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 whether 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), inhibitors)  they may modulate estrogen receptors (SERMS [tamoxifen,toremifene]),or tamoxifen,toremifene]),or  they may modulate the estrogen receptor (ER) with ER) pure agonist activity, eg, ER down-regulator down(fulvestrant). fulvestrant).
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Introduction
Oestrogens and established breast cancer
 oophorectomy: regression of advanced breast cancer in pre-menopausal women pre Adrenalectomy and hypophysectomy also produce similar effects in post-menopausal women. post-

Two major approaches for estrogen deprivation

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

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

Sources of Aromatase
enzyme of the cytochrome P-450 Psuperfamily and the product of the CYP19 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, and breastbreastcancer 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 liter) of about 7 pg per milliliter (25 pmol per liter). liter).

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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PrePre-menopausal estrogens
ovary is mainly responsible for circulating levels of oestrogen which vary 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 index in bodypostmenopausal women
 muscle 30% 30%  adipose tissue 15% 15%

estradiol in breast-carcinoma tissue is breastapproximately 10 times the concentration in plasma

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LOCAL AROMATASE WITHIN THE BREAST/BREAST CANCERS

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

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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 oestrogen 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 oestrogenresponses86 responses86 and (ii) successful therapy is invariably restricted to tumours which possess specific receptors for oestrogens.

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Inhibition of estrogen biosynthesis by aromatase inhibitors

blocking the last step ensures that biosyntheses of other steroid classes are not affected.

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Mode of Action of aromatase inhibitors

Aromatase inhibitors (e.g. anastrozole)

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Aromatase inhibition within the breast tumour cell

P-450 Aromatase + NADPH-cytochrome P-450 reductase ANDROGENS
(Testosterone, androstenedione, 16-OH-testosterone)

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
 Testololactone
unwanted androgenic side-effects. side-

 Formestane(2nd) and exemestane(3rd) Formestane(2 exemestane(3

converted by the aromatase enzyme into reactive intermediates, resulting in tight or irreversible binding. aromatase inactivator.

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Types of aromatase inhibitors

nonnon-steroidal (type II) inhibitors
 anti-epileptic drug, aminoglutethimide anti(i) 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 corticosteroid replacement therapy was required, (iii) aminoglutethimide may enhance aromatase activity by inducing aromatase mRNA and stabilizing the protein.
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Types of aromatase inhibitors

nonnon-steroidal (type II) inhibitors
 fadrozole(2nd), letrozole, anastrozole(3rd). fadrozole(2 anastrozole(3
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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increased potency of the third-generation thirdinhibitors is associated with better clinical efficacy

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In vivo effects
milligramme amounts daily, anastrozole (1 (1 mg), letrozole (2.5 mg) and exemestane (25 (2 (25 mg) reduce circulating oestrogen in postpostmenopausal women to levels often below the detection 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 adrenal Psteroidogenesis

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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 relapsecompared with 87 % of those assigned to tamoxifen (relative risk reduction, 17 percent; P=0 013) 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 (0 [9 those receiving tamoxifen alone (1.0 percent [30 (1 [30 cancers], P=0.001) or combined treatment (0.7 P=0 001) (0 percent [23 cancers]) [23
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adverse effects
The third-generation aromatase inhibitors appear thirdto 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 (2 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 estrogenaromatase inhibitors may prove to have an adverse effect on blood lipids  remains an important area for further research

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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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