Endocrine therapy in the treatment of metastatic breast cancer

Endocrine

Therapy

in the Treatment Breast Cancer Aman

The

goals

of treating

cancer are progression, patients that are

with not

generally responds

other moxifen

endocrine in this

inhibitors, accepted

they have Recently,

women inhibitor

metastatic

agent setting.

(ER)-positive endocrine

cancers therapy

benefit. Tafor metarecently, no

has shown superiority The nonsteroidal

replaced anastrozole

is

option. If a patient initially agent and then progresses,

and letrozole, therapy after

have failure

to aromatase

ta-

been widely of tamox-

megestrol acetate in this setwas shown to have at least

efficacy and with tamoxifen in the first-line has become

breast

or halt disease quality of life. In

agent may still provide used as first-line therapy for many years. Until

anastrozole as second-line

equivalent compared

apy this been

receptor rapidly,

the first treatment to an endocrine endocrine has been breast cancer

with

survival, slow the patient’s

estrogen progressing

another moxifen static

ifen; ting.

patients

to prolong and enhance

a superior for treating

side effect profile postmenopausal

setting. Thus, this aromatase a viable option for first-line ther-

in postmenopausal women. Trials of letrozole in setting are nearing completion. Exemestane has shown to be an effective second-line agent and to

have after

at least some efficacy failure of a nonsteroidal

sults are anxiously crine agents including of endocrine agent, lator Semin Saunders

as a third-line aromatase

awaited from trials the first member the estrogen-receptor

agent inhibitor.

even Re-

of new endoof a new class downregu-

class. Oncol 28:291-304. Company.

Copyright

0

2001

by

WB.

B

REAST CANCER is the most common cancer affecting women. It is estimated that in 2001, about 40,000 patients will die of recurring or metastatic tumors of the breast.l Although breast cancer is often relatively slow growing, its central position allows metastasis via breast parenchyma, along mammary ducts, or by way of breast lymphatics or the bloodstream. Some physicians consider breast cancer a systemic disease from its earliest stages, since occult micrometastases may be present at the time of initial diagnosis. NATURAL

HISTORY

OF BREAST

U. Buzdar

lapse as will 24% to 30% of women with nodenegative disease at diagnosis.3 Metastasis is more likely in patients with larger primary tumors, indicating more advanced disease, but even patients with tumors less than 0.5 cm have a 20% risk of axillary involvement, which is associated with an increased likelihood of metastatic disease.4 Metastatic spread occurs when a variety of factors, including growth factors, adhesion molecules, and local mediators, are present in both the primary and metastatic sites. Metastasis thus requires certain interactions among breast cells, stroma, and surrounding normal tissue.5 Theories vary as to whether breast cancer is a disease that can spread systemically from its earliest stages or whether tumors must mature in size and move progressively outward from their point of origin6 Both theories suggest the need for systemic hormonal therapy and chemotherapy as adjuvant treatments even in local disease, to prevent progression to metastasis, or to treat micrometastases before progression. Distant metastases most commonly involve the lung, liver, or bones, although the pleura, adrenal glands, ovaries, spleen, skin, and other organs are sometimes involved.6 The prognosis of metastatic breast cancer is poor; the median length of survival from time of recurrence is 18 to 24 months. Patients with estrogen receptor (ER)-positive tumors have longer survival than patients with ER-negative tumors. While some women may survive a decade or more after diagnosis of metastatic breast cancer, these women generally die with the disease, if not from it.7 Survival varies with the site of breast cancer recurrence; patients with locoregional recurrence usually have a better prognosis than those with distant recurrence. In patients

CANCER

At diagnosis, only 5% to 15% of breast cancer patients have distant metastases, but almost 40% have regional spread to at least one axillary node.2 Prognosis is directly related to the degree of nodal involvement. Of women diagnosed with nodepositive disease, 50% to 60% will experience reSeminars

of Metastatic

in Oncology, Vol 28, No 3 @me), 200 I: pp 29 I-304

From the Department of Breast Medical Oncology, M.D. A&rson cancer center, Houston, TX. Address reprint requests to Aman U. Bu&xr, MD, Department of Breast Medical Oncology, M.D. Anderson Cancer Center, Box 56, 1515 Holcombe Blud, Houston, TX 77037. Copyright 0 2001 by W.B. Saunders Company 0093-7754/01/2803-0010$35.00/0 doi:lO. 1053/sonc.2001.23495 291

AMAN

292

with bone vival, ceral

U. BUZDAR

distant metastases, those with spread to the usually have a better prognosis (median sur’28 months) than those with disease in vissites (median survival, 13 months).3 GOALS

OF TREATMENT

Collectively, studies suggest that current breast cancer therapies may prolong survival of patients with metastatic breast cancer without providing a definitive cure.8 A small fraction of patients remain free of disease in the long term.9 Because metastatic breast cancer is not currently curable, typical treatment goals are prolongation of survival and optimum palliative care, which includes maximizing the quality of life. Treatment can lessen the cancer burden and frequently provide some relief from cancer pain or symptoms. Lessening patient suffering and improving the quality of life are appropriate goals of therapy. Although a complete response is the ideal outcome with any therapy, in metastatic disease a partial response or even stabilization of disease for an extended period may confer a benefit and achieve therapeutic goals. Surgery, radiation, and systemic therapy all have a place in the treatment of metastatic cancer. While local tumors are typically treated first with surgery and radiation (with optional systemic therapy as an adjuvant), multifocal disease is usually treated with systemic therapy. For patients with multiple sites of recurrence and/or visceral disease not easily treated by local means, systemic therapy would be the first treatment option. Systemic treatment consists of either endocrine therapy or chemotherapy. Endocrine therapies are most commonly used to treat metastatic breast cancer in patients with ER-positive disease, while chemotherapy is generally used in cases refractory to endocrine therapy or in patients with ER-neg ative disease. Other variables that affect choice of endocrine therapy or chemotherapy for women with advanced breast cancer include age, overall prognosis, and location of metastases (Fig 1). Although there are reports suggesting that tumors with elevated expression of HER-2/neu protein are less likely to respond to endocrine therapy, this issue is not yet resolved.lO-l2 BASIS

FOR ENDOCRINE

TREATMENT

Because breast cancer cells usually develop from altered breast cells, they are often sensitive to sex

Fig I. Criteria for selection of systemic therapy for static breast cancer: endocrine therapy v chemotherapy. estrogen receptor; PR, progesterone receptor. Adapted permission.7

metaER, with

hormones, just as are breast cells. Estrogens in particular may promote growth of many breast cancer cells. Decreasing the level of estrogen or blocking its action often leads to a clinical response in patients with receptor-positive disease. This may be accomplished using a variety of approaches that act through different mechanisms (Table 1). Endocrine therapy was first shown to be effective in treating some cases of breast cancer more than 100 years ago, when Beatson demonstrated the effectiveness of oophorectomy in the treatment of metastatic breast cancer.13 Numerous endocrine manipulations have been investigated since that time. The demonstration of estrogen receptors in breast tumors provided a rational explanation for the response seen in some women and spurred investigation into alternative forms of endocrine therapy. Indeed, the most important factor predicting response to endocrine therapy is the presence of tumor cells rich in ER and progesterone receptor proteins. In patients with tumors positive for both ERs and progesterone receptors, 50% to 70% may benefit from endocrine therapy.14 Of patients whose tumors are positive for only one of the two receptors, 33% will respond to endocrine therapy.14 Patients with 10% or more tumor cells staining positive for these receptors should expect a clinical response from endocrine therapy.15 In patients whose tumors show no expression of ERs or progesterone receptors, endocrine therapies are generally not effective. Endocrine therapies that have been used include surgical procedures (including oophorec-

ENDOCRINE

THERAPY

OF

METASTATK

Table

BREAST

I. Mechanism

293

CANCER

of Action

of Endocrine

Treatments

Treatment Oophorectomy

Mechanism Eliminate

ovarian

Adrenalectomy

Reduce

androgens

Hypophysectomy

Reduce

ACTH,

Estrogens

Occupy

estrogen

receptors

(in premenopause)

occupy

estrogen

receptors

(in postmenopause)

Tamoxifen Tamoxifen Other

LHRH

“Total

inhibitors

analogs

(in postmenopause)

(mainly

(and thus

change

blockade”

Interference

with

Downregulates

in premenopause)

Breast

Cancer

of Action

estrogens estrogens)

FSH, LH (and

Hypothesized

withdrawal

antiestrogens

Aromatase

for

thus adrenal (thus

reducing

in estrogenic

effects

androgens

action

for “pure”

aromatase.

which

converts

release

from

sex steroids)

effects)

of tamoxifen

of estrogen gonadotrophin

and ovarian

estrogen

metabolites

antiestrogens androgens

to estrogens

the pituitary

(reduces

estrogen

secretion

from

ovaries) Occupy

Progestins Androgens

progesterone

Suppression

(in postmenopause)

Occupy

receptors

(reducing

of FSH and LH (thus androgen

receptors

reducing

(subsequent

ER and estrogen

action)

estrogens) reduction

of estrogen

receptor

limiting

the effects

of estrogen) Abbreviations: ne-releasing Reprinted

ACTH, hormone; with

adrenocorticotrophic ER, estrogen

hormone;

FSH, follicle-stimulating

hormone;

LH, luteinizing

hormone;

LHRH,

luteinizing

hormo-

receptor.

permission.37

tomy, adrenalectomy, or hypophysectomy), radiation ablation of the ovaries, and pharmacologic treatment. The type of endocrine therapy used depends in part on the source of estrogen production and the basal level of estrogens. In premenopausal women, estrogen production is high and focused in the ovaries. In these women, surgical, radiation, and pharmacologic ablation of the ovaries can be employed to decrease estrogen production. In postmenopausal women and those without functioning ovaries, relatively small amounts of estrogens are produced in peripheral tissues by conversion of androgens produced by the adrenal glands. These low levels of estrogens can be inhibited either by blocking the estrogen receptor, or by inhibiting the peripheral conversion of androgens to estrogens. Among the pharmacologic endocrine therapies for breast cancer are treatment with antiestrogens (including selective estrogen receptor modulators [SERMs]), luteinizing hormone-releasing hormone (LHRH) analogs, aromatase inhibitors, estrogens, progestins, and androgens. Antiprogestins and antiandrogens are of potential use, but are used rarely. Tumors that initially respond to one type of endocrine therapy often become refractory to that therapy, but they may respond to another type of endocrine therapy (Fig 2). Thus, endocrine ther-

apies are given in a sequential fashion, with second-, third-, and fourth-line endocrine therapies offered as resistance develops and the disease progresses. If a tumor becomes refractory to endocrine therapies (ie, does not respond to second- or third-line therapies after showing an initial response to first-line endocrine therapy) or if all endocrine options have been exhausted, chemotherapy or other treatments may be considered (Fig 3

j.

SELECTION

OF ENDOCRINE

TREATMENT

As discussed, the ER status of the tumor is the strongest determinant of whether a woman is likely to obtain benefit from endocrine therapy.

100 90

, i

Fig 2. Response rates to sequential women with metastatic breast cancer.**

endocrine

therapies

in

294

AMAN

Tam&fen within previous

ER+/PR+ or bone/s& tissue only or asymptomatic c visceral disease

U. BUZDAR

year

No prior tamoxifen or 5 1 year off tamoxifen

ER-IPRor symptomatic visceral disease

Chemotherapy progressive

Fig 3.

Guidelines

until disease

for

treatment

Beyond this variable, women diagnosed with metastatic breast cancer are a heterogeneous patient population and many of those differences will affect selection of therapies. In some cases, the patient will have been diagnosed with breast cancer for the first time and presents with metastatic disease at the onset. Such patients are likely to have never received endocrine therapy and, thus, may not have developed resistance. Other patients may have progressed to metastatic disease while receiving tamoxifen or other antiestrogen as adjuvant therapy for early-stage disease. Because the tumors in such patients progressed while receiving one endocrine therapy, they are likely to obtain little benefit from an additional course of the same treatment. However, they may still respond to a different endocrine therapy. Finally, in between these situations are women who received an adjuvant endocrine therapy for early-stage disease, discontinued that therapy for some time, then were found to have progressive disease. In such a case, the process of selecting an endocrine therapy should consider the disease-free interval and the duration of the initial treatment. The presence of ERs and other endocrine receptors in tumors may vary with menopausal status. More than half (63%) of postmenopausal women with breast cancer have ERs and progesterone receptors in their tumor cells, while 25% to 45% of premenopausal women have these receptors in their tumor cells. Premenopausal patients with tumors positive for ERs and progesterone receptors should be considered for treatment with tamoxifen or ovarian ablation as first-line endocrine therapy (Fig 4). If premenopausal patients respond to first-line therapy with tamoxifen, ovarian ablation should be

Failure to respond to 2 sequential regimens or ECOG status 23, discontinue chemotherapy of systemic

recurrence.

used as second-line therapy. If these patients respond to ovarian ablation, they may later be candidates for additional endocrine therapies. In postmenopausal women, it is common to use antiestrogens as first-line therapy, followed by aromatase inhibitors. However, results from recent trials suggest that nonsteroidal aromatase inhibitors are likely to replace antiestrogens as first-line therapy in postmenopausal women with advanced breast cancer (see below). After treatment with a nonsteroidal aromatase inhibitor and an antiestrogen, third-line endocrine therapies, such as a steroidal aromatase inhibitor or progestin, may still provide benefit. Subsequent therapies may also include androgens or estrogens (Fig 4).16 ENDOCRINE

TREATMENTS

Because endocrine therapy is generally associated with fewer severe side effects than chemotherapy, there has been increasing research into new endocrine agents and a large number of drugs are in development. The amount of information on drugs in development varies significantly according to the stage of development.

SelectiweEstrogen ReceptorModulators The SERMs are a diverse class of compounds that have both estrogenic and antiestrogenic properties. These compounds, and particularly the prototypical example tamoxifen, were once termed antiestrogens. However, because they have both estrogenic and antiestrogenic effects, they are now termed SERMS. The SERMS bind to the ER and either inhibit the receptor or lead to its partial activation. The precise effect of a SERM depends on the tissue and cell type. The SERMS of interest for treating breast cancer are antiestrogenic in

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Antiestrogen or LHRH agonist if response

Antiestrogen or nonsteroidal aromatase inhibitor

t

(Al)

if response

LHRH agonist or antiestrogen

m

if response

t Nonsteroidal or antiestrogen

Al

t Oophorectomy

if response

if response

t Steroidal

t Nonsteroidal

Al if response

t

t

Progestin

Steroidal if response

t Androgen

women. from

Al if response

t

m

Fig 4. Sequences of endocrine therapies for metastatic breast cancer in premenopausal and postmenopausal fied with permission et aLs9

Al if response

Progktin if response

m

t Androgen

ModiBuzdar

breast tissue; they prevent binding of estrogen to its receptor and do not themselves lead to activation of the receptor. Because the available SERMS bind to the receptor in a competitive manner, their inhibitory effects could potentially be overcome by high concentrations of estrogen. However, the SERM most commonly used to treat breast cancer, tamoxifen, has been shown to be as effective in premenopausal women (who have relatively high levels of circulating estrogen) as in postmenopausal women. Because the primary mode of action of SERMS involves blockade of the ER, SERMS are generally effective only in tumors that contain such receptors. Tamoxifen. Tamoxifen is the most widely used and extensively studied antiestrogen and its role in the management of patients with breast cancer is well established.17Js Tamoxifen was originally used in the management of patients with metastatic disease. Effectiveness of tamoxifen in this setting led to trials of its use in the adjuvant setting, and eventually to trials in breast cancer prevention. Tamoxifen is now approved and well established in each of these settings. For many years tamoxifen has been the standard first-line endocrine therapy for metastatic breast cancer in women with ER-positive disease. Numerous trials have been conducted in an attempt

to find an endocrine therapy with efficacy superior to that of tamoxifen. These efforts have failed until very recently when trials of the selective aromatase inhibitor anastrozole found superior efficacy and a better safety profile for first-line therapy in postmenopausal women with ER-positive breast cancer (see section on aromatase inhibitars). Tamoxifen produces an objective response in about one third of unselected patients. Among patients selected on the basis of positive ERs, the response rate is greater.17 The side effect profile of tamoxifen is well defined. The most common side effects are hot flashes and vaginal discharge; irreg ular menses, nausea, and edema can occur. Severe, but less frequent side effects include thromboemholism and an increase in the incidence of endometrial cancer from about one per 1,000 patients per year to about two to three per 1,000 patients per year. Tamoxifen has been associated with ocular changes (cataracts) that are not vision-threatening. Tumor “flare” following initiation of a course of tamoxifen may occur. Secondary benefits of tamoxifen include an improvement in blood lipid profiler9-22 and an increase in bone mineral density.23 Tamoxifen is administered orally with a usual therapeutic dosage of 20 mg/d.

AMAN

Second-line endocrine therapy is used only after a tumor is considered refractory to tamoxifen. If a woman is diagnosed with metastatic disease and received tamoxifen for adjuvant therapy within the previous 12 months, then she should be considered refractory to tamoxifen and offered secondline endocrine therapy.24 Toremifene. Toremifene has been approved for use in advanced breast cancer. Structurally similar to tamoxifen, with the addition of a single chlorine atom, it is sometimes referred to as chlorotamoxifen. Toremifene appears to be only one third as potent as tamoxifen, resulting in a higher daily dose (60 mg). Like tamoxifen, toremifene appears to be active only against tumor cells that are positive for estrogen or progesterone receptors.25j26 Toremifene also appears to produce estrogen-like effects in postmenopausal women.27,28 The results of clinical studies comparing toremifene with tamoxifen29-3’ have demonstrated efficacy of toremifene in metastatic disease. One large-scale US trial of toremifene versus tamoxifen in the treatment of metastatic breast disease has been published.29 In this trial, 648 previously untreated women with metastatic breast cancer were randomized to receive either 20 mg/d tamoxifen or 60 or 200 mg/d toremifene. Tumors were classified at entry as either ER-positive or ER-unknown. No statistical difference was detected between treatment arms for any of the major outcomes: response rate (19% v 21% w 23% for tamoxifen and lowand high-dosage toremifene, respectively); median survival time (32 w 38 e, 30 months, respectively); and time to disease progression. Pooled data from US and European trials showed similar results.31 These trials offered evidence that toremifene might be considered as an alternative first-line therapy in postmenopausal women with ER-positive advanced breast disease. In the studies of toremifene versus tamoxifen, both drugs were well tolerated. Side effects with toremifene were similar in type and incidence to side effects with tamoxifen. Hot flashes, vaginal discharge, and nausea were the most commonly reported for toremifene. Toremifene has proliferative effects on the uterus similar to those of tamoxifen.28 In the absence of long-term data on toremifene, it is not known whether there are any safety benefits over tamoxifen. Toremifene appears to be cross-resistant with tamoxifen, since overall response rates to toremi-

U. BUZDAR

fene were low in patients whose disease had progressed following tamoxifen therapy.sl-3s Because of this cross-resistance, toremifene is unlikely to be of benefit following tamoxifen in sequential endocrine therapy. Droloxifene. Droloxifene (3-hydroxytamoxifen) has a higher binding affinity for the ER than does tamoxifen.36 Its pharmacokinetics are also more rapid than those of tamoxifen, with a shorter elimination time. Phase II trials in postmenopausal women with advanced breast cancer show objective response rates of 30%, 47%, and 44% for ZO-, 40-, and lOO-mg doses of droloxifene, respectively. Median response durations were 12, 15, and 18 months, by increasing dose.37 Droloxifene is reported to be well tolerated. The most frequent side effects after oral administration were hot flashes, fatigue, and nausea. Droloxifene is a slightly weaker estrogen agonist than tamoxifen. Although phase III clinical trials comparing droloxifene to tamoxifen were initiated, development of this drug for breast cancer treatment has been halted due to lack of demonstrated superiority over tamoxifen. Use of droloxifene in the treatment of osteoporosis is still under investigation. Idox$eene. Idoxifene is another structural analog of tamoxifen designed to have few metabolites. Idoxifene has not yet been shown to produce a 4-hydroxy derivative, which theoretically may limit liver carcinogenicity in animals.3sJ9 Idoxifene has a binding affinity for the ER that is twice that of tamoxifen, but its antiestrogenic effects are less potent than those of tamoxifen as tested in immature rat uterine tissue.40 Idoxifene is in early clinical development. Data from a single phase I trial indicate that idoxifene may produce a clinical response in women with advanced breast cancer,41 but a more complete clinical program is needed to demonstrate the safety and efficacy of this drug. TAT-59. Another antiestrogenic drug in the early stages of development for the treatment of advanced breast cancer is TAT-59. This prodrug is dephosphorylated to its active metabolite, which shows good activity in inhibiting the growth of estrogen-sensitive tumors in rats and athymic mice.42-44 Clinical studies have not yet been published, but preliminary data show activity similar to tamoxifen. Raloxlfeene. Raloxifene, formerly known as keoxifene, is a selective ER modulator that exerts

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estrogenic effects on the skeletal and cardiovascular systems, but is primarily antiestrogenic in breast and endometrial tissue. Raloxifene has been tested mainly in the prevention and treatment of postmenopausal osteoporosis.45-48 It seems to improve bone mineral density (though not with the magnitude of estrogen therapy) and to decrease lowdensity lipoprotein (LDL) and total cholesterol without stimulating the breast and uterus. In one small clinical study of raloxifene in 14 patients with metastatic breast cancer who had failed tamoxifen, only one patient showed a minor response and there were no complete or partial responses.@ Another small study reported data on 18 previously untreated patients with metastatic breast cancer who were treated with 150 mg of raloxifene twice daily. Three patients achieved a partial response and five had stable disease.50 Raloxifene currently has no established role in breast cancer treatment or prevention, although a long-term clinical trial comparing the effects of raloxifene to those of tamoxifen in prevention of breast cancer in high-risk women is underway (the Study of Tamoxifen and Raloxifene [STAR]).

zole (an establishled second-line therapy) for second-line therapy of advanced breast cancer in postmenopausal women. An interesting and unique aspect of Faslodex is that substantial evidence supports the conclusion that it downregulates the ER, in addition to inhibiting the receptor. 56-59 This action appears to involve increased degradation of the receptor, as synthesis of the receptor is unaffected. Because of this action, Faslodex has been called an ER downregulator. The relative importance of receptor downregulation versus receptor inhibition remains to be established. Nevertheless, Faslodex may represent the first member of a new class of endocrine agents for breast cancer: the ER downregulators. Because the structure of Faslodex is based on the steroid backbone, it has poor availability when administered orally, in common with other steroid-based agents. As a consequence, Faslodex is administered as a monthly intramuscular injection. Presumably, the acceptance of this regimen among patients will be examined during the ongoing trials.

Pure Antiestrogens

In postmenopausal women, the ovaries no longer produce significant amounts of estrogen. However, peripheral tissues such as muscle, fat, skin, liver, and brain produce relatively low amounts of estrogen by converting adrenal androgens into estrogen. The aromatase enzyme catalyzes the conversion of androstenedione into estrone, and testosterone into estradiol. Inhibition of this enzyme, therefore, decreases estrogen levels and estrogen stimulation of tumors in postmenopausal women. Nonselective umnataseinhibitors:aminoglucethimide. Early aromatase inhibitors such as aminoglutethimide were nonselective. Such drugs inhibit the conversion of androgens into estrogens, but also block the conversion of other adrenal hormones into aldosterone and cortisol. When tested in women with advanced breast cancer, aminoglutethimide produced tumor response rates comparable to those observed with tamoxifen.60 However, the nonselective nature of its action often requires concomitant use of corticosteroids to maintain normal levels of cortisol. Patients receiving aminoglutethimide often experience side effects such as lethargy, dizziness, rash, orthostatic hypotension, and blockade of

As discussed, many of the SERMS have both estrogenic and antiestrogenic properties. In some cases, the estrogenic actions of these compounds can be a detriment, such as causing proliferation of the endometrium. Considerable effort has been directed at developing compounds that are antiestrogenic in breast tissue but not estrogenic in the endometrium. Such compounds are termed “pure” antiestrogens to distinguish them from earlier antiestrogens that had mixed agonist and antagonist actions. The first promising compound to be developed that shows potent antiestrogenic activity and no estrogenic activity is Faslodex (ICI-182,780; Astrazeneca Pharmaceutical, Wilmington, DE). Laboratory studies have shown that Faslodex inhibits the growth of breast cancer cells in athymic mice.QJz It has also been found to inhibit the endometrial proliferation induced by either estrogen or tamoxifen. 53 Early clinical studies in humans54155 found objective responses in women with advanced breast cancer who had progressed on tamoxifen, suggesting that Faslodex is not cross-resistant with tamoxifen. Phase III trials of Faslodex are underway to compare it with anastro-

Aromatase

Inhibitors

298

thyroxine synthesis.61 The side effect profile of aminoglutethimide and nonselective aromatase inhibitors often makes these drugs less desirable therapeutic choices than currently available aromatase inhibitors. Selective urOmataSe inhibitors. A number of aromatase inhibitors have been developed that are selective for the aromatase enzyme and, thus, do not require concomitant administration of corticosteroids. These selective aromatase inhibitors differ from one another in structural class (steroid or nonsteroid), potency, and type of inhibition (competitive or noncompetitive). Aromatase inhibitors that bind competitively compete with androgens for binding to the enzyme. In contrast, noncompetitive or “suicide” aromatase inhibitors bind to the enzyme irreversibly, rendering the enzyme useless until a new protein can be synthesized. In practice, this difference may be a minor detail because new enzyme can be synthesized rapidly in tissues where it is expressed. Therefore, effective concentrations of the active drug must be maintained regardless of whether the inhibitor binds reversibly or irreversibly. Selective, nonsteroidal aromatase inhibitors have become established as second-line endocrine therapy for advanced breast cancer in postmenopausal women. They have largely replaced progestins in this setting because of their superior sideeffect profile and similar efficacy. Trials comparing aromatase inhibitors against tamoxifen for firstline therapy have been completed very recently, and others are ongoing. The results of these trials are likely to lead to substantial use of aromatase inhibitors as first-line therapy, perhaps relegating tamoxifen to the second-line setting. Unfortunately, the aromatase inhibitors are reserved only for use in postmenopausal women, or women without functioning ovaries, because they can actually cause an increase in circulating sex-hormone levels in women with functioning ovaries. However, preliminary evidence suggests that they may find utility in premenopausal women whose ovarian function has been suppressed with an analog of LHRH.62 Anasrro&e. Anastrozole is an orally active, nonsteroidal, competitive aromatase inhibitor that has been available in the United States since 1996 for treatment of advanced breast cancer in postmenopausal women. Two phase III trials compared anastrozole to megestrol acetate.63264 Initial data

AMAN

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reported similar efficacy for the two drugs. The first trial was analyzed with a median follow-up time of 192 days. Of the 378 patients enrolled, 135 were randomized to receive anastrozole 1 mg daily, 118 to anastrozole 10 mg daily, and 125 to megestrol acetate 40 mg four times daily. Treatment response rates were 34%, 33.9%, and 32.8%, respectively, for the three treatments. There were no statistically significant differences between either agent in terms of objective response rate, time to objective progression of disease, or time to treatment failure. Both treatments were well tolerated, although megestrol acetate was more frequently associated with weight gain, edema, and dyspnea, while anastrozole was more often associated with gastrointestinal disorders, particularly mild, transient nausea.63 In a second phase III trial, 386 postmenopausal women whose breast cancer progressed following tamoxifen therapy were similarly randomized to anastrozole (1 mg or 10 mg daily) or megestrol acetate (40 mg four times daily). After a median follow-up of 6 months, outcomes for all treatment groups were equivalent in terms of objective response rates (lo%, 6%, and 6% for anastrozole 1 mg and 10 mg and megestrol acetate groups, respectively), percentage of patients with stable disease for more than 24 weeks (27%, 24%, 30%, respectively), time to treatment failure, and time to death. Physical quality--of-life scores were highest for those receiving 1 mg anastrozole, and psychologic quality-of-life scores were highest for those receiving 10 mg anastrozole. While both agents were well tolerated, more patients in the megestrol acetate group experienced 5% to 10% increases in body weight during the study, and weight gain appeared to continue over time.64 While initial, short-term analyses showed outcomes to be similar between anastrozole and megestrol acetate, a subsequent analysis showed statistically significant long-term benefits of anastrozole therapy.65 Because of essentially identical protocols, the two phase III trials described were combined for long-term follow-up analysis. After 31 months of follow-up in 764 patients, clinical benefits of anastrozole became evident. Anastrozole (1 mg) demonstrated a statistically significant survival advantage over megestrol acetate (I? < .025). The anastrozole (1 mg) treatment group also had a longer median time to death (26.7 months) compared with the megestrol acetate

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group (22.5 months), although this difference did not reach statistical significance (P = .09). Patients given anastrozole were more likely to survive 2 years (56.1% and 54.6% for 1 mg and 10 mg doses) than those given megestrol acetate (46.3%).65 Anastrozole appears to provide long-term survival benefits versus megestrol acetate. Anastrozole was the first selective aromatase inhibitor to be approved in the United States for treatment of postmenopausal women with advanced breast cancer after failure of tamoxifen. Recently, two identical trials have been completed studying anastrozole versus tamoxifen for first-line therapy of advanced breast cancer in postmenopausal women. Because these trials were intended to be combined, a combined analysis has been presented in preliminary form.66 Overall, the trials enrolled 5 11 women into the anastrozole arm ( 1 mg per day) and 510 into the tamoxifen arm (20 mg per day). Women were eligible if they had advanced breast cancer and their tumors were either ER- or progesterone receptor-positive or of unknown receptor status. The primary outcomes were time to progression (TTP) and objective response. Considering all patients, the median TTP was 8.5 months in the anastrozole arm and 7.0 months in the tamoxifen arm (I’ = .103). However, when only patients with ER-positive or progesterone receptor-positive tumors were included in the analysis, the median TTP was significantly better in the anastrozole arm (10.7 months [n = 3051 v 6.4 months in the tamoxifen arm [n = 3061; P = .022). Furthermore, patients in the anastrozole arm experienced a lower incidence of thromboembolism and vaginal bleeding. On the basis of these results, anastrozole should be considered as an option for first-line therapy of postmenopausal women with advanced breast cancer. Trials of anastrozole as adjuvant therapy for early breast cancer are underway. Fadrogole. Fadrozole is an orally active, nonsteroidal, competitive aromatase inhibitor that is available in Japan. While fadrozole is more selective than aminoglutethimide, it interferes with adrenal steroidogenesis to some extent.67z68 Fadrozole (1 mg twice daily) was tested against megestrol acetate (40 mg four times daily) in two doubleblind, randomized trials. Postmenopausal breast cancer patients (n = 683) whose disease had progressed following an initial response to first-line hormonal therapy were entered in the study. Out-

299

comes were similar for the two treatment groups in terms of time to progression, objective response rates, duration of response, and survival. Of the 345 patients treated with fadrozole, four (2%) had a complete response, 34 (10%) had a partial response, and 84 (24%) had stable disease for 8 weeks or more. Of the 332 megestrol-treated patients, 12 (4%) had a complete response, 35 (10%) had a partial response, and 80 (24%) had stable disease. The overall incidence and severity of adverse events were similar, but patients treated with megestrol acetate were more likely to report weight gain, fluid retention, and dyspnea, while fadrozole patients were more likely to report nausea and vomiting.69 Fadrozole has been compared with tamoxifen as first-line therapy. Of the 212 postmenopausal women with advanced breast cancer in this study, 27% responded to tamoxifen and 20% responded to fadrozole. Time to treatment failure was longer with tamoxifen (8.5 months) than with fadrozole (6.1 months), but this was not significant after adjustment for prognostic factors. Patients receiving fadrozole had fewer clinically relevant adverse events (World Health Organization toxicity grade ~2), which was notable in terms of severe cardiovascular events. Letro~ole. Letrozole is a selective, potent, nonsteroidal, competitive aromatase inhibitor now approved for second-line therapy in postmenopausal women with advanced breast cancer. Both high (2.5 mg) and low (0.5 mg) once-daily dosages have been tested in postmenopausal women with advanced breast cancer. In a large-scale study (N = 551) comparing letrozole to megestrol acetate (160 mg daily), high-dose letrozole was found to produce a significantly higher overall response rate (24%) than either megestrol acetate (16%, P = .04) or low-dose letrozole (13%, I’ = .004). Highdose letrozole was also superior to both megestrol acetate (I’ = .04) and low-dose letrozole (P = .002) in terms of time to treatment failure. The higher dosage of letrozole was also superior to the lower dosage in terms of time to disease progression (P = .02) and overall survival (I’ = .03). Letrozole was better tolerated than megestrol acetate in terms of serious adverse events, discontinuation due to poor tolerability, incidence of cardiovascular side effects, and reports of weight gain.70 In another randomized, multicenter, open-label

AMAN

trial, letrozole was tested in the treatment of postmenopausal women with advanced breast cancer. Groups given high or low dosages of letrozole were compared (n = 185 and n = 192, respectively) against aminoglutethimide (250 mg twice daily with corticosteroid support, n = 178). Overall response rates for the high- and low-dose letrozole and aminoglutethimide groups were 19.5%, 16.7%, and 12.4%, respectively. The median duration of response (shown by stable disease) was 2 1 months for patients receiving high-dose letrozole compared with 18 months for those receiving lowdose letrozole and 14 months for those receiving aminoglutethimide. Letrozole 2.5 mg produced superior results compared to aminoglutethimide in terms of time to progression, time to treatment failure, and overall survival. Fewer drug-related adverse events were attributed to letrozole than to aminoglutethimide.71 A trial of letrozole versus tamoxifen for first-line therapy has been completed. An ongoing trial is testing letrozole versus tamoxifen for adjuvant therapy in postmenopausal women with endocrine receptor-positive tumors. Voro~ook. Vorozole is a selective, nonsteroidal, competitive aromatase inhibitor. In preliminary trials, the usual 2.5 mg once-daily dose of this chiral compound was well tolerated and produced good objective response rates-from 21% to 33% in four studies.Tz-7s A larger phase III trial comparing vorozole to megestrol acetate in postmenopausal women with breast cancer demonstrated a response rate of 9.7% for vorozole and 6.8% for megestrol acetate and a clinical benefit in 23.5% and 27.2% of patients, respectively.76 Vorozole was associated with significantly more nausea, hot flushes, and arthralgia than was megestrol acetate, but megestrol was associated with significantly more dyspnea and weight gain. Although vorozole is effective and is well tolerated, its lack of advantage over other agents has led to discontinuation of clinical development. Fornres tane . Formestane (4-hydroxyandrostenedione) is an extensively studied, steroidal, noncompetitive aromatase inhibitor. It is nonestrogenie and highly selective for aromatase. In the largest clinical trial of formestane, patients who received at least 4 weeks of formestane in this open-label study showed a 26% response rate.77 In another open-label trial testing two dosages of formestane (250 mg Y 500 mg every 2 weeks),

U. BUZDAR

patients receiving the lower dose had a 29% response rate, while those on the higher dose reported a 46% response rate.78 In these studies, some patients reported weakness, lethargy, hot flashes, spotting, mild nausea and vomiting, and allergic reactions.77 The most common adverse event, though, is caused by the drug’s intramuscular route of administration. About 13% of patients experienced pain and/or inflammation at the injection site.68 Because of such injection site reactions, formestane may be less well tolerated by some patients than other endocrine therapies. While formestane’s irreversible binding to aromatase is a theoretic advantage, at least one study comparing it to anastrozole (a competitive aromatase inhibitor) showed no clinical advantage in decreased estradiol levels. In contrast, mean decreases in estradiol levels were 79% in the anastrozole (1 mg daily) group and 58% in the formestane (250 mg biweekly) group (P = .0001).79 It remains to be established whether irreversible binding offers any meaningful clinical benefit. Exemesmne. Exemestane, like formestane, is a steroidal, irreversible aromatase inhibitor. But unlike formestane, it is orally bioavailable. Although its mechanism of aromatase inhibition differs from that of the nonsteroidal inhibitors anastrozole and letrozole, it suppresses enzyme activity to a similar degree.80 Three phase II trials have now shown that exemestane can produce objective responses in postmenopausal women who have progressed on tamoxifen, progestins, aminoglutethimide, and/or a nonsteroidal aromatase inhibitor.81~83 Thus, exemestane may emerge as a viable third-line endocrine agent. A phase III trial was recently completed comparing exemestane to megestrol acetate in postmenopausal women with advanced disease that had progressed on tamoxifen.84 In 366 patients treated with exemestane (25 mg/d), the objective response rate (complete plus partial responses) was 15.0%. The objective response rate in women treated with megestrol acetate was 12.4%. Although this difference was not statistically significant, exemestane was significantly better than megestrol acetate in terms of median survival time (median not reached for exemestane v 123.4 weeks for megestrol acetate; I’ = .039), TTP (20.3 weeks w 16.6 weeks; P = .025), and time to treatment failure (16.3 weeks P, 15.7 weeks; P = .042). The three newest aromatase inhibitors (letro-

ENDOCRINE

THERAPY

OF METASTATIC

BREAST

zole, anastrozole, exemestane) have not been compared in the same trial and thus it is difficult to assess whether any one is superior to the other. Although the mechanism of action of exemestane differs, it remains to be determined whether this difference offers any clinical benefit or detriment. However, the different mechanism of action of exemestane may explain its activity after failure of a nonsteroidal aromatase inhibitor. All three agents should now be considered appropriate for second-line use after failure on tamoxifen. But because of its activity after failure of nonsteroidal agents, exemestane may be reserved for third-line use. As with anastrozole and letrozole, exemestane is being studied versus tamoxifen for first-line use in advanced disease and as adjuvant therapy in early-stage disease. LHRH

301

CANCER.

Agonists

Results from the Early Breast Cancer Trialists’ Collaborative Group reinforced the beneficial effect of ovarian ablation in premenopausal women. Results of a 15-year follow-up of women whose breast cancer was treated with ovarian ablation (by surgery or radiation) showed statistically better outcomes as compared to those who received no ablation. Women under 50 years of age at study randomization showed better recurrence-free survival rates (58.5% PI48.3%; P = .0004) and better overall survival rates (52.9% v 42.3%; P = .00007) than similar women with no ovarian ablation.85 LHRH agonists have been shown to provide medical and reversible ovarian ablation by reducing the levels of serum gonadotropin and ultimately the level of estradiol.86 Clinical trials must show whether medical ovarian ablation provides the same long-term benefits as surgery and radiation. A number of LHRH agonists have been evaluated for the treatment of breast cancer, including goserelin, buserelin, leuprolide, and triptorelin. Currlntly, only goserelin acetate implants are indicated in the United States for use in the treatment of breast cancer. Proges tins The only progestin indicated in the United States for treatment of postmenopausal advanced breast cancer is megestrol acetate, although medroxyprogesterone is sometimes used outside the United States. Both agents are synthetic derivatives of progesterone, and their mechanism of ac-

tion in breast cancer has not been elucidated. Megestrol acetate may produce about a 30% response rate in unselected patients with metastatic breast cancer.37 While this efficacy rate is about the same as that of tamoxifen, progestins are generally reserved for later therapy because of side effects,87 which include significant weight gain (>20 pounds), hypertension, tremor, and thromboembolism. CONCLUSIONS Endocrine therapy offers an effective treatment of receptor-positive metastatic breast cancer. When one endocrine therapy has produced a response, subsequen.t classes of endocrine agents are likely to be effective. Usually, the agents described are used sequentially, with antiestrogens first, aromatase inhibitors as second-line, and progestins and androgens used as third- and fourth-line therapy in postmenopausal women. However, results of recent trials are likely to push aromatase inhibitors into the first-line setting. Premenopausal women with advanced breast cancer frequently ablation using pharmacologic require ovarian (LHRH antagonists), surgical, or radiation treatments. Premenopausal women typically receive LHRH agonists or tamoxifen as first-line therapy, with the alternative treatment used as second-line therapy. Aromatase inhibitors alone are not appropriate for premenopausal women with functioning ovaries, although studies are examining their use in combination with LHRH agonists. Progestins and androgens may be utilized sequentially. The abundance of research on endocrine therapies is changing standard clinical practice. The hope is that current research will soon offer selective, well-tolerated endocrine therapies that not only enlarge the pharmacologic armamentarium, but also provide the most effective and best tolerated breast cancer therapies. REFERENCES 1. Greenlee RT, Murray T, Hill-Harmon MB, et al: Cancer statistics, 2001. CA Cancer J Clin 51:15-36, 2001 2. Carter CL, Allen C, Henson DE: Relation of tumor size, lymph

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