INTRODUCTION Beatson's historic observations on the regression of breast cancer following ovariectomy over 100 years ago provided the first insight into the estrogen-dependent nature of breast cancer. Endocrine therapy has become the treatment of choice for many patients with metastatic breast cancer. Selective targeting of the estrogen receptor pathway provides a more favorable benefit to toxicity ratio compared with systemic chemotherapy. Improvements in survival from first relapse with metastatic breast cancer have occurred over the last decades due to the development of newer more effective chemotherapy and hormone therapy. The use of endocrine treatment for metastatic breast cancer will be reviewed here. The role of chemotherapy and trastuzumab, and the general principles of therapy in patients with metastatic breast cancer are discussed separately. THE BENEFIT OF ENDOCRINE ABLATION Historically, 20 to 40 percent of patients with metastatic breast cancer experienced disease regression following resection of the adrenal glands and pituitary. However, these procedures have largely been replaced by medical endocrine therapies. For premenopausal women, surgical oophorectomy is still an acceptable option although it has been largely replaced by medical endocrine therapies. Oophorectomy results in objective responses in about one-third of unselected, premenopausal patients High dose estrogen was the first effective medical endocrine therapy for postmenopausal women and remained the therapy of choice for metastatic breast cancer through the mid to late 1970s. Estrogen therapy was quickly replaced by tamoxifen primarily because of its superior toxicity profile. However, long-term follow up of a tamoxifen & diethyl stilbestrol (DES) comparative trial has suggested that DES may produce superior survival in comparison with tamoxifen. Nevertheless, estrogen was increasingly viewed as an obsolete therapy replaced in the second and even third-line settings by megestrol acetate, medroxyprogesterone acetate, and/or aminoglutethimide In the 1990s, selective aromatase inhibitors (SAIs) replaced all of these alternatives for second-line therapy, since they have safety and efficacy advantages over megestrol acetate and aminoglutethimide Since long periods of estrogen deprivation may paradoxically sensitize breast cancer cells to pharmacologic estrogen deprivation, and DES is effective in women whose disease progresses on third generation SAI therapy, there has been renewed interest in estrogen therapy and new clinical studies with generic estradiol have been initiated. Intramuscular injection of a steroidal antiestrogen (fulvestrant) is another alternative for patients with advanced hormone receptor-positive disease. However, the current place of this medication in the endocrine therapy treatment algorithm remains unclear because trials have shown equivalence to tamoxifen and anastrozole For this topic review, endocrine therapies that target sex hormone receptors are classified as follows:
In addition to estrogen receptor-targeted agents, other signal transduction modulators are under development that target the growth, death, or differentiation of breast cancer cells. Agents in this new class of targeted therapies include the HER-2/neu or c-erbB-2 targeting antibody trastuzumab, several oral tyrosine kinase inhibitors targeting HER-2 and/or HER-1, mTOR inhibitors, COX2 inhibitors, farnesyl transferase inhibitors, and angiogenesis inhibitors. A treatment algorithm for endocrine therapy Since palliation is the principal goal of therapy for metastatic breast cancer, one can be relatively pragmatic about selection of endocrine agents for individual patients, following certain basic guidelines . The different endocrine therapies do differ somewhat in terms of efficacy, and substantially with regard to safety and tolerability. As a result, most physicians now favor SAIs over tamoxifen as the first choice for advanced disease, except in the setting of relapse on adjuvant SAI therapy. The treatment of patients with SAI-resistance has not been adequately studies and so choices are largely based on toxicity, rather than efficacy considerations. Premenopausal women For premenopausal women, appropriate initial therapeutic choices include tamoxifen or ovarian ablation/suppression (by ovariectomy or the use of a luteinizing hormone releasing hormone agonist [LHRH-a]. Combined hormone therapy is favored over tamoxifen alone by many physicians, because it results in higher response rates and longer time to progression, and there is possibly a small beneficial impact on overall survival. In a meta-analysis, combined therapy with tamoxifen plus an LHRH-a provided a modest disease-free and overall survival benefit compared to tamoxifen alone (22 percent reduction in mortality over seven years) which translated to an absolute improvement in median survival of two to three months. Ovarian ablation or suppression can be considered an alternative to chemotherapy for premenopausal women who progress after initial tamoxifen monotherapy. . An SAI is often introduced immediately following oophorectomy or in conjunction with LHRH-a therapy although there are no randomized trial data of LHRH-a versus LHRH-a plus SAI to support this practice. Postmenopausal women For postmenopausal women, either tamoxifen or SAI (anastrozole, letrozole, or exemestane) are reasonable initial choices for treatment-na๏ve patients Fulvestrant could also be considered in a patient for whom the parenteral route would be an advantage (non-compliance or a gastrointestinal disorder precluding long term oral therapy). Compared to tamoxifen there is evidence for a modest advantage for third generation aromatase inhibitor therapy in terms of a slightly higher response rate, and time to progression, particularly for letrozole. However, there is no clear advantage of any one SAI over another. Ovariectomy and LHRH-a are ineffective treatments for postmenopausal women and should not be offered Second-line therapy after disease progression on tamoxifen is usually instituted with an SAI. For women initially treated with an SAI, tamoxifen is appropriate and estrogen therapy can also be considered in carefully selected patients (no history of thrombosis, uncontrolled hypercalcemia or cardiovascular risk factors) For patients with disease progression following tamoxifen and an SAI, third-line endocrine therapy with fulvestrant, megestrol acetate, or generic estradiol (30 mg daily in divided doses) can be considered, while other active hormonal agents are appropriate for fourth line treatment and beyond. The following sections will discuss each class of endocrine therapy to justify this treatment algorithm. TAMOXIFEN Multiple studies have demonstrated the efficacy of the selective estrogen receptor modulators (SERMs) tamoxifen and the related newer agent toremifene in women with metastatic breast cancer. Toxicities are usually quite tolerable, but in most cases, the tumor eventually becomes resistant to the drug. Benefit of tamoxifen Tamoxifen significantly reduces breast cancer-related mortality and also reduces the risk of contralateral tumors when administered to women with early breast cancer Tamoxifen was first studied in the 1970s and it rapidly became the drug of choice for advanced disease, with response rates ranging from 16 to 56 percent. These benefits are primarily seen in ER-positive tumors, which have a 50 to 60 percent chance of response, but tumor response may also be seen in occasional ER-negative patients. The duration of response is usually between 12 to 18 months, and in some patients, benefit may persist for several years A single daily 20 mg oral dose is recommended in the United States; higher doses are no more effective and are more toxic. Tamoxifen has a half-life of seven days and steady state levels are reached after one month of therapy. The tissue half-life is prolonged and the drug may still be detected in tissues several months after treatment. The metabolism of tamoxifen is complex and a number of metabolites have antiestrogenic or estrogenic properties. Tamoxifen has been considered the drug of choice for initial hormone therapy in women with advanced breast cancer. However, this view has been challenged by the results of randomized trials comparing tamoxifen to either toremifene or to the SAIs anastrozole, letrozole and exemestane.
Tamoxifen is well absorbed orally. If a patient has a functioning alimentary tract, tamoxifen pharmacokinetics are not a major impediment to a favorable tumor response. In addition, the mixed agonist/antagonist actions of tamoxifen (and toremifene, see below) on the ER explains, in part, several clinical syndromes associated with its use, including tamoxifen-induced flare reactions and tumor regressions following drug withdrawal as described below. Toxicity of tamoxifen Tamoxifen was initially considered an "antiestrogen" in breast tissue, acting through competitive inhibition of estrogen binding to the ER. However, subsequent clinical and laboratory studies demonstrated a mixed agonist and antagonist activity that is tissue specific. Tamoxifen produces estrogenic effects on endometrium, increasing the risk of endometrial cancer. The estrogenic activity of tamoxifen is also associated with an increased risk of venous thrombosis Data collected from the National Surgical Adjuvant Breast and Bowel Project (NSABP) tamoxifen chemoprevention study, NSABP P-1, represents one of the most accurate sources of information on tamoxifen toxicity. In this trial, there was an excess incidence of serious adverse events (pulmonary embolus, deep venous thrombosis, cerebrovascular accident, cataracts and endometrial cancer) for patients receiving tamoxifen. Less serious, but troublesome side effects of tamoxifen included hot flashes, nausea, and vaginal discharge. Tumor flare reactions A transient "flare reaction", characterized by a dramatic increase in bone pain, an increase in the size and/or number of metastatic skin nodules, or skin erythema, occurs in 3 to 13 percent of patients from two days to three weeks after starting tamoxifen. Symptoms can be accompanied by hypercalcemia, which occurs in about 5 percent of patients Clinical flare has also been documented with high dose estrogen, but almost never during treatment with an aromatase inhibitor (eg, aminoglutethimide, letrozole, or anastrozole), suggesting that flare is associated with therapies exhibiting ER agonist properties. A tumor flare reaction may identify a subset of women with a higher degree of binding to ERs, who are more likely to respond to endocrine therapy. This was illustrated in one series of 40 women who underwent PET scans with fluorodeoxyglucose (FDG) and the estrogen analog 16 alpha-[18F]fluoroestradiol-17 beta (FES) prior to and 7 to 10 days after starting tamoxifen therapy. After tamoxifen treatment, tumor FDG uptake increased by a significantly greater amount in responders compared to nonresponders (mean increase, 28 versus 10 percent), and five of the responders had a clinical flare, compared to none of the nonresponders. Furthermore, the degree of estrogen blockade, as judged by FES uptake, was significantly greater in the responders (mean percentage decrease in uptake, 55 versus 19 percent). The management of patients having a flare reaction consists of aggressive treatment of pain and hypercalcemia. If symptoms are mild, tamoxifen therapy can be continued, but in more severe cases, it should be stopped and then reintroduced once symptoms have improved. Tamoxifen flare is transient; symptoms should resolve within four weeks. If symptoms continue beyond this point, objective evidence of disease progression should be sought. Hormone withdrawal response Prior to the introduction of tamoxifen, it was observed that 25 to 35 percent of patients treated with estrogens had a secondary response if the estrogen was stopped at disease progression. This same phenomenon has been observed upon withdrawal of tamoxifen, progestins, and exemestane although less frequently. Convincing withdrawal responses generally occur in patients who have experienced an initial response to hormone therapy Summary Tamoxifen has a complex risk to benefit profile due to its mixed agonist/antagonist actions. Tamoxifen therapy is suitable for almost any woman in whom endocrine therapy for metastatic breast cancer is being considered. However, estrogen deprivation therapy is an alternative initial approach with a lower risk of serious side effects (see below). Tamoxifen withdrawal therapy is appropriate for patients with an objective response to tamoxifen whose symptoms are minimal at the time of disease progression. Although usually short lived, some patients may experience disease stability for more than six months Tamoxifen resistance Drug resistance is the single biggest limitation of tamoxifen therapy for advanced breast cancer. Resistance in tumors that lack ER expression is easy to understand because the cells have become (or always were) desensitized to the growth effects of estrogen. However, patients with ER-positive metastatic breast cancer may fail to respond to tamoxifen (primary resistance), and nearly all responding patients eventually suffer disease progression (secondary resistance). Approximately one-third of patients with secondary tamoxifen resistance obtain clinical benefit from other endocrine therapies. Surprisingly, other endocrine therapies are also effective in about 15 percent of postmenopausal women with primary tamoxifen resistance Taken together, these observations suggest that tamoxifen resistance occurs in breast cancer cells that remain estrogen-dependent, and that the ER signal transduction pathway could be effectively targeted for alternative endocrine therapies. A basic understanding of the complex molecular biology of ER signal transduction, including that induced by tamoxifen, is discussed in detail elsewhere. The complexity of ER function explains, in part, why patients with breast tumors that express ER do not universally respond to tamoxifen or other endocrine therapies. Breast tumors that display responsiveness to endocrine therapies tend to be low histologic grade, well differentiated, and ER-positive, with a minimal level of proliferative activity. In such tumors, it is likely that ER signaling is central to mitogenesis, and steroid hormone occupancy of the ER drives cell growth and survival. In other tumors displaying evidence of enhanced mitogenic activity, or no ER expression, possible mechanisms of resistance include mutations and/or alternative mRNA splicing of the ER gene, interaction with other growth factor signal transduction pathways (particularly HER-2/neu, see below), and abnormal expression or function of coactivators and corepressors Even in tumors that are ER-positive, it is likely that an appropriate growth factor environment is necessary for efficient mitogenesis, with steroid hormone and growth factor signaling pathways "cross talking" to reinforce each others' signaling. One proposed model for both primary and secondary hormone resistance in breast cancer is that phenotypic changes in growth factor signaling pathways may perturb this balance of steroid hormone and growth factor interaction, providing a selective advantage for tumor cell proliferation despite hormone therapy. HER-2/neu and resistance to hormone therapy Since ER function is strongly influenced by peptide growth factor signaling, expression of these growth factors and their receptors has been studied in breast cancers that are resistant to endocrine therapy. One such growth factor is HER-2/neu, the expression of which downregulates ER expression. Signaling through HER-2/neu appears to bypass the estrogen requirement for breast cancer cell growth, and may drive initially ER-positive cells into an ER-negative, endocrine therapy resistant state. Moreover, other preclinical data suggest that in HER-2 transfected MCF-7 breast cancer cells, tamoxifen acts as an estrogen agonist rather than antagonist In initial studies, the presence of HER-2/neu, either by immunohistochemistry, or as detected in the serum with a sensitive immunoassay that measures the extracellular domain of the HER-2 protein, correlated with resistance to endocrine therapy in women with metastatic disease. However, later studies provided conflicting data; Further complicating this issue, the influence of HER-2/neu may be specific for individual types of endocrine therapies (eg, SERMS versus ligand-depleting therapies like aromatase inhibitors). Given the uncertainty of the clinical evidence regarding the relationship between endocrine therapy resistance and HER-2/neu expression, HER-2/neu positive, ER positive patients should not be denied the potential benefits of tamoxifen or other endocrine therapies in either the metastatic or early disease settings. OTHER ANTIESTROGENS Drugs such as tamoxifen that exhibit a selective agonist/antagonist profile, depending upon the specific organ or test system, have been designated as "selective estrogen receptor modulators" (SERMs) to reflect these remarkable properties. An ideal profile for a SERM is antiestrogenic activity in the breast, but retained beneficial estrogenic effects on bone mineralization and blood lipid profile, without adverse estrogenic effects on the endometrium. New SERMs Several newer SERMs have been evaluated for hormone therapy of metastatic breast cancer, especially in patients who are resistant to tamoxifen, but also as primary therapy. Of these, only toremifene has received FDA approval for use in metastatic disease. It is important to emphasize that, while new SERMs may represent a small advance in terms of safety, they are not necessarily more effective for treatment of breast cancer. Proven efficacy in advanced tamoxifen-resistant disease would provide critical evidence that a new endocrine therapy is more active than tamoxifen. However, it is likely that the newer SERMs will exhibit at least partial cross-resistance with tamoxifen. Toremifene(Fareston) Compared to tamoxifen, toremifene has equivalent activity and toxicity in patients with untreated metastatic breast cancer. In a meta-analysis of three trials involving 1421 women comparing toremifene with tamoxifen in postmenopausal women with ER-positive or ER-unknown advanced breast cancer, the response rates for toremifene and tamoxifen were 24 and 25 percent, and median survival times were 31 and 33 months, respectively Thus, toremifene is a reasonable alternative to tamoxifen for first-line treatment of advanced breast cancer. However, toremifene displays cross-resistance with tamoxifen and should not be used in women with tamoxifen-resistant disease. Summary In summary, none of the newer SERMs is more efficacious than tamoxifen when used as first-line treatment for metastatic breast cancer. In addition, raloxifene, idoxifene, and toremifene do not have significant activity in tamoxifen-refractory patients Pure antiestrogens Since resistance to tamoxifen might be due to its partial agonist properties, antiestrogens without agonist activity might be more effective. Fulvestrant (Faslodexฎ) Fulvestrant, a "pure" antiestrogen, has a steroid structure that blocks ER dimerization, inhibits DNA binding, increases ER turnover, and inhibits nuclear uptake of the receptor . As a result, it blocks ER function before coactivator binding, theoretically overcoming resistance that is driven by the agonist properties of tamoxifen. Preclinical studies in models of tamoxifen-resistant disease suggest that fulvestrant is a more effective estrogen antagonist than tamoxifen Fulvestrant is administered as a monthly intramuscular injection. Two small phase II trials of fulvestrant (250 mg monthly) have shown activity in tamoxifen-resistant advanced disease, with a total of 14 of 49 patients in both studies experiencing partial responses Two pivotal phase III trials comparing fulvestrant (250 mg IM monthly) to anastrozole (1 mg by mouth daily) in tamoxifen-resistant postmenopausal women with advanced breast cancer have been completed
As a result of these data, fulvestrant was approved by the United States Food and Drug Administration in April 2002 for treatment of hormone receptor-positive postmenopausal women with disease progression following antiestrogen therapy. One advantage of fulvestrant is that because it is administered as an injection in the physician's office, it may be reimbursable by insurance for patients who have no prescription drug coverage. With respect to first-line hormonal therapy, one trial has directly compared fulvestrant to tamoxifen in 587 women with previously untreated advanced breast cancer No significant advantage was shown for fulvestrant in terms of response rates, time to progression, or treatment tolerability. Others A second pure antiestrogen, EM800, is also being compared in a phase III trial with anastrozole. EM800 is orally active and structurally related to raloxifene ESTROGEN DEPRIVATION THERAPY Estrogen deprivation can be accomplished by ovariectomy or by the use of luteinizing hormone releasing hormone agonists (LHRH-a) or inhibitors of the enzyme aromatase. The benefit of ovarian ablation or LHRH-a therapy is restricted to women with functioning ovaries. After the menopause, as ovarian function declines, the relative proportion of estrogens synthesized in extragonadal sites increases, with nonovarian estrogens predominating in the circulation Aromatase inhibitors have become especially useful therapeutic agents in postmenopausal women. Aromatase mediates the peripheral conversion of androgenic precursors of adrenal origin (testosterone and androstenedione) to estradiol and estrone in adipose tissue, liver, muscle, and brain. In addition, aromatase activity has been shown in both the epithelial and stromal components of the breast, and local intratumoral synthesis of estrogens may contribute to breast cancer growth in postmenopausal women. The level of aromatase activity correlates with breast cancer cell proliferation, and quadrants of the breast bearing a breast cancer have more aromatase expression than in those not bearing tumors The aromatase enzyme complex consists of a P450 cytochrome (P450arom), and a flavoprotein, NADPH cytochrome P450 reductase, that regenerates active aromatase after completion of the aromatization reaction. The active site of aromatase contains a heme complex that is responsible for generation of the aromatized estrogenic steroids from androgenic precursors. Because estrogen production is the last step in the generation of steroidal compounds, selective inhibition of aromatase by interference with the heme complex does not block the production of corticosteroids or mineralocorticoids. Estrogen deprivation in premenopausal women Estrogen deprivation in premenopausal women can be accomplished through surgical ablation or the administration of an LHRH-a. Ovariectomy Ovariectomy results in objective responses in about one-third of unselected, premenopausal patients with metastatic breast cancer . Currently, tamoxifen is favored for first-line therapy in premenopausal women, since it has similar efficacy compared to ovariectomy and is more convenient Following disease progression on tamoxifen, responses to ovariectomy can occur, especially in patients who had an initial response to tamoxifen LHRH agonists Luteinizing hormone-releasing hormone agonists provide an alternative method for estrogen deprivation in premenopausal women who do not wish to undergo surgery. LHRH-a (eg, goserelin and leuprolide) are peptide analogs of LHRH that are 50 to 100-fold more potent than the natural hormone. Acting on the pituitary, LHRH-a initially stimulate FSH and LH secretion, then profoundly suppress the pituitary ovarian axis, resulting in a fall in serum estrogen to menopausal levels Although no initial rise in serum estrogen has been detected in women with advanced breast cancer treated with LHRH-a, breast cancer flare reactions may occur in some patients, and have been attributed to gonadotropin release Therapy with LHRH-a appears to be as efficacious in advanced breast cancer as ovariectomy. A prospective randomized trial in 138 premenopausal women with estrogen receptor (ER) or progesterone receptor (PR)-positive untreated metastatic breast cancer demonstrated that response rates, failure-free survival, and overall survival were equivalent for goserelin and ovariectomy, although hot flashes (75 versus 46 percent) and tumor flare (16 versus 3 percent) were more common with goserelin . LHRH agonists plus tamoxifen Combinations of LHRH-a with tamoxifen have been studied as first-line treatment in premenopausal women. A meta-analysis of four trials suggested that combined therapy was more effective than single agent LHRH-a, as the combination treatment was associated with a higher response rate (39 versus 30 percent), and a significant 30 percent reduction in the hazard of progression or death (hazard ratio 0.70 (95% confidence interval [CI] 0.58-0.85) Based on these results, it seems reasonable to recommend a combination of LHRH-a and tamoxifen as first-line endocrine therapy to premenopausal women with advanced breast cancer. However, since the overall survival gains from combination therapy are small, patients may also be offered sequential treatment with tamoxifen, followed by either LHRH-a or ovariectomy at the time of disease progression. Nonselective aromatase inhibitors Aromatase inhibitors can be classified as either selective or nonselective, based upon their interaction with the enzyme Aminoglutethimide Aminoglutethimide, the prototypic aromatase inhibitor, was first used at high doses in metastatic breast cancer as an alternative to surgical adrenalectomy. At these doses, the enzymatic conversion of cholesterol to delta-5-pregnenolone, an early step in adrenal steroidogenesis, is blocked, reducing the synthesis of all adrenal steroids, including glucocorticoids, mineralocorticoids, estrogens, and androgens. When lower doses were found to be as effective for patients with breast cancer, it was appreciated that inhibition of aromatase, rather than suppression of steroidogenesis, was predominantly responsible for the therapeutic action of aminoglutethimide in breast cancer. However, even at the lowest doses effective in breast cancer, aminoglutethimide can inhibit the formation of corticosteroids by blocking multiple enzymes involved in steroid biosynthesis, thereby exposing patients to the risk of glucocorticoid deficiency. Development of selective aromatase inhibitors The finding that aminoglutethimide was effective in tamoxifen resistant patients provided a strong rationale for the development of more potent and selective aromatase inhibitors. A family of "nonsteroidal" inhibitors was developed that specifically disrupted the aromatase active site, thereby inhibiting the generation of estrogenic compounds without affecting the production of other adrenal steroids. These second and third generation selective aromatase inhibitors (SAIs) suppress postmenopausal estrogen levels by selectively inhibiting the aromatase enzyme. Two SAIs, anastrozole and letrozole, are approved in the United States and Europe for postmenopausal women with tamoxifen-refractory advanced breast cancer. Steroidal SAIs, exemestane and formestane, have also been developed. The specificity of the third generation compounds appears to be nearly complete, with little to no effect on basal levels of cortisol or aldosterone Anastrozole (Arimidex) Anastrozole was the first SAI to be approved in both North America and Europe. A daily dose of 1 mg of anastrozole rapidly suppresses the production of estradiol, estrone and estrone sulfate. Even at higher doses (5 to 10 mg), anastrozole does not affect basal or ACTH-stimulated cortisol and aldosterone levels The activity of anastrozole in postmenopausal tamoxifen-refractory breast cancer has been evaluated in two international phase III clinical trials that compared anastrozole (1 or 10 mg daily doses) with megestrol acetate (40 mg four times daily). In an overview analysis of both trials incorporating data from 764 patients, the objective response rates (complete and partial) were low in all three groups:10.3 percent in the 1 mg anastrozole group; 8.9 percent in the 10 mg anastrozole group, and 7.9 percent in the megestrol acetate group. However, 25, 23, and 26 percent of patients respectively had stable disease for six months or longer, suggesting clinical benefit even without objective response There were no differences in disease free survival (DFS) among the three treatment arms; however, patients who received 1 mg of anastrozole had a longer median survival that those on megestrol acetate (26.7 months vs. 22.5 months p = 0.02), and a higher two year survival rate (56 versus 46 percent). Anastrozole was associated with less weight gain but more nausea and vomiting than megestrol acetate. Two randomized trials comparing anastrozole with tamoxifen as first line therapy in postmenopausal women with newly diagnosed metastatic breast cancer have shown at least equivalent activity with fewer thromboembolic events and episodes of vaginal bleeding. These and other trials comparing a first line SAI to tamoxifen are discussed in detail below Letrozole q(Femara) Letrozole is a more potent suppressor of aromatase activity than anastrozole. Like anastrozole, letrozole combines selectivity and promising activity against advanced breast cancer in phase II trials. Letrozole doses of 0.5 mg and 2.5 mg both suppress serum estrogen concentrations by more than 90 percent (to less than 0.5 pmol/L). The serum half-life of 50 hours allows once daily dosing, and since only 5 percent is excreted in the urine, letrozole can be safely prescribed in patients with renal insufficiency. Letrozole was directly compared to megestrol acetate in two multicenter studies, one in Europe and one in the United States:
Letrozole (2.5 or 0.5 mg per day) was also compared to aminoglutethimide (250 mg twice daily) in 555 women with tamoxifen-resistant breast cancer. Response rates were highest for 2.5 mg letrozole (19.5 percent), compared with 0.5 mg (16.7 percent) and aminoglutethimide (12.4 percent). Letrozole 2.5 mg was superior to aminoglutethimide in time to progression, time to treatment failure, and overall survival (median survival 30 versus 19 months). Data from trials of these SAIs have challenged the dogma that visceral metastases are resistant to endocrine therapy. This was illustrated by one analysis that combined data in patients with visceral disease from two randomized trials of letrozole versus either megestrol or aminoglutethimide. Letrozole resulted in higher response rates (18 to 24 percent versus 11 and 15 percent for aminoglutethimide and megestrol), and a longer median survival (21 to 28 months versus 16 months for either aminoglutethimide or megestrol). It is reasonable to conclude that letrozole and anastrozole should be considered the new standard in endocrine therapy for tamoxifen-resistant metastatic breast cancer in postmenopausal women. It is not clear that either agent is superior, although letrozole has been shown in pharmacokinetic studies to be a more effective aromatase inhibitor in terms of both in vivo inhibition of aromatisation and suppression of estrone and estrone sulfate levels. Letrozole (2.5 mg daily) was directly compared to anastrozole (1 mg daily) in 713 postmenopausal women with locally advanced or metastatic breast cancer who relapsed after first line antiestrogen therapy. The objective response rate was significantly higher with letrozole (19 versus 12 percent); however, this did not translate into an advantage in terms of overall survival or time to progression. Letrozole is also approved in the United States for the first-line treatment of hormone receptor- positive or unknown postmenopausal women with metastatic breast cancer following the demonstration of comparable efficacy to tamoxifen in this setting. This trial, and others comparing SAI therapy with tamoxifen for first-line endocrine therapy of metastatic breast cancer are discussed in detail below . Megestrol acetate (see below) may still play a small role in the third line setting, while aminoglutethimide should now be considered obsolete. Steroidal aromatase inhibitors Steroidal aromatase inhibitors are resistant to the action of aromatase, irreversibly binding the active site of the enzyme and blocking the conversion of androgenic substrates to estrogens . They are considered "suicide" inhibitors because they permanently inactivate aromatase. As a result, recovery of aromatase requires synthesis of new aromatase molecules. Since suicide inhibition prolongs drug action, intermittent rather than daily dosing is possible, potentially improving the side effect/benefit ratio. Exemestane and formestane Exemestane (Aromasin) and formestane (Lentaron, available outside of the United States) are androgenic steroids in which side-chain substitutions bind the active site of aromatase, preventing the conversion to estrogenic metabolites. Formestane is 60-fold more potent an inhibitor of aromatase than is aminoglutethimide, and suppresses 65 percent of estrogen production in vivo. In patients with tamoxifen-refractory advanced breast cancer, formestane (250 mg every two weeks) has an objective response rate of 23 to 39 percent, and stabilizes disease in an additional 14 to 29 percent . Phase III studies have demonstrated therapeutic equivalence to aminoglutethimide and megestrol in women who have failed tamoxifen. Formestane has also been compared to tamoxifen as first line endocrine therapy in postmenopausal women Formestane side effects include hot flashes, rash, facial swelling, and sterile abscesses at the injection site. It must be administered parenterally since oral bioavailability is limited. It has been approved in many countries (Lentaronฎ), although not yet in the United States. Compared to formestane, exemestane (Aromasinฎ) is more potent and is well absorbed orally. A daily 25 mg dose suppresses serum estradiol and estrone to between 60 to 74 percent of control. It is approved in the United States for second-line use after failure of other hormonal agents. the efficacy of exemestane as a second-line agent is illustrated by the following:
A response to exemestane can be observed in patients who never responded to tamoxifen (primary tamoxifen resistance) and in those who have failed other nonsteroidal aromatase inhibitors. These findings challenge the dogma that further endocrine therapy should not be offered to patients who do not show an initial response to tamoxifen. Exemestane, in particular, may be active even after failure of multiple hormone maneuvers . In one report of patients refractory to both tamoxifen and megestrol acetate, exemestane produced an objective response rate of 13 percent, an additional 17 percent had stable disease For the first-line of initial treatment of metastatic breast cancer, preliminary data suggest the equivalence (and possible superiority) of exemestane compared to tamoxifen. Selective aromatase inhibitor therapy for premenopausal women SAIs are usually not administered to premenopausal women because the reduced feedback of estrogen to the hypothalamus and pituitary leads to an increase in gonadotropin secretion. The clinical consequences of ovarian aromatase deficiency are best illustrated by the development of hypergonadotropic hypogonadism, multicystic ovaries, virilization, and bone demineralization in individuals with hereditary aromatase deficiency However, emerging data suggest that premenopausal women with advanced breast cancer may do well with combinations of LHRH-a and an SAI . As an example, in one study,12 of 16 women had an objective response or durable stable disease with anastrozole plus goserelin after failing goserelin plus tamoxifen The combination was well tolerated, and there was no significant rise in serum gonadotropins or androgen levels during therapy. The safety of combined ovarian suppression plus an SAI compared to ovarian suppression plus tamoxifen is under study in the adjuvant setting. Although the addition of an SAI to ovarian ablation could be considered in premenopausal women who become menopausal during therapy for metastatic breast cancer, the data concerning the safety and efficacy of such an approach are sparse. Alternative treatments for premenopausal women with metastatic breast cancer resistant to tamoxifen and ovariectomy or LHRH-a include megestrol acetate or chemotherapy. Tamoxifen versus SAI for first line endocrine therapy in postmenopausal patients Tamoxifen has been considered the optimal first-line endocrine therapy for postmenopausal women with advanced breast cancer, including those who relapse after adjuvant tamoxifen, as long as the relapse-free duration is at least one year. However, the safety and efficacy of SAIs, both in patients with primary tamoxifen resistance, and in previously untreated patients, has now been established. Anastrozole Two randomized studies have compared anastrozole with tamoxifen as first line treatment for women with newly diagnosed ER positive or ER unknown metastatic breast cancer. In the first trial, 668 postmenopausal women were randomly assigned to receive either tamoxifen (20 mg daily) or anastrozole (1 mg daily) The objective response rates were identical (33 percent), as was the time to progression (8.2 versus 8.3 months). Women receiving anastrozole had significantly fewer thromboembolic events (4.8 versus 7.3 percent), and less vaginal bleeding (1.2 versus 2.4 percent). Similar findings were noted in the identically designed second trial with one major exception: anastrozole use was associated with a significantly longer time to disease progression (11.1 versus 5.6 months), although a similar two year survival rate (69 and 68 percent, respectively) Letrozole Letrozole has also been directly compared to tamoxifen as first line therapy in 916 postmenopausal women with advanced breast cancer. In the most recent update of this study, compared to tamoxifen, letrozole was associated with a significantly higher overall response rate (32 versus 21 percent), longer time to progression (9.4 versus 6 months), and longer time until chemotherapy was required (16 versus 9 months). The difference in median survival (34 versus 30 months) did not reach the level of statistical significance. Exemestane Similar results were noted in a randomized EORTC trial comparing tamoxifen (25 mg daily) and exemestane (25 mg daily) in 382 hormone-naive women with metastatic breast cancer. In a preliminary report, exemestane was superior in terms of objective response rate (44 versus 29 percent) and median progression-free survival (10.9 versus 6.7 months). Summary As a result of these data, anastrozole, letrozole, and exemestane can all be considered an equivalent (and possibly superior) choice to tamoxifen for first line treatment of advanced breast cancer in postmenopausal women with ER positive or ER unknown breast cancer SEX STEROID HORMONES Patients who have low volume disease that is restricted to bone or soft tissue, few disease-related symptoms, and a history of a response to either tamoxifen or an SAI (or both) may be considered candidates for further endocrine therapy using progestins, androgens, or estrogens. Of these, progestins are the most likely to be considered. Progestins Megestrol acetate (160 mg per day) and medroxyprogesterone acetate are progestational agents with significant activity in advanced breast cancer. Medroxyprogesterone acetate, which requires intramuscular dosing, offers no clear advantages in terms of efficacy or safety The optimal dose of megestrol acetate for the treatment of advanced breast cancer is 40 mg four times daily. Although early studies suggested that higher doses were more active, this was not confirmed in randomized controlled trials. In these studies, higher doses were associated with more weight gain, fluid retention, vaginal bleeding and a lower quality of life. Progestins are also associated with an increased risk of thromboembolic events; as a result, their use should be avoided in patients with thromboembolic disorders or other risk factors for thromboembolic disease. The mechanism of action of progestins in the treatment of advanced breast cancer is unclear. They may inhibit aromatase activity or increase estrogen turnover, since estrogen levels fall during therapy. They may also act through the glucocorticoid receptor, androgen receptor, or progesterone receptor; activity appears to be maintained in patients who are refractory to SAIs. Unfortunately, trials that compare SAIs with megestrol acetate have not employed a cross-over design; as a result, the activity of megestrol acetate after SAI failure has not been systematically studied. For these reasons, megestrol acetate should not be abandoned as a therapeutic alternative until its activity has been reevaluated in appropriate patients with disease that is refractory to both tamoxifen and SAIs. Androgens Androgens, including testosterone, fluoxymesterone, and the less virilizing agent testolactone, are rarely used to treat metastatic breast cancer Although they have response rates of around 20 percent , major side effects include virilization, edema and jaundice; in addition, they are inferior to high dose estrogens for treatment of metastatic disease The weak androgen danazol, which also inhibits pituitary gonadotropin secretion, has a single agent response rate of 20 percent; side effects include edema and hot flashes. If androgen therapy is considered, fluoxymesterone (Halotestinฎ, 10 mg by mouth twice daily) is a reasonable choice High dose estrogen Before the advent of contemporary endocrine therapy options, advanced breast cancer in postmenopausal women was commonly treated with high dose estrogen; this approach is ineffective before the menopause. While the mechanism of action is largely unknown, breast cancer regressions in animal models are associated with suppression of insulin-like growth factor signaling Patients with prior heavy exposure to endocrine therapy (tamoxifen, megestrol acetate, SAI) may still respond to diethylstilbestrol (DES) (5 mg orally three times daily). Obtaining DES is difficult in the United States so alternative estrogens may have to be considered Pharmacologic doses of estrogen are limited by side effects including breast tenderness, vaginal discharge, nausea/vomiting, and more seriously, heart failure and venous thrombosis. As with progestins, estrogens are contraindicated if the patient has a thromboembolic disorder or other risk factors for thromboembolic disease. COMBINATION ENDOCRINE THERAPY VERSUS SEQUENTIAL SINGLE AGENTS The most commonly studied endocrine therapy combinations are antiestrogen/estrogen deprivation combinations, and antiestrogen/sex steroid combinations. Antiestrogen/estrogen deprivation therapy combinations Combinations of antiestrogens with drugs that diminish serum estrogen concentrations have been studied in premenopausal women. The improvements in response rate, progression-free survival, and overall survival associated with the combination of LHRH-A plus tamoxifen when compared with LHRH-A alone in premenopausal women were discussed previously These data contrast with studies in postmenopausal women in which the combination of tamoxifen and aminoglutethimide is no more active than tamoxifen alone, and considerably more toxic There are no published studies combining SAIs and tamoxifen in postmenopausal women with metastatic breast cancer. However, at least in the adjuvant setting, the combination of anastrozole plus tamoxifen does not appear to be better than either drug alone, as shown in the ATAC trial. Thus, tamoxifen and SAIs should be used in sequence and not in combination. It is particularly important to avoid combining letrozole and tamoxifen since tamoxifen may accelerate the hepatic clearance of letrozole, decreasing its efficacy Antiestrogen/sex steroid combinations Tamoxifen has been combined with androgens, estrogens and progestins In general, the additional toxicity of these combinations has not been offset by meaningful gains in clinical outcome, as measured by time to progression or overall survival. Combining sex steroids with tamoxifen is therefore not recommended. |