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Nonsteroidal and Steroidal Aromatase Inhibitors in Breast Cancer

Nonsteroidal and Steroidal Aromatase Inhibitors in Breast Cancer

ABSTRACT: Anastrozole (Arimidex), letrozole (Femara), and exemestane (Aromasin) are members of the third generation of aromatase inhibitors that has now replaced aminoglutethimide (Cytadren), the progestins, and tamoxifen (Nolvadex) as the hormonal therapy of choice in estrogen-receptor-positive, postmenopausal, metastatic breast cancer. This article will review the role of aromatase in the pathogenesis of breast cancer and the results of recent studies that have established the role of its inhibitors in estrogen-receptor-positive breast cancer. We will also briefly outline the rationale and design of ongoing studies. [ONCOLOGY 15(8):965-979, 2001]


The hormonal dependency of  breast cancer was first
recognized more than a century ago.[1] Although it has yet to be proven that estrogen
is directly responsible for the initiation of breast tumors, it is clear from
epidemiologic evidence,[2] from "prevention" studies using the
antiestrogen tamoxifen (Nolvadex),[3] and from the clinical impact of hormonal
manipulation[4,5] that estrogen is a significant factor in the maintenance and
progression of established tumors.

Estrogen is produced by aromatization of androgens. In
premenopausal women, androgens are synthesized from cholesterol by the adrenals
and the ovaries in roughly equivalent proportions. Approximately 60% of
estrogens in premenopausal women are synthesized in the aromatase-rich cytoplasm
of the granulosa cells of the ovaries. Aromatization by the cycling ovary is
regulated by follicle-stimulating hormone that is regulated, in turn, by
estrogen in a negative feedback loop. The remaining 40% of estrogens in
premenopausal women are synthesized in the peripheral tissues, particularly in

At menopause, ovarian production of both estrogen and the
estrogen precursor androstenedione ceases, so that most of the circulating
estrogen in postmenopausal women derives from the peripheral conversion of
adrenal androgens. Circulating estrogen levels in postmenopausal women are
approximately 20% of those of premenopausal women, and they achieve a
steady-state concentration in the absence of cyclical ovarian function.[6]

Intratumoral Aromatase

Although circulating levels of estrogens are relatively low in
postmenopausal women, aromatase expression is maintained in breast tissue after
menopause. Estrogen levels in the breast tissue of postmenopausal women are thus
significantly higher than those detected in plasma, and may be as high as the
plasma levels in premenopausal women.[7,8]

Although the exact site of aromatase production in breast cancer
tissues has not yet been determined, both immunocytochemistry and in situ
hybridization techniques have demonstrated aromatase enzyme and mRNA expression
in the epithelial cells of the terminal ductal lobular units and the surrounding
stromal cells of the normal human breast.[9] Tumor cells may produce aromatase
themselves or they may produce cytokines that induce tumor-stromal-cell
expression of aromatase.[10] Importantly, breast cancer tissues that retain
aromatase expression may be able
to function in an autocrine fashion
by producing their own growth factor.[11-13]

The functional significance of tumor aromatase has not been well
defined but is suggested by several lines of evidence. Aromatase activity is
frequently found to be much higher in tumor tissue than in surrounding benign
tissue from the same breast, supporting a role for aromatase activity in the
emergence of the malignant phenotype.[14,15] Studies of tumor aromatase levels
and known prognostic factors, such as tumor cell proliferative activity or lymph
node involvement, have yielded conflicting results. No clear correlation between
the level of tumor aroma-tase activity and the biological behavior of the tumor
has yet been demonstrated.[14,16,17]

Studies examining the relationship between aromatase expression
and estrogen- and progesterone-receptor positivity have also been
inconsistent.[16,18,19] Notably, two small studies have suggested a correlation
between tumor aromatase activity and response to aromatase inhibition therapy
with aminoglutethimide (Cytadren).[20,21]

The Aromatase Inhibitors

There are two general categories of aromatase inhibitors: (1)
the nonsteroidal inhibitors, which bind competitively with aromatase, and (2)
the steroidal inhibitors, which bind irreversibly (see Table

First- and Second-Generation Aromatase Inhibitors

The first aromatase inhibitor with documented antitumor efficacy
was the nonsteroidal agent aminoglutethimide. Although its use as second- or
third-line endocrine therapy achieved response rates of 20% to 40%, the drug was
associated with problematic effects. Aminoglutethimide inhibits the production
of other adrenal steroids, including cortisol, and therefore must be taken with
hydrocortisone. A high incidence of skin rash and fatigue also made the drug
difficult for many patients to tolerate. Other early aromatase inhibitors, such
as fadrozole (CGS 16949A) and the parenterally administered formestane (4-OHA),
demonstrated antitumor activity and fewer adverse effects than
aminoglutethimide, but they have now been supplanted by the third-generation
inhibitors described below.[22]

Aromatase Inhibitors

The current generation of nonsteroidal inhibitors includes
anastrozole (Arimidex), letrozole (Femara), and vorozole (Rivizor), all of which
are administered orally as a once-daily dose. The development of vorozole has
been terminated, so it will not be discussed below. The only registered
steroidal inhibitor of the current generation is exemestane (Aromasin).

Relative Potency of
Aromatase Inhibitors

The in vivo potency of aromatase inhibitors is defined by their
ability to suppress both aromatase activity and plasma estrogen levels. In vivo
aromatase activity is assessed by radioimmunoassay of urinary estrogens
following administration of radiolabeled androstenedione.[23] Plasma endogenous
estrogens are usually measured with highly sensitive radioimmunoassays after
separation with high-performance liquid chromatography.[24]

While the early aromatase inhibitors inhibited aromatization by
approximately 90% in postmenopausal women, the third-generation aromatase
inhibitors are far more potent, suppressing aromatization by approximately
98%.[25] When radioimmunoassays are used to assess estrogen suppression, they
generally correlate with the degree of aromatization suppression observed (see

Table 2

The randomized clinical studies of letrozole[26] and
vorozole[27] vs aminoglutethimide have demonstrated that the improvement in
aromatase inhibition provided by the third-generation inhibitors is clinically
meaningful, but the clinical relevance of any differences between members of the
third generation is less clear. While most aromatization studies are not
randomized studies—so that any comparison of their results must be interpreted
with caution—one small (n = 12) randomized, crossover study has compared
anastrozole to letrozole.[28] This study demonstrated that letrozole is a more
potent aromatase inhibitor than anastrozole (aromatization suppression rates
were > 99.1% vs 97%, P = .003, with confirmatory estrogen suppression data).

The clinical relevance of this small difference, demonstrated at
a level of inhibition that is so close to complete, remains uncertain. Equally
uncertain is the clinical relevance of exemestane’s irreversible binding to
aromatase, compared with the competitive, reversible binding of the nonsteroidal agents.


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