Aromatase and its inhibitors in cancer treatment

Introduction
Role

of oestrogens in the development of breast cancer

enhanced susceptibility to breast cancer linked to increased oestrogen exposure whet her from endogenous or exogenous sources. ablation of ovarian function before the age of 35 years reduces subsequent appearance of breast cancer oophorectomy: regression of advanced breast cancer
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Introduction
mechanisms

of action of endocrine therapies are threefold

they may lower the estrogen level in the tumor (oophorectomy, aromatase inhibitors), they may modulate estrogen receptors (SERMS [tamoxifen,toremifene]),or they may modulate the estrogen receptor (ER) with pure agonist activity, eg, ER downregulator (fulvestrant).
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Introduction
Oestrogens

and established breast cancer

oophorectomy: regression of advanced breast cancer in pre-menopausal women Adrenalectomy and hypophysectomy also produce similar effects in post-menopausal w omen.

Hormonal Therapies for Postmenopausal Women with Hormone-responsive Advanced Breast Cancer Mechanism of Action Therapy
Estrogen Compete with endogenous estrogen for Receptor binding sites on estrogen receptors; may Antagonists also downregulate the ER protein in human breast cancer cells Aromatase estrogens Inhibitors Progestins antitumor Inhibit conversion of androgens to

Exact mechanism unknown; occupy progesterone receptors; direct

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Miller WR. Br Med Bull. 1990;47:470-483. Goldhirsh A and Gelber RJ. Semin Oncol. 1996;23:494-505. . Gradishar WJ, Jordan VC. Hematol Oncol Clin North Am. 1999;13:435-455, viii.

Two major approaches for estrogen deprivation

blocking

the specific receptors for oestrogen agents which specifically block the key enzyme (aromatase) in the biosynthesis of oestrogen

Best Practice & Research Clinical Endocrinology & Metabolism Vol. 18, No. 1, pp. 132, 2004

Sources of Aromatase
enzyme

of the cytochrome P-450 superfamily and the product of the CYP19 gene placenta and in the granulosa cells of ovarian follicles at lower levels, in several nonglandular tissues, including subcutaneous fat, liver, muscle, brain, normal breast, an d breast-cancer tissue
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Sources of Aromatase
Residual

estrogen production after menopause is solely from nonglandular sources, in particular from subcutaneous fat. At menopause, mean plasma estradiol levels fall from about 110 pg per milliliter (400 pmol per liter) to low but stable levels of about 7 pg per milliliter (25 pmol per liter).
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Selective versus Nonselective Aromatase Inhibition Cholesterol

Multiple steps involving cytochrome P450 enzymes and production of steroid intermediates Aldostero ne Cortisol Androstenedi one Selective Inhibitors Nonselective Inhibitors

Aromatase

Testoster Aromatase one

Estrone

Estradiol

Federman DD. The Adrenal. In: Dale DC, Federman DD, eds. Scientific American Medicine. New York, NY: Scientific American Inc.; 1997.

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Revised Draft Detailed Review Paper on Aromatase Dr. Gary E. Timm, Work Assignment Manager, U.S. EPA Endocrine Disruptor Screening Program, Washington, D.C.

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Pre-menopausal estrogens
ovary

is mainly responsible for circulating levels of oestrogen which v ary through the menstrual cycle.

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Estrogen production after menopause

nonglandular

sources -

subcutaneous fat, skin, muscle, liver and breast cancer.

peripheral

aromatase activity and plasma estrogen levels correlate with body-mass in dex in postmenopausal women
muscle 30% adipose tissue 15%

estradiol

in breast-carcinoma tissue is approximately 10 times the concentration in plasma 16

 both

mammary adipose tissue and about 70% of breast cancers possess a romatase activity levels tend to be higher in breast fat from patients with cancer quadrants bearing cancer have the greatest activity.

LOCAL AROMATASE WITHIN THE BREAST/BREAST CANCERS

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BREAST ENDOCRINOLOGY
i)

substantially higher oestradiol than in circulation ii) breast is able to concentrate oestrogen iii) mammary adipose tissue and breast cancers are capable of local oes trogen biosynthesis.

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BASIC BIOLOGICAL RATIONALE FOR AROMATASE INHIBITORS

(i)

all endocrine therapies have in common the ability to block oestrogen -driven trophic responses86 and (ii) successful therapy is invariably restricted to tumours which possess sp ecific receptors for oestrogens.

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Hormone Receptor Status: Relationship to Menopausal Status

Menopausal Status Receptor Status (%) ER+/PgR+ ER+/PgR- ER-/PgR+ ER-/PgRPre (n=488) Post (n=826) 45 63 12 15 15 5 28 17

Bland KI, et al. Surg Forum 1981;32:410-412.

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Inhibition of estrogen biosynthesis by aromatase inhibitors

blocking

the last step ensures that biosyntheses of other steroid classes a re not affected.

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Mode of Action of aromatase inhibitors

Aromatase inhibitors (e.g. anastrozole)

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+ NADPH-cytochrome P-450 reductase ANDROGENS

(Testosterone, androstenedione, 16-OH-testosterone)

Aromatase inhibition within the breast tumour cell P-450 Aromatase tumour
growth OESTROGENS
(Oestradiol, oestrone)

Aromatase Inhibitors

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Aromatase Inhibition in Premenopausal Women

increase

in gonadotropin secretion increases the weight of the ovaries induction of ovulation in women with infertility

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Types of aromatase inhibitors

Steroidal

analogs
androgenic side-effects.

Testololactone
unwanted converted

Formestane(2nd) and exemestane(3rd)

by the aromatase enzyme into reactive intermediates, resulting in tight or irre versible binding. aromatase inactivator.

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Types of aromatase inhibitors

non-steroidal
(i)

(type II) inhibitors

anti-epileptic drug, aminoglutethimide

the drug was not particularly potent and had to be used at high concentrations, (ii) inhibition of enzymes involved in cortisol production meant that concomitant corticoster oid replacement therapy was required, (iii) aminoglutethimide may enhance aromatase activity by inducing aromatase mRN A and stabilizing the protein.
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Types of aromatase inhibitors

non-steroidal

(type II) inhibitors

fadrozole(2nd), letrozole, anastrozole(3rd).

bind

reversibly to the aromatase enzyme. high potency and great specificity; inhibitory effects on aromatase without affecting the synthesis of other steroids.

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Placental microsome

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Particulate fraction of Br Ca

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increased potency of the thirdgeneration inhibitors is associated with better clinical efficacy

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In vivo effects
milligramme

amounts daily, anastrozole (1 mg), letrozole (2.5 mg) and exemestane (25 mg) reduce circul ating oestrogen in post-menopausal w omen to levels often below the detecti on amount of current assays.

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Clinical Development and Pharmacology

Aminoglutethimide

first aromatase inhibitor initially developed as an anticonvulsant but was withdrawn from use after reports of adrenal insufficiency subsequently found to inhibit several cytochrome P-450 enzymes involved in ad renal steroidogenesis

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Arimidex and Tamoxifen Alone or in Combination [ATAC] trial

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 89

% anastrozole were relapse-free at 3 years, as compared with 87 % of those assigned to tamoxifen (relative risk reduction, 17 percent; P=0.013) Incidence of contralateral invasive breast cancer was significantly lower in the patients receiving anastrozole alone (0.3 percent [9 cancers]) than in those receiving tamoxifen alone (1.0 percent [30 cancers], P=0.001) or combined treatment (0.7 percent [23 cancers]) 43

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adverse effects
The

third-generation aromatase inhibitors appear to be very well tolerated commonest hot flashes, vaginal dryness, musculoskeletal pain, and headache significantly lower incidence of hot flashes, vaginal bleeding, vaginal discharge, and venous thromboembolism and a significantly higher incidence of musculoskeletal symptoms and fractures than those receiving tamoxifen
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adverse effects
no

evidence to suggest an increased risk of uterine carcinoma with aromatase inhibitors (incidence, 0.1 percent, vs. 0.5 percent with tamoxifen) or venous thromboembolism (2.1 percent and 3.5 percent, respectively) skeletal effects
Tamoxifen reduces bone demineralization Whereas aromatase inhibitors may enhance this process by lowering circulating estrogen levels
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adverse effects
cardiovascular

effects

In contrast, the estrogen-lowering effects of aromatase inhibitors may prove to have an adverse effect on blood lipids remains an important area for further research

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Resistance to endocrine tx
General

resistance

Lack of estrogen signalling system Clonal heterogeneity and outgrowth of hormone-independent cells Estrogen hypersensitivity Drug metabolism/efflux

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Resistance to endocrine tx
Specific

resistance

High/enhanced aromatase activity Mutated aromatase Alternative non-synthesized sources or exogenous supply of estrogens

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Conclusions
In

the treatment of advanced disease, letrozole is convincingly better than tamoxifen, and anastrozole is at least as good. In early breast cancer, adjuvant therapy with anastrozole already appears to be superior to adjuvant therapy with tamoxifen in reducing the risk of relapse, and letrozole appears to be more effective than tamoxifen as preoperative therapy
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