer SERM, lasofoxifene, on the incidence of oestrogen receptor-positive breast cancer in postmenopausal women with osteoporosis compared with placebo. Lasofoxifene was associated with a reduced incidence of oestrogen receptor-positive breast cancer and a reduced incidence of vertebral and nonvertebral fractures. It was associated with an increased risk of thromboembolic events but not stroke or endometrial cancer. However, none of these chemopreventive trials have so far demonstrated a reduction in overall or breast cancer-specific mortality.

In early breast cancer, tamoxifen has been the gold standard of adjuvant endocrine therapy for both premenopausal and postmenopausal breast cancer for over two decades. In an overview of the effects of chemotherapy and hormonal therapy for early breast cancer involving 194 randomized controlled trials by the Early Breast Cancer Trialist’s Collaborative Group (EBCTG) (5), a 31% reduction in the annual breast cancer death rate with 5 years of adjuvant tamoxifen was reported at 15 years of follow-up. Breast cancer is relatively unusual in that although the risk of distant recurrence is greatest during the first decade, it may still remain substantial during the second decade and indeed continue indefinitely. It is therefore highly significant that in the trials comparing allocation to a control arm or 5 years of tamoxifen the benefits are persistent with the reduction in the 15-year probability of death from breast cancer being about three times as great as the 5-year probability (Fig. 11.2.1.1) (1). The benefit from tamoxifen treatment occurred irrespective of age, menopausal status, or the use of concomitant chemotherapy and was confined to those patients with oestrogen receptor-positive cancers. Overall, this gave an 8% reduction in 5-year mortality for patients with primary operable breast cancer and there was no apparent added benefit for doses of tamoxifen greater than 20 mg/day. There was a 47% reduction in the incidence of contralateral breast cancer at 5 years.

Adjuvant tamoxifen is typically administered for 5 years. In the EBTCG overview the reduction in recurrence rate and breast cancer death are highly significant in both the trials of 1–2 years of tamoxifen but were greater for 5 years. The NSABP B-14 study (6) compared 5 to 10 years of adjuvant tamoxifen in women with oestrogen receptor-positive, axillary node-negative breast tumours. No advantage beyond 5 year was found and following 7 years of follow-up a slight advantage was observed in patients who discontinued tamoxifen compared with those who continued to receive it in terms of disease-free survival (p = 0.03). However, this study only examined node-negative patients and in two further trials (aTTOm and ATLAS (7, 8)) preliminary results showed a small reduction in breast cancer recurrence in those randomized to continue tamoxifen; however, no significant difference was observed for breast cancer or overall mortality. Additionally, in the aTTom trial (3), an increase in endometrial cancer incidence, although not mortality, was noted. Further follow-up is required to reliably assess the longer-term effects on recurrence and overall effects, if any, on mortality.

Thus, tamoxifen 20 mg/day for 5 years alone or in addition to chemotherapy remains the standard endocrine agent of choice for early breast cancer in premenopausal patients. Other agents to be used in addition to tamoxifen or in place of tamoxifen in postmenopausal women will be discussed below.

Clinical experience of tamoxifen over 30 years has allowed reliable assessment of its side effects. Other than the short-term and usually mild side effects of hot flashes, altered menses, and nausea, some long-term beneficial and detrimental side effects, predominantly as a result of its differential oestrogenic and antioestrogenic effects in different tissues, have been identified. Tamoxifen acts predominantly as an oestrogen agonist on bone, increasing mineral density and thereby potentially reducing the risk of osteoporotic fractures. Similarly, it lowers serum cholesterol, potentially decreasing the risk of heart disease. The risk of developing deep vein thrombosis and pulmonary emboli is increased in women taking tamoxifen and there is an increase in risk of developing endometrial cancer, due to tamoxifen’s oestrogenic stimulation of the endometrium. However, the 2005 EBCTG overview did not demonstrate a significant excess mortality related to these effects and, overall, there is no doubt that the benefits of tamoxifen substantially outweigh the risks when given as adjuvant therapy to patients with primary breast cancer.

In contrast to tamoxifen, which antagonizes oestrogen at the receptor site, the oral aromatase inhibitors such as anastrozole (Arimidex^TM), letrozole (Femara^TM), and exemestane (Aromasin^TM) all reduce serum oestrogen levels in postmenopausal women by preventing the conversion of adrenal androgens (androstenedione and testosterone) into oestradiol and oestrone by the cytochrome P450 enzyme aromatase (Fig. 11.2.1.2) (9).

While oestrogens are primarily synthesized in the ovary in premenopausal women under the control of stimulatory effects of luteinizing hormone and follicle-stimulating hormone, following the menopause mean plasma oestradiol levels fall from about 400–600 pmol/l to around 25–50 pmol/l. These residual oestrogens come solely from peripheral aromatase conversion, particularly in subcutaneous fat, and plasma oestrone levels correlate with body mass index in postmenopausal women. Of note, aromatase inhibitors are contraindicated in premenopausal women without additional ovarian suppression because the suppression of peripheral aromatase results in a reduced feedback to the hypothalamus and an increase in ovarian stimulation (9).

Intracellular aromatase is present not only in peripheral adipose tissue but also in the breast tumour itself, thus providing the breast tumour cell with two different sources of oestrogen. In situ aromatization within breast tumours has been shown to be a key determinant of tumour oestradiol levels, and tumour growth rate in cell models reflecting the postmenopausal state. Aromatase inhibitors have been shown not only to reduce plasma oestrogen levels but also inhibit in situ aromatase activity and reduce endogenous oestrogens within the breast (10).

The currently approved ‘third-generation’ aromatase inhibitors all powerfully inhibit oestrogen synthesis and may be considered as steroidal (type 1) or nonsteroidal (type 2) (Fig. 11.2.1.3) (9). In contrast to the second-generation inhibitors such as fromestane, they are highly specific with almost no effect on cortisol or aldosterone levels.

Nonsteroidal aromatase inhibitors, such as anastazole and letrozole, interact noncovalently with the haem moiety of aromatase and occupy its substrate binding site, preventing the binding of androgens to the catalytic site. This antagonism is reversible and the type 1 aromatase inhibitors can be competitively displaced from the active site by endogenous substrate. In contrast, the steroidal type 1 inhibitor exemestane is an analogue of the natural aromatase substrate androstenedione and is recognized by the active site of aromatase as alternative substrate. However, it appears to be converted by aromatase into a reactive intermediate that binds irreversibly and covalently to the substrate binding site of aromatase, permanently inactivating the enzyme. In theory, irreversible steroidal aromatase inhibitors may be expected to have a longer duration of action because oestrogen synthesis can only resume following de novo synthesis of aromatase. However, this occurs relatively quickly (1–2 days). Additionally, the pharmacokinetics properties of each specific aromatase inhibitor affect the duration of oestrogen suppression. The nonsteroidal aromatase inhibitors anastrozole and letrozole have similar pharmacokinetics with half-lives approximating 48 h, while the half-life of the steroidal aromatase inactivator exemestane is 27 h. All are administered on a once-daily schedule.

Between 1995 and 2000 the three third generation aromatase inhibitors were established clinically when a series of randomized controlled trials in over 2000 women demonstrated clinical superiority over megestrol acetate as second-line therapy after tamoxifen. This was in contrast to previous trials with the second-generation inhibitors fadrozole and formestane, which had all failed to show any such advantage. The improvements in clinical endpoints for the third-generation aromatase inhibitors, together with their consistent superior tolerability profile over megestrol acetate (i.e. reduced weight gain and thromboembolic events) defined the aromatase inhibitors by the late 1990s as the standard endocrine treatment for advanced postmenopausal breast cancer following tamoxifen failure (11).

Subsequent trials in advanced breast cancer asked whether aromatase inhibitors could challenge tamoxifen as the first-line endocrine agent of choice. Previously, no first- or second-generation aromatase inhibitor had proved superior to tamoxifen. In addition to comparing tolerability, the potential of these studies with the new third-generation aromatase inhibitors was to see whether the near complete oestrogen blockade provided by these drugs could deliver greater control of hormone-sensitive breast cancer than tamoxifen, thus circumventing the problem of acquired resistance due to the partial agonist effects of tamoxifen (12).

Data from four randomized controlled trials of third-generation aromatase inhibitors in advanced disease consistently suggested improved efficacy over tamoxifen (Table 11.2.1.1) (13–18). The largest of these, a randomized double blind phase III trial in over 900 postmenopausal women with locally advanced or metastatic breast cancer, compared letrozole 2.5 mg with tamoxifen 20 mg daily (16, 17). Patients treated with letrozole had a significantly higher objective tumour response rate (30 versus 20%, p <0.001), clinical benefit rate (49 versus 38%, p <0.001), and prolonged time to disease progression (median time to progression of 9.4 months versus 6.0 months, hazard ratio 0.72, p <0.0001). Of particular note in this trial, nearly 20% patients had received prior tamoxifen in the adjuvant setting, although had ceased more than a year (median 3 years) prior to development of metastatic disease; in this subgroup, retreatment with tamoxifen had a low response rate of 8% compared with a 32% response rate with letrozole. The improvements in clinical efficacy for letrozole resulted in an early improvement in survival during the first 2 years, with overall 64% patients treated with letrozole alive at 2 years compared with 58% treated with tamoxifen (p = 0.02) (20), although with longer follow-up this difference was lost. The explanation for this may relate to the high number (>50%) of patients who prospectively crossed over to the alternate treatment at the time of progression, as significantly more patients benefited from second-line letrozole after progression on tamoxifen than to second-line tamoxifen after letrozole. There were no significant differences in toxicity between the two treatments (17).

With the data from these trials supporting the improved efficacy over tamoxifen, the third-generation aromatase inhibitors have now become the standard of care for first-line endocrine therapy in postmenopausal women with oestrogen receptor-positive advanced breast cancer.

The establishment of the efficacy and tolerability of aromatase inhibitors in advanced breast cancer encouraged the development of a number of trials examining their use in the adjuvant setting. Therapeutic approaches addressed include the adding to or substituting tamoxifen with an aromatase inhibitor and the optimal sequencing and duration of therapy.

Resistance to tamoxifen can occur both de novo and after a period of time leading to disease relapse. Sequencing strategies using two noncrossresistant agents have been evaluated in studies comparing the efficacy of using tamoxifen for an initial period of 2 to 3 years followed by a switch to an aromatase inhibitor to complete 5 years of adjuvant endocrine therapy versus tamoxifen monotherapy.

Hormone receptor-positive breast cancers often run a chronic relapsing course and the value of extended adjuvant endocrine therapy beyond 5 years with aromatase inhibitors will also be discussed.

Two large studies have assessed the efficacy of the aromatase inhibitors compared with tamoxifen as adjuvant endocrine therapy in postmenopausal women with early breast cancer (Table 11.2.1.2) (25–27).

The Arimidex, Tamoxifen, Alone or in Combination (ATAC) trial was the first large clinical trial to investigate the role of aromatase inhibitors as adjuvant therapy for breast cancer. Over 4 years, 9366 postmenopausal women from 21 countries were enrolled. The hypothesis tested was that anastrazole was noninferior or superior to tamoxifen, and that the combination was superior to tamoxifen alone. The combination treatment was discontinued after the initial analysis because it showed no efficacy or tolerability benefits over tamoxifen alone. A possible explanation for this is that tamoxifen acts as an oestrogen receptor agonist in the absence of any oestrogen, and as there is no oestrogen to antagonize, the net effect of the tamoxifen–anastrazole combination is identical to that of tamoxifen alone.

The most recent analysis from this trial reported the outcome following a median follow-up of 100 months (25). Overall, anastrazole monotherapy compared with tamoxifen was associated with improved disease-free survival (DFS) in hormone receptor-positive patients hazard ratio (HR) 0.85, p = 0.003. Absolute differences in time to recurrence increased over time: time to recurrence 2.8% at 5 years (anastrazole 9.7% versus tamoxifen 12.5%) and 4.8% at 9 years (anastrazole 17.0% versus tamoxifen 21.8%). In addition, recurrence rates remained significantly lower on anastrazole compared with tamoxifen after treatment completion: HR 0.75, p = 0.01. However, these differences in preventing/delaying disease recurrence did not result in a difference in overall survival between the two treatments.

The Breast International Group (BIG)-198 trial (26) was a four-armed study that assessed both the efficacy of aromatase inhibitors versus tamoxifen as well as switching strategies. It recruited 8028 women who were randomized to four treatment arms. Patients in arms A and B received tamoxifen or letrozole respectively for 5 years from randomization. Those in arm C received tamoxifen for 2 years followed by a switch to letrozole for 3 years and those in arm D received letrozole for 2 years followed by tamoxifen for 3 years.

In 2005, at a median follow-up of 25.8 months, letrozole demonstrated a significant improvement in DFS over tamoxifen (HR 0.81, p = 0.003) and distant disease-free survival (DDFS) (HR 0.73, p = 0.001) (26). These results led to the unblinding of the tamoxifen alone arm and 25.2% of patients selectively crossed over to letrozole. This has complicated subsequent intention to treat analyses of the monotherapy arms. A recent update of the study at a median follow-up of 76 months (27) included both an intention to treat analysis and a censored analysis at the time of crossover (Table 11.2.1.2). This demonstrated a statistically significant improvement in DFS and DDFS in favour of letrozole over tamoxifen in the intention to treat population with a trend towards overall improved survival.

In a recent meta-analysis (28), an overall 5-year gain of 2.9% and 8-year gain of 3.9% for recurrence for aromatase inhibitors over tamoxifen was noted. This was associated with a 1.1% reduction in breast cancer mortality at 5 years but was no longer statistically significant at 8 years.

Several recent trials have evaluated tamoxifen montherapy for 5 years versus tamoxifen for 2–3 years followed by a switch to an aromatase inhibitor (Table 11.2.1.3) (29–32). The largest of these studies was the Intergroup Exemestane Study (IES) (29), which compared switching to exemestane after 2–3 years of tamoxifen to continuing on tamoxifen for the remainder of a 5-year endocrine treatment period. This demonstrated not only a statistically significant improvement in DFS but also in overall survival. These findings were also confirmed in the Austrian Breast and Colorectal Cancer Study Group (ABCSG) 8 trial with anastrazole (32). A meta-analysis including 9015 patients with a mean follow-up of 3.9 years of the trials of switching versus tamoxifen montherapy demonstrated a 3.1% gain for a switching strategy versus tamoxifen monotherapy for recurrence at 3 years and a 3.5% gain at 6 years. This was associated with a statistically significant reduction in breast cancer mortality and death from any cause of 1.6% and 2.2% respectively at 6 years.

The BIG 1–98 trial is the only trial so far to have reported a comparison between the use of an upfront aromatase inhibitor versus a switching strategy. At a median follow-up of 71 months, there was no significant difference in disease-free recurrence, overall survival, or time to distant recurrence between the switching and the letrozole monotherapy arms, although there was trend in favour of upfront letrozole. This trend was greatest in node-positive patients, with a 1.4% difference in breast cancer recurrence in node-negative patients and a 2.3% difference in node-positive patients at 5 years. Interestingly, there was no significant difference in breast cancer recurrence between the letrozole followed by a switch to tamoxifen and the letrozole monotherapy arm. The clinical significance of this is that patients who commence an aromatase inhibitor but experience side effects or toxicity may be safely switched over to tamoxifen to complete their adjuvant endocrine therapy.

Hormone receptor-positive breast cancers have a chronic relapsing nature, more so than hormone receptor-negative cancers with risk of recurrence continuing indefinitely with approximately half of all recurrences occurring between 5 and 15 years after surgery despite 5 years of adjuvant tamoxifen treatment. There is, therefore, a rationale for considering extended adjuvant endocrine therapy beyond 5 years. The MA-17 study (35) was a double blind, placebo controlled trial designed to test whether 5 years of letrozole therapy in postmenopausal women who have completed 5 years of adjuvant tamoxifen could lead to an improvement in DFS. The trial demonstrated a significant improvement in DFS in all patients and overall survival in node positive patients in the letrozole containing arm. Following completion of 5 years of letrozole, patients from this treatment group are now being randomized to receive another 5 years of letrozole or placebo, i.e. up to year 15.

In general, the third-generation aromatase inhibitors are well tolerated although symptoms of oestrogen withdrawal are common. The commonest side effects include hot flashes, musculoskeletal stiffness, and vaginal dryness. However, in the clinical trial setting the different side-effect profiles of tamoxifen and aromatase inhibitors do not appear to impact on patient’s quality of life (36). Interestingly, the appearance of vasomotor or joint symptoms within the first 3 months of treatment has been associated with a greater decrease in breast cancer recurrence in the ATAC trial (37).

In the trials comparing the third-generation aromatase inhibitors with tamoxifen, the adverse events associated with tamoxifen’s oestrogenic properties, such as venous thromboembolism and endometrial cancer, were significantly less common in the aromatase inhibitor groups (38). However, tamoxifen is also thought to have a protective effect against the development of osteoporosis and an increased risk of osteoporosis and fractures has been observed with the aromatase inhibitors compared with tamoxifen (26, 38). The ASCO guidelines recommend that postmenopausal women who receive an aromatase inhibitor should have their bone mineral density evaluated, with calcium and vitamin D supplementation or bisphosphonate use dependent on the result (39). Tamoxifen has been associated with a decreased rate of myocardial infarction and related death compared with placebo (40), which is thought to be attributable to a lipid-lowering effect. Increases in cardiovascular events (41) and hypercholesterolaemia (38) have been observed with aromatase inhibitors over tamoxifen.

The relatively short follow-up time and overall small numbers of cardiovascular events in these studies make it difficult to conclude whether the apparent differences between the aromatase inhibitors and tamoxifen is a real effect or related to a beneficial effect of tamoxifen. The fact that most women presenting with early breast cancer can now expect long-term survival means that long-term vigilance of cardiovascular morbidity and mortality in these studies is warranted.

Cumulatively, the results of these adjuvant aromatase inhibitor trials have led to a substantial increase in the use of aromatase inhibitors in early breast cancer, but also to some uncertainty as to whether all postmenopausal patients should be treated with an upfront aromatase inhibitor or tamoxifen for 2 to 3 years followed by a switch to an aromatase inhibitor subsequently.

The studies comparing tamoxifen followed by a switch to an aromatase inhibitor have not only demonstrated improved DFS compared with tamoxifen monotherapy but also improved overall survival. Inevitably, however, these studies have not included patients who relapsed early on tamoxifen, i.e. before the year 2–3 switch point, and in the short-term women at high risk of relapse may benefit from the improved DFS seen with the aromatase inhibitors. However, in the longer-term it is possible that there may also be a benefit from the sequential use of two noncrossresistant agents. Longer-term follow-up of these studies will help to address some of these issues and provide further information on the long-term side effects of aromatase inhibitors. Current guidelines from the American Society of Clinical Oncology recognize this controversy stating that the optimal adjuvant hormonal therapy for postmenopausal women with hormone receptor-positive breast cancer includes an aromatase inhibitor as initial therapy or after treatment with tamoxifen (42) and ultimately treatment tolerability and relative toxicities must also be considered.

In 1896, Beatson published the first report of surgical oophorectomy as a treatment modality for advanced breast cancer in premenopausal women. This was followed, in the 1920s, by radiotherapy-induced ovarian ablation, which was shown to be equally effective, and since then ovarian ablation by either means has been used as a therapy for premenopausal patients with advanced breast cancer.

LHRH agonists, which initially stimulate and then exhaust the LHRH receptors in the pituitary, cause reversible suppression of ovarian function and are currently used as an alternative to ovarian ablation for treatment of advanced breast cancer in premenopausal women. The initial stimulation of luteinizing hormone can cause a short ‘flare’ in disease-related symptoms, followed by a complete inhibition of luteinizing hormone secretion, decreasing oestradiol levels to near castration levels. This effect is reversible on withdrawal of the LHRH agonist. The LHRH agonist goserelin 3.6 mg administered by deep subcutaneous injection every 4 weeks is licensed in the UK for the treatment of breast cancer.

The EBCTG (5) reviewed trials involving almost 8000 women with oestrogen receptor-positive or oestrogen receptor-unknown early breast cancer who were randomized to ovarian ablation by surgery, or irradiation, or ovarian suppression with an LHRH agonist. Overall, there was a definite effect of ovarian ablation or suppression both on recurrence and breast cancer mortality (Fig. 11.2.1.4) (1). However, the effects of ovarian treatment appear smaller in the trials where both groups got chemotherapy than in the trials where neither did. A more recent meta-analysis (19) only analysed trials where oestrogen receptor status was known and used LHRH agonists as the method of ovarian suppression. The primary endpoints were any recurrence and death after recurrence, with a median follow-up time of 6.8 years. In particular, a benefit was observed when LHRH agonists were used after chemotherapy, either alone or with tamoxifen in women aged 40 years or younger in whom chemotherapy is less likely to induce permanent amenorrhea. Optimum duration of use is unknown. Prospective trials are underway such as the SOFT study, which include the use of ovarian suppression/ ablation in combination with an aromatase inhibitor versus ovarian suppression combined with tamoxifen versus tamoxifen alone, which will hopefully allow a more detailed assessment of the value of this approach.

Fulvestrant is a novel type of oestrogen receptor antagonist which, unlike tamoxifen, has no known agonist effects. It is administered intramuscularly and does not appear to cause endometrial proliferation and is less likely than tamoxifen to cause thromboembolism. Fulvestrant binds to the oestrogen receptor, but, due to its steroidal structure and long side-chain, induces a different conformational shape with the receptor to that achieved by the nonsteroidal antioestrogen tamoxifen. Because of this, fulvestrant prevents oestrogen receptor dimerization leads to the rapid degradation of the fulvestrant–oestrogen receptor complex, producing the loss of cellular oestrogen receptor. Thus fulvestrant, unlike tamoxifen, inhibits oestrogen receptor binding with DNA and produces abrogation of oestrogen-sensitive gene transcription (43). It has been shown that due to its unique mechanism of action, fulvestrant delays the emergence of acquired resistance compared with tamoxifen in an MCF-7 hormone-sensitive xenograft model (44). The lack of agonist effects means that fulvestrant did not support the growth of tumours that became resistant to, and subsequently stimulated by, tamoxifen.

In a small phase II study in advanced disease, fulvestrant was shown to produce remissions of 2 years in tamoxifen-resistant tumours in postmenopausal women (20). Clinical data with fulvestrant in advanced breast cancer following resistance to aromatase inhibitors is limited but results from phase II trials in this setting have reported clinical benefit rates of between 19 and 52%. On the basis of these findings, several phase III clinical trials of fulvestrant are currently investigating the additional roles for fulvestrant in breast cancer therapy, either following prior nonsteroidal aromatase inhibitor treatment, or in combination with aromatase inhibitors (to maintain low oestradiol levels) as first-line therapy. The comparator for several of these studies is the steroidal aromatase inactivator exemestane, which in phase II studies has shown some efficacy following progression on nonsteroidal aromatase inhibitors.

The Evaluation of Faslodex versus Exemestane Clinical Trial (EFECT) (45) assessed the efficacy of fulvestrant versus exemestane in patients who had progressed on treatment with nonsteroidal aromatase inhibitors and found no significant difference in the effectiveness or tolerability between either approach with a clinical benefit rate of 32.2 and 31.5%, respectively. Both treatments were well tolerated with no significant differences observed in adverse events or quality of life.

The primary aim of the Study of Faslodex versus Exemestane with/without Arimidex (SoFEA) trial is to compare progression-free survival in patients who have progressed on a nonsteroidal aromatase inhibitor, and who are subsequently treated with either fulvestrant plus continued anastrozole, or with fulvestrant alone. Secondary aims include a comparison of fulvestrant versus exemestane and an examination of biological markers of response. In addition, two trials (FACT and SWOG 226) will compare the efficacy of a combination of fulvestrant plus anastrozole with anastrozole alone in the first-line setting.

As aromatase inhibitors move forward into the adjuvant setting the results of these trials will help define optimal sequencing of endocrine therapies, and in particular whether fulvestrant used alone or in combination with aromatase inhibitors is the most effective strategy (46).

Synthetic progestogens/androgens, such as medroxyprogesterone (usually 500–1500 mg/day orally) and megestrol acetate (100–200 mg/day orally), have been used in the treatment of advanced breast cancer, although their main benefit is relief of metastatic bone pain. Their mechanism of action is unclear but may be a combination of adrenal and/or gonadal suppression, ‘antioestrogenic’ effects on oestradiol dehydrogenase and the oestrogen receptor, and direct effects through the progesterone receptor. In doses sufficient to be effective, they cause steroidogenic side effects such as weight gain and cardiovascular and thromboembolic complications in most patients. The results of trials evaluating the new generation of aromatase inhibitors have now clearly shown them to be more effective and less toxic than megestrol acetate or medroxyprogesterone and these agents have now largely been replaced as second-line therapy for treatment of advanced breast cancer.

Androgens are used rarely for the treatment of advanced breast cancer due to side effects but the mechanism of action probably overlaps that of progestogens. Corticosteroids have been used although less than 10% patients with advanced breast cancer respond. However, corticosteroids particularly at higher doses, are often effective at controlling symptoms, particularly those associated with inflammation, local oedema, and pain. Dexamethasone at 8 mg twice a day for short periods are very effective at controlling the symptoms of neurological metastases especially for raised intracranial pressure and cord compression during radiotherapy treatment.

High-dose oestrogen therapy had been used in the treatment of advanced breast cancer until the introduction of tamoxifen in the 1970s, which was shown to be both effective and better tolerated. A phase II trial has explored the use of high-dose oestrogen therapy in highly refractory, advanced breast cancer (22) using diethylstilbestrol 15 mg/day or oestradiol 30 mg/day. The clinical benefit rate was 40% with a median duration of response of 9 months. Another trial compared low-dose oestradiol 6 mg/day with high-dose 30 mg/day (23) in women with aromatase inhibitor-resistant advanced breast cancer. The lower dose was found to be equally as effective as the higher dose with a clinical benefit rate of 29% but with fewer side effects.

Abiraterone acetate, an inhibitor of cytochrome P 17 is a key enzyme in androgen and oestrogen biosynthesis. Abiraterone has previously shown activity in castration-resistant prostate cancer, which is thought to remain driven by ligand-dependent androgen receptor signalling (24). Around 60–70% of breast cancers are thought to be androgen receptor-positive; however, the role of the androgen receptor in breast cancer remains incompletely understood. A phase I study of abiraterone in breast cancer patients is currently underway.

Despite adjuvant chemotherapy and endocrine therapy, a proportion of patients with oestrogen receptor-positive breast cancer will still relapse and ultimately die of the disease. Further developments depend on finding methods to prevent and overcome resistance to endocrine therapy.

Endocrine resistance may occur both initially (de novo) or subsequently (acquired) in oestrogen receptor-positive breast cancer. Laboratory studies using oestrogen receptor-positive breast cancer cells exposed to long-term oestrogen deprivation (i.e. analogous to aromatase inhibitor use) or tamoxifen therapy have demonstrated that various growth factor pathways and oncogenes involved in the signal transduction cascade become activated and utilized by breast cancer cells to bypass normal endocrine responsiveness. Exposure to long-term oestrogen deprivation and subsequent development of acquired resistance, may be accompanied by adaptive increases in oestrogen receptor gene expression and intercellular signalling, resulting in hypersensitivity to low oestradiol levels.

There is evidence for increased cross-talk between various growth factor receptor signalling pathways and oestrogen receptor at the time of relapse on long-term oestrogen deprivation, with the oestrogen receptor becoming activated and supersensitized by a number of different intracellular kinases, including mitogen-activated protein kinases (MAPKs), human epidermal growth factor receptors (EGFR/HER1) and HER2/HER3 signalling, and the insulin-like growth factor (IGFR)/AKT pathway.

As such, these various signalling pathways, including activated oestrogen receptor itself, have become the targets for pharmacological intervention (47). Approaches used have included maximal blockade of oestrogen receptor signalling, as with fulvestrant, combining endocrine therapy with agents targeted against the HER family of growth factor receptors, and combinations with drugs that target downstream signalling pathways. A variety of agents have been developed including monoclonal antibodies and tyrosine kinase inhibitors, which target key proteins along signal transduction cascades with the aim of blocking tumour cell access to pathways that facilitate resistance to hormone therapy. Clinically, trials utilizing these approaches in advanced breast cancer have yielded mixed results thus far (Table 11.2.1.4) (33, 34, 48–51).

Based on preclinical evidence that endocrine resistance can be delayed by the use of EGFR/HER1 inhibition in vitro (52), a number of studies have explored the use of the small molecule tyrosine kinase inhibitor of EGFR/HER1 gefitinib (33, 34). However, the benefits were relatively modest (Table 11.2.1.4) with no improvements in objective response rates. These studies did not preselect patients with EGFR/HER1 overexpression and it is possible that with a relatively biologically heterogeneous trial population the true benefits may be underestimated.

Enhanced expression of HER2 and subsequent downstream MAPK activation has been found in breast cancer cells that become resistant to endocrine therapy. A randomized phase II trial (TAnDEM) compared the monoclonal antibody against HER2 trastuzumab plus anastrazole versus anastrazole alone in advanced breast cancer and found improved progression free survival from 2.4 to 4.8 months in favour of the combination arm (48).

Similarly, dual targeting of EGFR and HER2 with the orally active small molecule tryrosine kinase inhibitor lapatanib has been used in combination with endocrine therapy in the treatment of metastatic breast cancer. The first results of the EGF30008 trial (49) demonstrated an improved progression free survival from 10.8 to 11.9 months in favour of the combination arm in the intent to treat population (p = 0.026). In patients overexpressing HER2 there was an improvement in progression free survival from 3 months in the letrozole alone arm to 8.2 months (p = 0.019) with the combination and clinical benefit rates of 29 and 48%, respectively. Interestingly, although no improvement in progression free survival was observed for the combination arm in the HER2-negative population overall there did appear to be a trend for improvement with the combination arm in HER2-negative patients who were classified as endocrine resistant, i.e. they had relapsed within less than 6 months of receiving tamoxifen. This suggests that prior endocrine therapy may be an important determinant of who is most likely to benefit from targeted combination therapy.

Downstream from the cell surface growth factor receptors, pathways such as the phosphoinositide 3 kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) have also been targeted as a therapeutic means to overcome endocrine resistance. The mTOR inhibitor temsirolimus has been combined with letrozole in the advanced setting (Table 11.2.1.4) and has failed to demonstrate any significant benefit for the combination. This may be due in part to a failure to identify patients in whose tumours depend on PI3K–mTOR activation or due to compensatory feedback loops that exist leading to enhanced AKT activation.

Neoadjuvant/presurgical studies in early breast cancer with sequential biopsies may help to identify biomarkers that predict which patients are most likely to benefit from a particular treatment. The neoadjuvant study comparing the combination of the mTOR inhibitor everolimus and letrozole versus letrozole alone (53) concluded that patients with a specific PI3K mutation appeared to have a relatively poor response to letrozole alone but responded well to the combination treatment. However, the neoadjuvant setting may not identify the compensatory pathways that exist in advanced disease.

Further progress will depend on understanding the mechanisms behind the development of endocrine resistance and the compensatory pathways that emerge in individual patients at any one particular time. The identification of biomarkers predictive of response will allow better selection of patients for treatment with specific combinations of targeted and endocrine therapies.

Adjuvant endocrine therapy for early breast cancer has led to significant improvements in both disease-free and overall survival and is generally a well-tolerated treatment. The Early Breast Cancer Collaborative Group overview (1) confirmed that 5 years of tamoxifen almost halved the annual recurrence rate and reduced the breast cancer mortality rate by a third at 15 years from diagnosis.

In postmenopausal patients, aromatase inhibitors either upfront or in sequence offer further incremental benefits over tamoxifen. Questions to be answered by ongoing prospective studies include whether ovarian suppression/ ablation in addition to tamoxifen or in combination with aromatase inhibitors offers a further benefit in premenopausal patients. Additionally, a reduction in the incidence of contralateral breast cancer were observed in the adjuvant aromatase inhibitor trials and studies such as IBIS-2 are looking at the chemopreventative effects of aromatase inhibitors in women with ductal carcinoma in situ or high risk of breast cancer.

Aromatase inhibitors have had a major impact on the treatment of breast cancer and further progress depends on understanding the mechanisms that underlie the development of endocrine resistance. Clinical trials examining the use of targeted agents as a means to overcome resistance are challenging given that compensatory pathways probably vary over time and from patient to patient. The identification of biomarkers will help to define which tumours are most likely to respond to particular treatments. Key aspects to be addressed in future will be the best trial design with appropriate target selection and patient selection with activation of the relevant target. Ultimately, this should help identify which patients benefit most from specific drug combinations and over the next few years we should learn whether this combination approach, of endocrine therapy with the new generation targeted agents, leads to significant improvements in the treatment of hormone-positive breast cancer.