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Endocrine Therapy for Breast Cancer

Endocrine Therapy for Breast Cancer

ABSTRACT: In addition to ovarian ablation by means of surgery or irradiation, a wide variety of endocrine agents are now available for the management of breast cancer, in both the metastatic and adjuvant settings. Currently available endocrine agents include antiestrogens, progestational drugs, and aromatase inhibitors. Randomized trials and meta-analyses have greatly clarified the specific roles of the more established of these agents in both premenopausal and postmenopausal women. However, the exact combination and sequence of these drugs are still under investigation. The addition of the bisphosphonates has also helped improve the quality of life of patients with metastatic disease. Among new endocrine agents currently under development are the pure antiestrogens, selective estrogen receptor modulators (SERMs), and a group of drugs with effects intermediate between the two. [ONCOLOGY 14(4);483-493,2000]


Introduction

Endocrine approaches to the treatment of
metastatic breast cancer were first suggested in the late 1800s by
Beatson.[1] At about the same time, Schinzinger[2] suggested the use
of irradiation to the ovaries as perhaps the first form of
“adjuvant systemic therapy.” Surgical removal of the
ovaries and/or ovarian ablation by irradiation arose from these
original ideas and became standard therapy in the 1950s and ’60s
both for metastatic breast cancer and in the adjuvant setting. As the
human endocrine system became better understood, it seemed clear that
these treatments worked by reducing estrogen levels. It was also
observed that women who underwent surgical ovarian removal without
hormone replacement were at a greatly reduced risk of developing
breast cancer.[3] This was perhaps the first demonstration of
endocrine prevention.

During the 1950s and ’60s, a variety of other endocrine
approaches were developed, but these were mainly surgical. They
included the use of adrenalectomy and hypophysectomy as second-line
endocrine therapies for premenopausal women who initially had
positive responses to ovarian ablation. Unfortunately, these
procedures were accompanied by both immediate complications and the
long-term requirement for various types of endocrine replacement.
Nevertheless, these ablative therapies were used with considerable
success into the 1970s.

With the development of modern endocrine agents, including the
antiestrogens, progestational agents, and first, second-, and
third-generation aromatase inhibitors, a wide variety of more
palatable endocrine approaches are now available. These newer
endocrine therapies continue to supplement and rival chemotherapeutic
and radiation approaches in the management of breast cancer.

Treatment of Metastatic Disease

The most appropriate hormonal therapy for a patient with metastatic
breast cancer depends, in large part, on the patient’s
menopausal status.

Premenopausal Women

As mentioned above, the role of ovarian ablation as a treatment for
premenopausal women with metastatic disease has long been
appreciated. First introduced around the turn of the 20th
century,[1,2] this therapy was used, without any ability to select
patients, for many decades.

With the discovery of the estrogen receptor by Jensen et al[4] in the
1950s, it became apparent that women who have measurable estrogen
receptors and, subsequently, progesterone receptors in their tumors
were more likely to respond to endocrine maneuvers than were those
who have only one or neither receptor measurable.[5] Levels of
estrogen and progesterone receptors were also found to predict
response to hormonal therapy.[5]

About 30% of women with tumors positive for either estrogen or
proges-terone receptors and about 60% of women with tumors positive
for both receptors will respond to endocrine maneuvers. Women with
higher levels of estrogen and/or progesterone receptors are more
likely to respond than are those with lower but still positive
levels.[5] The use of ovarian ablation remained limited in the 1960s,
’70s, and early ’80s however, by the requirement for either
a course of pelvic irradiation or a major surgical procedure.

A further development during the 1990s was the widespread
availability of ovarian ablation by laparoscopic means. This
relatively simple procedure can be carried out in the outpatient
setting in most women requiring surgical ovarian ablation, and has
made ovarian ablation a more acceptable therapy.

Early in the development of tamoxifen (Nolvadex), small, comparative
studies[6-8] showed that tamoxifen was equally effective to ovarian
ablation in the metastatic setting. A subsequent meta-analysis,
although still containing a relatively small number of patients
randomized between these two treatments, further clarified the
approximate equivalence of these two therapies.[9] Because tamoxifen
could be administered orally, had few side effects, and did not
result in permanent ovarian ablation, it became the drug of choice in
many situations for the treatment of premenopausal women with
metastatic disease.

In the 1970s, the luteinizing hormone–releasing hormone (LHRH)
analog were developed. These agents, particularly goserelin
(Zoladex), were explored in metastatic breast cancer, and numerous
phase II studies showed activity in this setting. Subsequently, the
results of a large randomized study confirmed the equivalence of
goserelin to ovarian ablation.[10]

More recently, four small studies comparing tamoxifen plus an LHRH
analog to an LHRH analog alone have suggested that the combination
may be superior in terms of time to progression and overall
survival.[11] Once again, meta-analysis of these four trials has been
helpful in suggesting that there may be a benefit to the combination
in comparison to an LHRH analog alone.[11]

Because tamoxifen is generally used as first-line therapy in this
setting, however, the more germane question remains whether tamoxifen
plus an LHRH analog is superior to tamoxifen alone. Randomized trials
to answer this question should be considered.

Treatment Recommendations—In the meantime, it seems clear
that premenopausal women who are estrogen receptor and progesterone
receptor positive and/or have suitable clinical characteristics (eg,
long disease-free interval, soft-tissue and/or bone involvement,
pleural effusion, slow pace of disease) remain candidates for
endocrine approaches to the treatment of breast cancer. These women
can receive either tamoxifen or ovarian ablation by medical,
surgical, or radiotherapeutic means as first-line endocrine therapy.
The combination of an LHRH analog and tamoxifen could also be
considered for first-line treatment.

For women whose disease responds to initial ovarian ablation but
subsequently progresses, tamoxifen should be considered as
second-line therapy. For women who begin therapy with tamoxifen,
ovarian ablation by medical, surgical, or radiotherapeutic means
should be considered as a second-line treatment.

It should be remembered that such drugs as the aromastase inhibitors
and the progestational agents have not been shown to be effective in
women who are still premenopausal. Thus, some form of ovarian
ablation should precede the use of these drugs.

Postmenopausal Women

Diethylstilbestrol (DES) was once considered the first-line treatment
for all postmenopausal women. With the advent of tamoxifen, however,
this much less toxic drug was quickly adopted, perhaps even before
the results of randomized trials showing its equivalence were available.[12]

Until a few years ago, second-line therapy was probably best
delivered by medroxyprogesterone acetate or megestrol acetate
(Megace), both of which have been shown to be equivalent to tamoxifen
in a variety of randomized clinical trials. However, these
progestational agents have an unpleasant side effect profile that
includes dyspnea, weight gain, and an increased risk of deep-vein
thrombosis and pulmonary emboli.

Over 15 years ago, aminoglutethimide (Cytadren), the prototype of the
aromatase inhibitors, became available. In postmenopausal women,
virtually all estrogen is produced by aromatase, an enzyme found in
brain, muscle, and peripheral fat that converts androgenic hormones
produced by the female adrenal gland to estrogens.

Unfortunately, aminoglutethimide was nonspecific, in that it also
blocked 11-, 17-, and 21-hydroxylation in the adrenal pathway of
steroidogenesis, resulting in reduced production of the
mineralocorticoids and glucocorticoids required for life. Thus,
aminoglutethimide, in daily doses higher than 500 mg, required
concurrent hydrocortisone replacement. Aminoglutethimide tended to
cause drowsiness, and maculopapular rashes were also common side
effects of this agent. The accompanying cortisone had its own set of
side effects.

The development of the second-generation aromatase inhibitors, such
as formestane (Lentaron), was not terribly helpful, since these were
injectable and thus harder to use. Now, however, a wide variety of
third-generation aromatase inhibitors, including anastrozole
(Arimidex), letrozole (Femara), and exemestane (Aromasin), have been
developed. Each of these drugs has been compared against
aminoglutethimide or megestrol acetate in randomized clinical studies.[13-15]

All three third-generation aromatase inhitors have been shown to be
superior to megestrol acetate to some degree. Randomized trials of
anastrazole have shown improved overall survival,[15] while
randomized trials of letrozole have shown improved time to treatment
failure and improved overall survival in comparison to megestrol
acetate.[16] Similarly, randomized trials comparing exemestane to
megestrol acetate have shown improvements in time to treatment
failure, time to progression, and overall survival.[17] In addition,
comparisons of letrozole to aminoglutethimide (500 mg) used without
hydrocortisone have demonstrated the superiority of the
third-generation aromatase inhibitor.[18]

Two trials comparing anastrozole to tamoxifen as first-line therapy
for metastatic disease were presented at the 1999 European Cancer
Conference (ECCO). One large European study randomized over 650 women
to receive either tamoxifen or anastrozole.[19] This study showed
almost identical response rates, time to treatment failure, and time
to progression for the two drugs. However, less than half of the
patients were known to be estrogen receptor positive; estrogen
receptor status in the remaining patients was unknown. A similarly
designed North American study of about 350 women randomized to
tamoxifen or anastrozole, of whom about 90% were positive for
estrogen or progesterone receptors, showed a statistically
significant benefit, with respect to both time to treatment failure
and time to progression, in favor of an astrozole.[20]

The somewhat different results of these two trials seem problematic,
and further examination of the data is underway. These preliminary
results suggest, however, that this particular aromatase inhibitor
may be at least equivalent, if not superior to, tamoxifen in the
first-line setting. Further follow-up will be required to confirm
these results and to assess survival. Certainly, these data have
generated great interest in the upcoming results of a randomized
study in which anastrozole (A) is being compared to tamoxifen (T) and
to the combination of the two drugs (AT) as adjuvant therapy for
receptor positive or unknown postmenopausal women (the so-called ATAC trial).

Treatment Recommendations—Based on currently available
data, postmenopausal women with metastatic disease should be treated
first with tamoxifen, followed by a second-generation aromatase
inhibitor (anastrozole, letrozole, or exemestane) and then, probably,
by megestrol acetate. Drugs with a more problematic side effect
profile, such as fluoxymesterone and danazol, can be reserved for
fourth-line therapy when required. The rapid development of the
aromatase inhibitors and the suggestion that at least one of them,
anastrozole, may be equivalent to if not better than tamoxifen in the
first-line metastatic setting, suggest that the sequence of hormonal
therapies may change over the next few years as more data become available.

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