Update on Endocrine Therapy for Breast Cancer...stilbestrol was introduced in the 1940s as an...

Vol. 4, 52 7-534, Marc/i 1998 Clinical Cancer Research 527

Review

Update on Endocrine Therapy for Breast Cancer

Aman U. Buzdar’ and Gabriel Hortobagyi

The University of Texas M. D. Anderson Cancer Center, Houston,

Texas 77030

Abstract

The choice of endocrine agent for breast cancer de-

pends on the menopausal status of the patient, the stage of

disease, prognostic factors, and the toxicity profile of the

agent. Endocrine therapies are typically given sequentially,

with the least toxic therapy given first. Tamoxifen is consid-

ered first-line endocrine therapy for all stages of breast

cancer. New antiestrogens in development include nonste-

roidal agents related to tamoxifen and pure steroidal anties-

trogens Luteinizing hormone-releasing hormone agonists

are an effective form of endocrine therapy for premeno-

pausal women with advanced breast cancer, and aromatase

inhibitors are effective in postmenopausal women. Newer

and more selective aromatase inhibitors that are p.o. active

and have improved side-effect profiles have been developed.

Recent trials have found these agents to improve survival in

comparison to the progestins; thus, aromatase inhibitors are

replacing progestins as second-line therapy for metastatic

disease. Current trials are examining the potential role of

aromatase inhibitors as first-line therapy for metastatic dis-

ease or as adjuvant therapy for early disease. The antipro-

gestins and antiandrogens studied thus far have had only

limited success in breast cancer clinical trials.

Introduction

It has been over a century since Beatson demonstrated that

oophorectomy was effective for treating advanced breast cancer.

( 1 ) Since then, endocrine therapies have become firmly estab-lished for managing all stages of breast cancer.

In the last few years, many advances have been made in

endocrine approaches to breast cancer therapy. Treatment

choices have been refined and optimized by the development of

assays for the presence of estrogen and progesterone receptors

in tumors. Surgical techniques (i.e., oophorectomy, hypophy-

sectomy, and adrenalectomy) have been largely replaced by a

variety of pharmaceuticals (i.e., antiestrogens, LHRH2 agonists,

aromatase inhibitors, androgens. estrogens, and progestins), and

Received 9/22/97: revised 12/16/97: accepted 12/16/97.The costs of publication of this article were defrayed in part by thepayment of page charges. This article must therefore be hereby markedadvertisement in accordance with 18 U.S.C. Section 1734 solely toindicate this fact.

‘To whom requests for reprints should be addressed, at Department ofBreast Medical Oncology, M. D. Anderson Cancer Center, Box 56,1515 Holcombe Boulevard, Houston, TX 77030. Phone: (713) 792-

2817; Fax: (713) 794-4385.

2 The abbreviations used are: LHRH, luteininzing hormone�releasing

hormone: ER, estrogen receptor; PR, progesterone receptor; FDA, Food

and Drug Administration: AG. aminoglutethimide.

research is ongoing to find new agents with greater efficacy and

improved safety profiles. Certain hormones (estrogens) can have

a major positive impact on the general health of women (i.e.,

preventing osteoporosis, lowering serum lipid levels, and reduc-

ing menopausal symptoms). Thus, new endocrine agents that

improve general health in addition to having antitumor activity

would be highly desirable both in the breast cancer setting and

for hormone replacement in healthy postmenopausal women

(2, 3).

The decision to use endocrine therapy for breast cancer is

based on a number of prognostic factors. Probably the most

important indicator of response to endocrine therapy is the

presence of ERs and PRs in the tumor. Approximately 30% of

unselected breast cancer patients respond to endocrine therapy.

Estrogen receptor and progesterone receptor data help to iden-

tify patient subgroups who may benefit from endocrine therapy.

Endocrine therapy response rates in advanced disease average

33% in tumors positive for one hormone receptor and 50-70%

in tumors positive for both hormone receptors (4). Furthermore,

20-30% of patients treated with endocrine therapy have stable

disease and achieve similar benefits as those patients responding

to endocrine therapy. Hormone receptor positivity is more com-

mon in postmenopausal than premenopausal breast cancer pa-

tients (Fig. 1 ; Ref. 5). Other predictors of response include prior

response to endocrine therapy, soft tissue or bony (as opposed to

visceral) metastases, long disease-free interval, older age, well-

differentiated tumors, and HER-2/neu negativity.

Most endocrine agents act by either blocking the produc-

tion of estrogen (ovarian ablation and aromatase inhibitors) or

the action of estrogen at the cellular level (antiestrogens); how-

ever, for some agents (e.g. , supraphysiological doses of estro-

gens, androgens, and progestins), the mechanism of action is

unknown. The choice of endocrine agent depends on the men-

opausal status of the patient, because this factor determines the

source of estrogen: ovarian or adrenal (peripheral; Fig. 2).

In premenopausal women, the ovary actively produces high

basal estrogen levels. One treatment option is ovarian ablation,

which can be accomplished by surgery, radiation, or LHRH

agonist therapy. Of the surgical techniques, oophorectomy is

still used in premenopausal women with advanced breast cancer,

but hypophysectomy and adrenalectomy were abandoned once

pharmacological approaches became available (6). Antiestrogen

therapy (i.e., tamoxifen) has proven effective in premenopausal

patients as well.

In postmenopausal women, ovarian function has ceased,

and estrogen is primarily produced in peripheral tissues such as

fat and muscle. Endocrine therapies for postmenopausal women

include antiestrogens, progestins, and aromatase inhibitors.

Although endocrine therapies operate through different

mechanisms, they often have similar objective response rates.

Because breast cancer is a progressive disease and the develop-

ment of drug resistance is common, endocrine therapies are

given sequentially, with the least toxic therapy given first.

In some cases, endocrine therapies have been almost en-

tirely abandoned on the basis of toxicity. For example, diethyl-

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o Premenopausal#{149}Postmenopausal

Hypothalamus

47PostmenopausalPremenopausal

(FSH7/’�

Gonadotrophins

Ovary

IProgesterone

Adrenal gland

Prolactin

Growth hormone �

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Androgens

1�Peripheral 1�ssues

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Fig. 2 Routes of synthesis of estrogen and progesterone in premeno-pausal and postmenopausal women.

528 Endocrine Therapy for Breast Cancer

irJ1ER+, PR+ ER+, PR- ER-, PR+ ER-, PR-

Receptor Status

Fig. 1 Breast cancer patients grouped according to their menopausal

status and the hormone receptor status of their tumors.

stilbestrol was introduced in the 1940s as an endocrine therapy

for postmenopausal advanced breast cancer (6). Because dieth-

ylstilbestrol was associated with side effects such as upper

gastrointestinal distress, thromboembolic risk, fluid retention,

stress incontinence, and withdrawal bleeding, it all but disap-

peared from the clinic after the introduction of tamoxifen in the

1970s. Likewise, androgens are associated with virilization,

nausea, hepatotoxicity with cholestasis, increased libido, and

hypercalcemia; as a consequence. they have been relegated to

fourth-line therapy for advanced breast cancer in postmeno-

pausal women.

Current and Future Directions in Endocrine Therapy

Nonsteroidal Antiestrogens

Tamoxifen Tamoxifen (Fig. 3) is the first-line endocrine

therapy for all stages of breast cancer. It was first approved by

the FDA in 1977 for the treatment of advanced breast cancer in

postmenopausal women and has since been approved for: (a) the

treatment of advanced breast cancer in premenopausal women;

(b) use with chemotherapy; (c) adjuvant monotherapy in post-

menopausal women with node-positive breast cancer; (d) the

treatment of node-negative breast cancer; and (e) male breast

cancer.

In postmenopausal women with advanced breast cancer,

tamoxifen induces objective responses in about one-third of

unselected patients; a higher response rate is observed in women

with ER-positive tumors (7). Adjuvant therapy with tamoxifen

has reduced recurrence rates, mortality, and the incidence of

contralateral breast cancer (8). The duration for which to give

adjuvant tamoxifen therapy is an issue that remains to be re-

solved. It is clear that 5 years is better than 2 years, (9) but there

are conflicting data as to whether longer than 5 years would be

even better (or worse). The National Cancer Institute recom-

mended limiting adjuvant tamoxifen to 5 years after the Na-

tional Surgical Adjuvant Breast and Bowel Project B-l4 trial

revealed no additional benefit of longer therapy in patients with

node-negative breast cancer (10). However, the Eastern Coop-

erative Oncology Group recently published preliminary results

(1 1) of a trial showing prolonged disease-free survival with

longer than 5 years compared with 5 years in women with

ER-positive breast cancer.

Because tamoxifen was found to prevent new tumors from

developing in the opposite breast, the drug is presently being

studied in worldwide breast cancer prevention trials in healthy

women at increased risk for the disease ( 12). The use of tamox-

ifen in healthy women has been controversial. Although tamox-

ifen is generally considered safer than alternative endocrine

therapies such as androgens, estrogens, and progestins, it is not

without toxicity. In addition to vasomotor and gynecological

side-effects (e.g., hot flashes, vaginal discharge, and irregular

menses) and an increase in the rate of thromboembolic events

(1% in the B-14 trial; Ref. 10), the drug has been associated with

a modest increase in the risk for endometrial cancer (2 cases per

1000 patients/year; Refs. 13 and 14).

About 250 cases of tamoxifen-associated endometrial can-

cer have been reported since 1985 (15). It is not known what

role tamoxifen plays in the etiology of these cancers (13);

tamoxifen may act as a tumor initiator or promoter or may only

enhance detection of preexisting endometrial cancer (detection

bias). Because exposure to unopposed estrogen has been linked



�9,,,,,g”s��__NMe2 Ct

Tamoxifen Toremifene

�

Raloxifene

OH

�cH2�,SO(CH2)3CF2CF3HO

Clinical Cancer Research 529

Droloxifene

ICI 182, 780

(Faslodex)

Fig. 3 Chemical structures of selected antiestrogens.

to endometrial cancer, the partial estrogenic activity of tamox-

ifen has been suspect. It is important to note that all of the

nonsteroidal antiestrogens in clinical development exhibit some

degree of estrogen agonist activity (2). These new agents will

require vigorous long-term study before a conclusion can be

reached regarding the risk of endometrial cancer.

Toremifene. Several new nonsteroidal antiestrogens

have been developed, and one of these, toremifene, has been

approved by the FDA for use in advanced breast cancer. In a

comparative trial involving women with advanced breast cancer

(16), toremifene (60 and 200 mg) showed similar efficacy andsafety to tamoxifen (20 mg). The higher dose of toremifene had

no benefit over the lower dose and was associated with an

excess of liver function abnormalities; thus, 60 mg/day

toremifene was approved for advanced breast cancer.

Toremifene is not yet indicated for adjuvant therapy, and long-

term data are lacking on the agent. Therefore, it is not yet known

whether toremifene will have any safety advantage compared

with tamoxifen. However, it has been shown that toremifene,

like tamoxifen, has a proliferative (estrogenic) effect on the

uterus (17). The ultimate place of toremifene in therapy remains

to be seen. Due to major cross-resistance between the two

agents, it is unlikely that toremifene will be used as second-line

therapy after tamoxifen (18, 19).

Droloxifene. Droloxifene (3-hydroxytamoxifen) is an

antiestrogen in advanced clinical trials that shows higher bind-

ing affinity for the estrogen receptor than tamoxifen (20). In a

multicenter Phase II trial involving postmenopausal women

with advanced breast cancer (2 1 ), objective responses were seen

in 30% of patients receiving 20 mg of droloxifene, compared

with 47% of the 40-mg group and 44% of the 100-mg group.

The median response durations were 12, 15, and 18 months,

respectively. The most common side effects with droloxifene

were hot flashes, lassitude, and nausea. Ongoing Phase III trials

are comparing the safety and efficacy of droloxifene to tamox-

ifen. Interestingly, because droloxifene is eliminated from the

body more rapidly than tamoxifen, it may have a role in com-

bination chemohormonal therapy (6).

Raloxifene. Raloxifene is a benzothiophene antiestrogen

that was being developed for breast cancer therapy but now is in

clinical trials for the prevention and treatment of postmeno-

pausal osteoporosis (22). In postmenopausal women, raloxifene

(50 mg/day) was associated with significant reductions in total

serum and low-density lipoprotein cholesterol as well as serum

markers of bone turnover (i.e., osteocalcin and alkaline phos-

phatase; Ref. 23). If raloxifene becomes available for the pre-

vention of osteoporosis in healthy postmenopausal women, a

side benefit may be a reduction in the risk for breast cancer and

coronary heart disease (3, 24).

Steroidal Antiestrogens

As discussed, the nonsteroidal antiestrogens all possess

partial estrogenic activity. Steroidal antiestrogens have been

developed that have no estrogenic activity and are thus less

likely to have a proliferative effect on the endometrium. These

compounds were derived from the estradiol molecule, in con-

trast to the nonsteroidal antiestrogens, which were derived from

the triphenylethylene structure of tamoxifen. One steroidal an-

tiestrogen, ICI 182,780 (Faslodex; Fig. 3), has entered clinical

trials. In vitro, this agent has a high affinity for the estrogen

receptor and high potency against ER-positive breast cancer cell

lines (25). In a clinical trial (26), 56 postmenopausal women

were randomized to ICI 182,780 (6 or 18 mg by injection) or no

treatment for 7 days before primary breast surgery. ICI I 82,780

significantly reduced expression of ER (P < 0.01 ), progesterone

receptor (P < 0.05), and Ki67 (proliferation-associated nuclear

antigen; P < 0.05) in ER-positive breast tumors. Expression of

an estrogen-regulated protein (p52) was reduced, irrespective of

tumor ER status.

In a Phase I trial (27), 19 patients with advanced breast

cancer who had become resistant to tamoxifen received ICI

182,780 until progression (median, 25 months; Ref. 28). Thir-

teen patients responded to treatment (7 with a partial response

and 6 with stable disease), indicating a lack of cross-resistance

with tamoxifen. IC! 182,780 was well tolerated.

Although further clinical study of IC! I 82,780 is necessary,

potential advantages include a lack of proliferative effect on the

endometrium and a lack of cross resistance with tamoxifen. If

the efficacy and safety of IC! 182,780 are established in Phase

III trials, this agent may have a role as second-line therapy after

tamoxifen.

LHRH Agonists

In premenopausal women with advanced breast cancer, a

desirable goal of endocrine therapy is to inhibit ovarian estrogen



FormestaneAminoglutethimide

NC)(�.)(CN

H3C CH3 H3C CH3

Anastrozole Fadrozole

ffN

� N,,)\ CH3

NC�H-�&-CN ClGJH�jN;

Letrozole Vorozole

Fig. 4 Chemical structures of selected aromatase inhibitors.


production, which is under the control of circulating gonado-

tropins produced by the pituitary. Gonadotropin production is

under the control of hypothalamic LHRH, which is normally

released in a pulsatile fashion. Continuous treatment with

LHRH agonists dramatically reduces levels of serum gonado-

tropins. and hence estradiol; in premenopausal women, this is

essentially a medical (and reversible) form of castration (29).

LHRH agonists may also have a direct cytotoxic effect on

cancer cells (30).

Although a number of LHRH agonists have been evaluated

for the treatment of breast cancer (e.g. , goserelin, buserelin,

leuprolide, and triptorelin), only goserelin acetate implant is

indicated (FDA approved) for breast cancer in the United States.

Objective response rates to LHRH agonists have ranged from

31-63% in premenopausal women with advanced breast cancer,

similar to response rates seen with oophorectomy (30). As with

other endocrine therapies, the frequency of response to LHRH

agonists is higher in tumors that are hormone receptor positive.

Side-effects with LHRH agonists consist of injection site reac-

tions, tumor flare, and menopausal symptoms.

Recent results from the Early Breast Cancer Trialists’

Collaborative Group have contributed to a renewed interest in

ovarian ablation as adjuvant therapy (8), and studies of the

adjuvant use of LHRH agonists in premenopausal women are

under way. In 1992, the Early Breast Cancer Trialists’ Collab-

orative Group published results of a 15-year follow-up on the

effects of ovarian ablation (by surgery or radiation) on recur-

rence and death in women diagnosed with early breast cancer.

For women

Fig. 5 Simplified diagram depicting steroid hor-

mone synthesis and the effects of selective versusnonselective aromatase inhibitors.

lll� -

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Nonselective

mechanisms of interaction with aromatase results in clinical

differences among these agents is yet to be determined.

Formestane. Formestane (4-hydroxyandrostenedione) is

a selective suicide aromatase inhibitor indicated for advanced

breast cancer in postmenopausal women (outside of the United

States). In 136 unselected patients with advanced breast cancer,

formestane (250 mg i.m. every 2 weeks) demonstrated a 26%

response rate (34). In this study, 13% of patients had injection

site reactions, and five patients experienced an anaphylactoid

reaction after inadvertent iv. administration. Although the high

selectivity of formestane represents a major advance, the need

for i.m. administration is an impediment to widescale accept-

ance of this agent in clinical practice.

Anastrozole Anastrozole is a selective, nonsteroidal

competitive aromatase inhibitor that was approved by the

United States FDA in 1996 for the treatment of advanced breast

cancer in postmenopausal women. After once-daily oral dosing

of I mg in postmenopausal women, serum estradiol levels are

suppressed to assay limits (35). Two Phase III multicenter trials

have been conducted comparing double-blind anastrozole ( 1 and

10 mg/day) with open-label megestrol acetate (40 mg q.i.d.) for

second-line treatment of advanced breast cancer in 764 post-

menopausal women (36). About 40% of patients in each group

benefited from therapy in terms of objective response or stable

disease (37). There were no significant differences among the

three treatments with respect to objective response rates or time

to disease progression (median, 21 weeks). However, a recent

update with longer follow-up has revealed a significant advan-

tage in overall survival for the group receiving I mg/day anas-

trozole compared with megestrol (37). Patients treated with I

mg of anastrozole had a 22% lower risk of death compared with

megestrol acetate. Gastrointestinal disturbances were more com-

mon in patients receiving anastrozole compared with patients

receiving megestrol acetate, although the difference was not

significant. In contrast, megestrol acetate was associated with

significant and progressive weight gain. Ongoing Phase III trials

are comparing the safety and efficacy of anastrozole with ta-

moxifen for first-line use in the metastatic setting. In addition,

anastrozole is being evaluated for use as an adjuvant treatment.

Fadrozole Fadrozole (CGS 16949A) is a nonsteroidal,

p.o. active, competitive aromatase inhibitor that has undergone

extensive clinical testing in postmenopausal women with ad-

vanced breast cancer. It is not available in the United States, but

it is available in Japan. Fadrozole exhibits greater potency and

selectivity than AG (2, 38), but it is not entirely selective

because it appears to interfere with adrenal steroidogenesis to

some extent (39, 40).

Fadrozole (I mg bid.) was studied in two double-blind

Phase III studies in which it was compared to megestrol acetate

(40 mg q.i.d.) for second-line therapy of advanced breast cancer

(38). A total of 683 postmenopausal women were enrolled. The

combined overall response rates were 12.2% for fadrozole and

14.2% for megestrol acetate. No significant differences between

treatments were seen in response rates, response durations, time

to progression, or median survival. Fadrozole was associated

with a higher incidence of nausea and vomiting, whereas pa-

tients treated with megestrol acetate were more likely to have

experienced dyspnea, edema, and weight gain.

Fadrozole (1 mg b.i.d.) has also been compared with ta-

moxifen (20 mg/day) for first-line treatment of postmenopausal

women with advanced breast cancer (4 1 ). A total of 2 12 women

were enrolled. Prognostic factors were balanced between the

two treatment groups, with the exception of an excess of visceral

metastatic disease in the fadrozole group. Response rates were

20% for fadrozole and 27% for tamoxifen; time to treatment

failure was 6. 1 and 8.5 months, respectively. Fadrozole was

better tolerated than tamoxifen [WHO grade 2 toxicity 13%

versus 27% of patients, respectively (P 0.009)].

Letrozole. Letrozole (CGS 20267) is a nonsteroidal

competitive aromatase inhibitor that, like anastrozole, offers

high selectivity and once-daily oral dosing (2). Recently. letro-

zole was approved for use as second-line treatment in post-

menopausal women with advanced disease. Letrozole has been

studied in two Phase III trials, one comparing letrozole to

megestrol acetate, the other to aminoglutethimide. Both studies

involved postmenopausal women with advanced breast cancer

who had progressed on antiestrogen therapy. The first study (42)

consisted of three treatment groups: 0.5 mg/day letrozole, 2.5

mg/day letrozole, and 160 mg/day megestrol acetate. Letrozole

(2.5 mg) produced a significantly higher response rate (P =

0.047), with a trend toward a longer time to treatment failure

than megestrol acetate. The 2.5-mg letrozole dose appeared to

be significantly more effective than the 0.5-mg dose, although

the degree of estrogen suppression was similar for the two



Fig. 6 Endocrine treatment sequences for postm-enopausal and premenopausal women.


Postmenopausal Premenopausal

Tamoxifen Tamoxifen or LHRH agonist

� if respo”�””-�._�,,� ““�‘ if response

LHRH agonist or tamoxifenAnastrozole,� if response No

Megestrol � Response � if responseOophorectomy4�if � I if responseAntstrozoleAndrogen

Cytotoxic

Chemotherapy if responseMegestrol

if response

Androgen

doses. Compared to letrozole, megestrol acetate was associated

with a higher incidence of serious adverse events (primarily

cardiovascular and thromboembolic events) and weight gain.

The second study compared letrozole (0.5 and 2.5 mg/day) with

AG (250 mg bid.) and was performed with more rigorous

criteria for response (43). Overall, the objective response rates

for letrozole were lower (16.7 and 17.7% for 0.5 and 2.5 mg,

respectively) than in the previous study, probably as a result of

the more rigorous criteria used. The objective response rate for

AG was 1 1 .2% (no P given). However, letrozole was signifi-

candy better than AG in time to progression (risk ratio, 0.68;

P < 0.004 for 2.5 mg of letrozole). More patients in the AG arm

reported adverse events, and letrozole was well tolerated.

Vorozole. Vorozole is yet another selective nonsteroidal

competitive aromatase inhibitor that is active when taken p.o.

Two preliminary reports have appeared describing results from

Phase III trials with vorozole (44, 45). In one of these, vorozole

(2.5 mg/day) was compared with megestrol acetate (40 mg

q.i.d.) in 452 postmenopausal women with advanced breast

cancer who had failed on tamoxifen (45). In this open-label

study. vorozole and megestrol acetate had comparable response

rates (complete response + partial response, 10.5% versus

7.6%), with vorozole showing a nonsignificant trend toward a

longer response duration (18.2 versus 12.5 months, P = 0.07).

Although both treatments were well tolerated, vorozole had a

lower incidence of weight gain.

As a group, the selective, nonsteroidal aromatase inhibitors

(anastrozole, fadrozole, letrozole, and vorozole) have similar

efficacy to megestrol acetate, which had occupied the position

of second-line therapy for metastatic disease in postmenopausal

women. However, the new aromatase inhibitors have signifi-

cantly better side-effect profiles, particularly with regard to

weight gain. Thus, the selective, nonsteroidal aromatase inhib-

itors are replacing megestrol acetate for second-line use in this

group of patients. This relationship is illustrated in Fig. 6 for

anastrozole. the first member of this group of drugs to be

approved in the United States.

Aromatase inhibitors are not indicated for premenopausal

women because compensatory mechanisms can actually cause

an increase in estrogen production by the ovaries. However,

aromatase inhibitors may be valuable in premenopausal women

who have progressed after oophorectomy (Fig. 6).

Progestins

Progestins have been used for treating metastatic breast

cancer since the 1950s, although their mechanism of action

remains uncertain. Currently, the only progestin indicated for

postmenopausal advanced breast cancer in the United States is

megestrol acetate. A second progestin, medroxyprogesterone

acetate, is available outside the United States for breast cancer

and worldwide in a depot form for contraceptive use. Both of

these agents are synthetic, p.o. active derivatives of progester-

one (46).

Overall response rates for megestrol acetate in metastatic

disease are about 30% in unselected patients (47). Although the

efficacy of megestrol acetate appears to be similar to that of

tamoxifen, the side-effect profile of this progestin has relegated

it to second-line therapy. Weight gain is the most significant

side-effect associated with progestin therapy and appears to be

related to an increase in appetite rather than fluid retention.

Although weight gain would be desirable in the subset of breast

cancer patients with cachexia, it has a negative impact on body

image for the majority of patients. Thromboembolism represents

a serious side-effect of the progestins and may occur in 4-5% of

patients.

Antiprogestins

Because progesterone (as well as estrogen) is believed to

stimulate proliferation of breast epithelium, it has been hypoth-

esized that antiprogesterone therapy would be effective in the

treatment of breast cancer. Mifepristone (RU486) is the first

clinically available antiprogestin. Currently available overseas

as an abortifacient, the agent has undergone clinical study for

the treatment of advanced breast cancer (48).

In a Phase II trial (49), mifepristone (200 mg/day) was

administered to 28 women with previously untreated, PR-

positive advanced breast cancer. Three patients had a partial

response for an overall response rate of 10.7%. Toxicity was

mild to moderate, consisting primarily of nausea, lethargy,




anorexia, and hot flashes. The investigators concluded that the

efficacy of mifepristone was minimal, despite an optimal patient

population.

A second antiprogestin, onapristone, has undergone early

clinical evaluation, but its development was discontinued due to

liver toxicity (2).

Both mifepristone and onapristone are nonselective anti-

progestins; they also bind to glucocorticoid and androgen re-

ceptors. New antiprogestins are in development that are more

potent and more selective for the progesterone receptor (50).

Antiandrogens

Because androgen receptors are present in 30-50% of

primary breast cancers (5 1 ), there has been interest in studying

the use of antiandrogens for this disease.

Flutamide, a pure nonsteroidal antiandrogen used in the

treatment of prostate cancer, has been evaluated in Phase II

clinical trials for metastatic breast cancer. In one such trial (52),

only one response lasting 8 weeks was observed in 29 evaluable

patients, leading the investigators to discontinue further evalu-

ation of flutamide for breast cancer.

A study of metastatic breast cancer in males found that the

combination of an antiandrogen (cyproterone acetate) with an

LHRH antagonist (buserelin) induced objective responses in 7

of 1 1 patients (53). The side-effects of this treatment were loss

of libido, impotence, and hot flashes. Further studies are needed

to define the role of antiandrogens and combinations of antian-

drogens with LHRH antagonists in male breast cancer.

Discussion

In the last 5 years, a variety of new endocrine agents have

entered advanced clinical trials, and three of these, anastrozole,

toremifene, and letrozole, have received marketing approval in

the United States. Two classes of endocrine agents are the focus

of much of the research: the antiestrogens and the aromatase

inhibitors.

Because tamoxifen has been so successful in the adjuvant

breast cancer setting, the search is on for new antiestrogens that

bind ER with higher affinity and show reduced estrogenic

activity in the endometrium. A new type of steroidal antiestro-

gen has been developed that is completely devoid of estrogen

agonist activity and lacks cross-reactivity with tamoxifen. The

ultimate clinical role of this new therapy awaits the results of

Phase III trials.

Because long-term estrogen deprivation in postmenopausal

women can contribute to osteoporosis and cardiovascular dis-

ease, the use of agents such as steroidal antiestrogens presents

an important dilemma. Without the estrogen-agonist protective

effects on bones and lipids (e.g., as offered by the nonsteroidal

antiestrogen tamoxifen), if these agents are to be used as adju-

vant therapies, other agents to prevent osteroporosis and cardio-

vascular events may also have to be administered concomi-

tantly.

The development of selective nonsteroidal aromatase in-

hibitors that can maximally suppress estrogen levels and are

formulated for once-daily oral dosing is another advance in

endocrine therapy for breast cancer. Because they have fewer

side-effects than the progestins, selective aromatase inhibitors

are expected to replace progestins as second-line therapy after

tamoxifen. Whether the new selective aromatase inhibitors will

have a role in the adjuvant setting remains to be tested in clinical

trials. One rationale for using aromatase inhibitors as adjuvant

therapy is their good tolerability profile in combination with

efficacy rates comparable with other endocrine therapies for

treatment of postmenopausal advanced breast cancer; again, the

possible effects of long-term estrogen deprivation in aggravat-

ing osteoporosis and cardiovascular disease would need to be

taken into account.

The hope is that the newer endocrine therapies discussed in

this report will offer clinicians the ability to treat patients with

hormone-responsive breast cancer better (i.e. , with less

toxicity).

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1998;4:527-534. Clin Cancer Res A U Buzdar and G Hortobagyi Update on endocrine therapy for breast cancer.

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