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Aromatase Inhibition and Antiestrogen Therapy in Early Breast Cancer Treatment and Chemoprevention

Aromatase Inhibition and Antiestrogen Therapy in Early Breast Cancer Treatment and Chemoprevention

ABSTRACT: The aromatase inhibitors represent an important class of hormonal agents for the management of breast cancer. The third-generation aromatase inhibitors have replaced megestrol acetate as second-line hormonal therapy in advanced breast cancer, and large clinical trials are maturing to establish their efficacy relative to tamoxifen (Nolvadex) in the first-line metastatic setting. The increased potency, increased specificity, and established efficacy of aromatase inhibitors in advanced breast cancer have provided the rationale for a large number of randomized trials in the adjuvant setting evaluating anastrozole (Arimidex), exemestane (Aromasin), and letrozole (Femara). These trials are addressing the value of these agents in sequence with, instead of, and in combination with tamoxifen. The relationship between estrogen exposure and breast cancer risk has long been accepted and traditionally related to estrogen-receptor-mediated events. The emergence of the estrogen genotoxicity hypothesis as a mechanism for breast cancer carcinogenesis provides additional rationale for considering aromatase inhibitors in the chemoprevention setting. [ONCOLOGY 15(Suppl 7):28-34, 2001]

Introduction

Hormonal therapy remains an integral part of the management
of breast cancer for most women. Tamoxifen (Nolvadex) has been the hormonal
agent of choice for women with estrogen-receptor- and/or progesterone-
receptor-positive tumors in both the adjuvant and metastatic disease settings.
It has also demonstrated efficacy in the chemoprevention setting. Although
tamoxifen has had a profound and positive impact on the management of breast
cancer, the availability of the newer anti-aromatase agents offers the potential
for improving the therapeutic index in women with breast cancer. In addition,
these agents offer a new approach for consideration in chemoprevention of the
disease.

Estrogen and Breast Cancer

Estrogen exposure has long been known to be a risk factor for
breast cancer development. Early menarche, late menopause, and obesity in the
postmenopausal setting (which is associated with high estrogen levels) are all
associated with greater risk of breast cancer. Particularly striking in this
regard are the data on surgically induced menopause from Trichopoulos et al,[1]
who found a 60% reduction in breast cancer risk in women so treated compared
with those experiencing a natural menopause. Although they found the reduction
greatest for women whose menopause was induced before age 35, reductions were
also seen in women up to the age of 50 years.

Interference with estrogen action and reduction in estrogen
production are two major approaches taken in the management of hormone-dependent
breast cancer. The interference with estrogen action is best exemplified by the
use of tamoxifen, where the mechanism of action is thought to be primarily
related to competition with estrogen for the estrogen receptor, which results in
decreased expression of estrogen-regulated genes.[2] Reduction in estrogen
production is exemplified by the use of ovarian ablation in premenopausal women
and use of agents that inhibit the aromatase system in postmenopausal women.

Converting to Estrogen

In postmenopausal or castrated women, the major source of
estrogen is the peripheral conversion of androstenedione, which is secreted by
the adrenal gland, via aromatase, which is a complex of a cytochrome P450
hemoprotein and a flavoprotein, NADD (nicotinamide adenine dinucleotide
diphosphate) cytochrome P450 reductase. Aromatization is the rate-limiting step
in the conversion of androstenedione to estrone, which can subsequently be
reduced to estradiol.

Adipose tissue contains substantial aromatase activity and is
responsible for much of the peripheral conversion of androstenedione to estrone.
The breast, however, is also a site for this peripheral conversion, with obvious
implications for breast cancer development. Miller and O’Neill[3] examined
aromatase activity in different quadrants of mastectomy specimens and found the
activity was always higher in the quadrant associated with the tumor.

High Estradiol Levels

The concentration of estradiol in plasma is substantially lower
in post-menopausal than in premenopausal women. Despite this differential,
Pasqualini et al[4] found that the levels of estradiol in breast cancer tissue
were similar in premenopausal and postmenopausal women, and that the levels of
estrone sulfate were significantly higher in the latter patients. Esteban et
al[5], using immunohistochemical methodology, found that 15 (40%) of 38 breast
cancers demonstrated significant immunoreactivity for aromatase. Utilizing an
assay for aromatase activity that quantifies production of tritiated water
release from 1-tritiated- androstenedione, Lipton et al[6] found measurable
aromatase activity in 69% of 113 breast cancers.

The finding of relatively high estradiol levels in breast
cancers in postmenopausal women and the identification of aromatase activity
raises the question of the relative importance of in situ aromatization vs
enhanced uptake from plasma. An intriguing study addressing this issue was
performed by Yue et al,[7] who developed a model in which aromatase- and
sham-transfected MCF-7 cells were inoculated into ovariectomized nude mice and
then androstenedione was administered. Heterotransplants in which
aromatase-transfected MCF-7 cells were implanted in one flank and
sham-transfected cells in the other flank demonstrated that the tumor weight was
7.6-fold larger and the estradiol concentration 3- to 4-fold higher in the
aromatase-transfected tumors.

Yue also examined the impact of estradiol administration by
silastic implants and androstenedione by injection in ovariectomized mice with
implantation of aromatase-transfected MCF-7 cells. The estradiol administration
always produced lower tumor growth rates and lower estradiol levels than
androstenedione, supporting the position that in situ aromatization plays a
major role in determining the tissue estradiol levels.[7] An additional
consideration is that, whereas circulating estrogens may be bound to sex hormone
binding globulins, this would not be the case in estrogens produced in situ and
acting in a paracrine or intracrine fashion.

Aromatase Inhibitors

The three generations of aromatase inhibitors are listed in
Table 1
. Steroidal aromatase inhibitors, also known as type I, interact with the
substrate binding site on the peptidic moiety of the enzyme complex in an
irreversible manner, which has led to their designation as aromatase
inactivators. Nonsteroidal aromatase inhibitors, also known as type II,
coordinate with the iron atom of the cytochrome P450 moiety of the enzyme in a
reversible manner. The striking change that has occurred with the advent of the
third-generation aromatase inhibitors is the increased potency and increased
specificity, with activity confined to aromatase inhibition, over earlier
generations.[8] Additionally, these agents have markedly improved tolerability.
Of particular importance is that the clinical antitumor efficacy has been shown
to be improved with third-generation agents.

Gershanovich et al[9] performed a prospective randomized trial
in postmenopausal women with advanced breast cancer comparing letrozole (Femara)
with aminoglutethimide (Cytadren), and found that letrozole resulted in superior
time to disease progression, time to treatment failure, and overall survival,
and was associated with fewer side effects.

Large randomized phase III trials comparing megestrol acetate
with each of the third-generation aromatase inhibitors resulted in replacing
megestrol acetate (Megace) as the treatment of choice in women with advanced
breast cancer who have failed tamoxifen.[10-13]

Aromatase Inhibitors vs Tamoxifen

First- and Second-Generation Inhibitors

Several, albeit relatively small, randomized clinical trials
have been performed comparing first- and second-generation aromatase inhibitors
with tamoxifen as first-line hormonal therapy in the advanced breast cancer
setting. In a study by Smith et al,[14] 117 patients were randomly assigned to
receive either tamoxifen or aminoglutethimide, and the two treatments were
associated with equal objective response rates (30%) and median durations of
response (15 months). Although toxicity was greater with aminoglutethimide, the
level of efficacy appeared equal between the two agents.

Formestane (4-OHA, 4-hydroxy-androstenedione) was compared with
tamoxifen in 348 evaluable patients with objective response rates of 33% and
37%, median durations of response of 15 and 20 months, and overall survivals of
35 and 38 months, respectively.[15] However, time to disease progression and
time to treatment failure significantly favored tamoxifen.

Fadrozole (CGS 16949A) was compared with tamoxifen in 212
evaluable patients. Response rates were 20% and 27%, respectively, and mean
times to treatment failure were 6.1 and 8.5 months, respectively (P = .09).[16]
Thus, although aromatase inhibitors were shown to have activity, tamoxifen
remained the hormonal agent of choice in the first-line setting.

Third-Generation Inhibitors

Information relating to the value of third-generation aromatase
inhibitors relative to tamoxifen is beginning to appear; the most mature data
relate to anastrozole (Arimidex). Buzdar et al[17] recently presented the
results of two randomized double-blind studies (T27, T30) that compared
anastrozole and tamoxifen as first-line therapy for advanced breast cancer. This
large study involved 1,021 patients who were estrogen-receptor positive and/or
progesterone-receptor positive, or who had an unknown receptor status. The
complete response and partial response rates were similar (anastrozole 29%,
tamoxifen 27%), with median times to treatment failure of 8.5 and 7.0 months,
respectively.

Of particular interest is that the progression-hazard ratio had
a lower bound of 1.0, indicating that anastrozole was at least equivalent to
tamoxifen in this regard. In subset analysis, in the 57.7% of patients known to
be hormone-receptor positive, a significantly longer time to progression was
identified for the anastrozole group. From a toxicity standpoint, fewer
thromboembolic events and vaginal bleeding were seen with anastrozole.

Other Aromatase Inhibitors

Less information is available with the other aromatase
inhibitors. A large randomized study involving more than 900 patients comparing
letrozole with tamoxifen has completed accrual. Results should be forthcoming. A
phase III study of exemestane (Aromasin) vs tamoxifen is being conducted as an
extension of a randomized phase II trial[18] that had demonstrated encouraging
results regarding exemestane efficacy.

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