Oncologist. 1998;3(2):129-130.  

Molecular Action and Clinical Relevance of Aromatase Inhibitors.

Murphy MJ Jr.

AlphaMed Press, Miamisburg, Ohio, 45342-3758, USA. mjm@alphamed press.com

BREAST CANCER: HIGH PREVALENCE AND RISING INCIDENCE: Breast cancer is the most
common form of cancer among women in Europe, North and South America and
Australasia; approximately 1 in 10 women in Western countries will develop
breast cancer during their lifetime. It is estimated that the disease will
affect five million women worldwide over the next decade, and the incidence of
breast cancer is increasing on average by about 1% per year in industrialized
countries and at a greater rate in developing countries. COMPLEX ETIOLOGY:
Although the specific etiology of breast cancer remains unknown, a number of
factors are recognized which increase a woman's risk of developing the disease.
Genetic predisposition, or family history of breast cancer, is known to be
responsible for 5% of all cases. However, the variation in incidence throughout
populations, and changes relating to population migration and adoption of
altered lifestyles, all point to the critical importance of nongenetic
determinants. Such factors include early menarche, late menopause, late age at
birth of first child or nulliparity, a history of benign breast disease, and
diet. There is also evidence that hormones play a major role in the etiology of
breast cancer, with the risk of developing malignancies related to the
cumulative exposure of the breast to estrogen and progesterone, which stimulate
the growth of tumor cells. TREATMENT FOR EARLY BREAST CANCER: SURGERY -/+
ADJUVANT THERAPY: At the time of diagnosis, approximately 50% of patients will
be diagnosed with early breast cancer. This proportion is increasing as a
consequence of the introduction of early detection programs. Surgery remains the
primary treatment for early breast cancer, and the frequency of radical
mastectomy has been replaced by breast conserving surgery. After surgery, other
therapeutic modalities such as radiation, chemotherapy or endocrine therapy may
be given in the adjuvant setting. Surgical cure rates vary for patients with
early breast cancer; the US figure is approximately 40%, and there are no
definitive means to predict those who will be cured and those who will have
recurrent disease. As a result, following primary surgical treatment, adjuvant
therapy is usually recommended to destroy any remaining cancer cells at the
primary site, to control micrometastases and to prolong disease-free survival,
with the ultimate aim of providing an overall survival benefit. Upon disease
recurrence in the remaining 60% of patients, endocrine therapy and chemotherapy
represent the two general classes of treatment. One of the principle decisions
to be taken in advanced breast cancer is which therapy to select in order to
maximize patient benefit. The choice is largely dependent upon prognostic
factors and whether the patient is pre- or postmenopausal. ENDOCRINE THERAPY OR
CHEMOTHERAPY IN ADVANCED BREAST CANCER: Unlike chemotherapy, endocrine therapy
is not cytotoxic and is therefore better tolerated by the patient. A recent
study comparing therapy for prognostically different groups showed that patients
benefiting most from the use of sequential endocrine agents are those regarded
as low risk. The preferred sequence of treatment has been suggested to be
tamoxifen followed by selective aromatase inhibitor and then a progestin.
ENDOCRINES AND ENZYMES OFFER NEW TREATMENTS FOR ADVANCED BREAST CANCER:
ESTROGEN-DRIVEN BREAST CANCER: Since 1896, when Sir George Beatson demonstrated
that ovariectomy induced regression of mammary tumors in women, the aim of
endocrine breast cancer therapy has been to selectively deprive the body of
estrogen. Ovariectomy accomplished this by removing the gland that is the
predominant source of estrogens in premenopausal women. Since the avoidance of
such surgery is preferable, emphasis is devoted to the pharmacological
inhibitors of estrogen production. ENDOCRINE PATHWAY REVEALS "ACHILLES' HEEL":
Like other steroid hormones, the two circulating estrogens-estrone and
estradiol-are produced from cholesterol. Inhibiting the enzymes that are
involved at earlier steps in the branching pathway of steroidogenesis could have
an undesirable impact on the production of other physiologically important
hormones such as aldosterone and cortisol. Since aromatase catalyzes the last
step in estrogen production, it makes an ideal target for the development of
selective and potent inhibitors (Fig. 1). STRUCTURE OF AROMATASE REVEALS SECRETS
OF SELECTIVE INHIBITION: Aromatase is a cytochrome P450 enzyme, with both an
iron-containing and a steroid-binding site. The substrate, androstenedione, sits
in the enzyme's steroid-binding site, that site which otherwise catalyzes the
formation of estrogen. From this structural relationship, there are, therefore,
two reasonable ways to inhibit aromatase: * by occupying the steroid-binding
site of the enzyme with a compound such as formestane (Lentaron®), or * by
binding the iron with nitrogen-containing compounds such as aminoglutethimide
(Orimeten®), the oldest aromatase inhibitor. AROMATASE INHIBITORS: STEROIDAL
AND NON-STEROIDAL: Formestane (Lentaron®) is the only commercially available
steroidal compound which inhibits aromatase and must be administered
parenterally. Other new aromatase inhibitors such as fadrozole (Afema®) and
letrozole (Femara®) are orally active nitrogen-containing compounds that
bind the heme iron of aromatase. AMINOGLUTETHIMIDE VERSUS LETROZOLE: OLD VERSUS
NEW: Although aminoglutethimide has long been used to treat advanced breast
cancer, its aromatase inhibition is not selective. Consequently,
aminoglutethimide also binds to and thereby inhibits several other cytochrome
P450 enzymes in the steroidogenesis pathway. An ideal aromatase inhibitor would
fit the catalytic site of aromatase optimally and would thus interact only with
aromatase. The affinity of letrozole (Femara®) for the heme group of
aromatase makes it a selective and potent inhibitor (Fig. 2). In fact, studies
show that Femara® has little effect on the other adrenal steroids, and is
the most selective aromatase inhibitor available today.

PMID: 10388095 [PubMed - as supplied by publisher]