Aromatase inhibitors Introduction: 1- In the USA it is estimated that breast cancer will account for approximately 32% of all new cases of cancer in 2005. 2- Although treatment has improved and death rates have declined in recent years, breast cancer still accounts for approximately 15% of all cancer deaths in women. 3-Oestrogen is the principal hormone involved in the development of breast cancer.

3- Endocrine agents have, therefore, been designed to block the supply of oestrogen to the breast tumour, either by inhibiting the production of oestrogen or by blocking its action at the oestrogen receptor. 4- For more than 30 years, tamoxifen, an antioestrogen that inhibits the activity of oestradiol at its receptor, has been the mainstay of hormonal therapy for all stages of breast cancer in postmenopausal women. 5- why ?? a- tamoxifen does not completely block the activity of the oestrogen receptor, and the remaining partial oestrogen agonist activity is thought to be responsible for some of its unfavourable side effects, such as an increased risk of endometrial cancer and thromboembolism events . B-development of resistance to tamoxifen is a significant problem in breast cancer treatment.

What hormone therapy is: 1- Hormones are substances that occur naturally in the body where they control the growth and activity of normal cells.  Although they do not usually affect cancer cells, in breast cancer the situation is different. 2- The female hormones oestrogen and progesterone are naturally produced by the ovaries before menopause.  After the menopause, oestrogen is made in much smaller amounts by small glands above the kidneys, called the adrenal glands.  These hormones affect the growth of some breast cancer cells.  This means that drugs or treatments that block the effects of hormones, or lower the levels of oestrogen and progesterone, can be used as a treatment for some types of breast cancer.

A-hormone therapy to treat breast cancer: ****Before breast surgery           After breast surgery****           That has spread or come back ****after it was first treated Who has hormone therapy for breast cancer B-TEST ON CANCER CELLS : (ER status ) : Hormone therapy isn't always a suitable treatment for breast cancer.  You will have tests on your cancer cells to see if they have oestrogen receptors (ER).  These are areas that allow oestrogen to lock onto the cell.  The hormone then stimulates the cancer cell to grow.  If you don't have these, your specialist may suggest you have chemotherapy after surgery instead of hormone therapy. 

****Hormone therapy before surgery: To shrink a cancer in the breast before surgery. .  It may mean you can have just the cancer removed, rather than needing a mastectomy.  ****Hormonal therapy after surgery : This is the commonest time to have hormone therapy for breast cancer.  Hormone treatment has been proved to reduce the risk of breast cancer coming back. 

patient selection 1-Aromatase inhibitors are used only in women with no ovarian function. 2- In women with intact ovarian function, aromatase inhibition may increase estrogen production by increasing gonadotropin-releasing hormone levels; the follicle-stimulating hormone level; aromatase production; the luteinizing hormone level; and ovarian steroid synthesis, particularly synthesis of androstenedione, the substrate for aromatase. Thus, ovarian ablation (either surgical or pharmacologic) must precede the use of aromatase inhibitors in premenopausal women.

Aromatase enzyme . Aromatase (cytochrome P-450 [CYP] 19) catalyzes the rate-limiting step (conversion of steroidal C-19 androgens to C-18 estrogens) in estrogen biosynthesis. Aromatization is the final step in steroid biosynthesis and, therefore, aromatase is an attractive target for selective inhibition

Figure 2. Proposed mechanism of oestrogen biosynthesis.

Aromatase inhibitors Types of aromatase inhibitors :

According to selectivity : Non-selective: 1-Aminoglutethimide(Cytadren R ) 2- testolactone (teslac) Selective: **Anastrozole (Arimidex) Letrozole** (Femara) Exemestane** (Aromasin) Vorozole** (Rivizor) Formestane** (Lentaron) Fadrozole** (Afem

Aminoglutethimide : 1- It blocks the production of steroids derived from cholesterol and is clinically used in the treatment of Cushing's syndrome and metastatic breast cancer . 2- Mechanism : It blocks aromatase in the generation of estrogens from androstenedione and testosterone. 3- Side effects : hepatotoxicity, inhibition of cortisol in the human body, and it may also cause hypothyroidism. 4- clinical uses : a- suppression of adrenal function in patients with Cushing's syndrome. b- It is also a 2nd or 3rd line choice for the treatment of hormone sensitive (estrogen and progesterone) metastatic breast cancer

Anastrazol Letrozol Drug Arimedex Femara® Trade name Selective Selectivity Non steroidal Type Anastrozole inhibits the enzyme aromatase, which is responsible for converting androgens to estrogens. Anastrozole binds reversibly to the aromatase enzyme through competitive inhibition. Brand name for letrozole, an oral antiestrogen. inhibits the enzyme aromatase in the adrenal glands that produces the estrogens (estradiol and estrone) and thereby lowers their levels. Definition 1- ARIMIDEX is indicated for adjuvant treatment of postmenopausal women with hormone receptor-positive early breast cancer. 2- ARIMIDEX is indicated for the first-line treatment of postmenopausal women with 1- adjuvant treatment of postmenopausal women with hormone receptor positive early breast cancer. 2-extended adjuvant treatment of early breast cancer in postmenopausal women who have received 5 years of adjuvant tamoxifen therapy Indication

1- 2.5 mg tab administered once a day, without regard to meals. hormone receptor-positive or hormone receptor unknown locally advanced or metastatic breast cancer. The dose of ARIMIDEX is one 1 mg tablet taken once a day. For patients with advanced breast cancer, ARIMIDEX should be continued until tumor progression 1- 2.5 mg tab administered once a day, without regard to meals. 2- Patients treated with Femara do not require glucocorticoid or mineralocorticoid replacement therapy. Dosage and administration Constipation, diarrhea, nausea, vomiting, upset stomach, loss of appetite, body aches and pains, breast swelling/tenderness/pain, headache, dry mouth, scratchy throat, increased cough, dizziness, trouble sleeping, tiredness/weakness, flushing and sweating Hot Flashes/Flushes , Arthralgia/Arthritis Weight Increase Nausea ,Fatigue , Lethargy, Malaise, ,bone Myalgia Fractures , edema , myocardial infarction, osteoporosis (which is why prescriptions of Letrozole are often accompanied by prescriptions of osteoporosis-fighting medications such as bisphsphonates ). side effects

No studies in pregnanr women . Category D . anastrozole increased pregnancy loss (increased pre- and/or post-implantation loss, increased resorption, and decreased numbers of live fetuses. embryotoxic and fetotoxic, as indicated by intrauterine mortality, increased resorption, increased postimplantation loss, decreased numbers of live fetuses. Pregnancy (rats) No studies in pregnanr women . Category D . not recommended for use in premenopausal women as safety and efficacy has not been established Since fatigue , dizzines have been observed with femara and somnolence commonly unreported caution is advised when driving or using machinery Precaution 1-hypersensitivity to arimidex or any of eash excipients . 1-hypersensitivity to femara or any of eash excipients . 2-women of premenopausal endocrine status . Contraindication

AROMASIN® (exemestane) Tablets Steroidal Aromatase inhibitors AROMASIN® (exemestane) Tablets

AROMASIN® (exemestane) Tablets 25 mg of exemestane, an irreversible, steroidal aromatase inactivator

Mechanism of Action Exemestane is an irreversible, steroidal aromatase inactivator, structurally related to the natural substrate androstenedione. It acts as a false substrate for the aromatase enzyme, and is processed to an intermediate that binds irreversibly to the active site of the enzyme causing its inactivation, an effect also known as “suicide inhibition.” In clinical research, compared to women that continued tamoxifen for 5 years, women who switched to Aromasin after 2 to 3 years of tamoxifen had a 31% lower risk of breast cancer recurrence and a 14% decrease in mortality.

Mechanism of Action aromasine

Indications AROMASIN is indicated for: 1. Adjuvant treatment of postmenopausal women with estrogen receptor positive early breast cancer who have received two to three years of tamoxifen and are switched to AROMASIN for completion of a total of five consecutive years of adjuvant hormonal therapy. 2. AROMASIN is indicated for the treatment of advanced breast cancer in postmenopausal women whose disease has progressed following tamoxifen therapy.

Pharmacokinetics Absorption Distribution Metabolism Excretion rapidly absorbed. at least 42% Is absorbed from the GIT distributed extensively into tissues. terminal half-life of about 24 hours In urine and feces less than 1% of the dose is excreted unchanged in urine plasma levels increased by approximately 40% after a high-fat breakfast. 90% bound to plasma proteins. Exemestane is extensively metabolized Studies using human liver preparations indicate that cytochrome P-450 3A4 (CYP 3A4) is the principal isoenzyme involved in the oxidation of exemestane. more rapidly absorbed in the women with breast cancer than in the healthy women (tmax 1.2 vs 2.9 hrs) oral clearance in women with advanced breast cancer was 45% lower than the oral clearance in healthy postmenopausal women, with corresponding higher systemic exposure. Mean AUC values following repeated doses in women with breast cancer (75.4 ng•h/mL) were about twice those in healthy women (41.4 ng•h/mL).

DOSAGE AND ADMINISTRATION The recommended dose of AROMASIN in early and advanced breast cancer is one 25 mg tablet once daily after a meal In postmenopausal women with early breast cancer who have been treated with 2–3 years of tamoxifen, treatment with AROMASIN should continue in the absence of recurrence or contralateral breast cancer until completion of five years of adjuvant endocrine therapy. For patients with advanced breast cancer, treatment with AROMASIN should continue until tumor progression is evident.

DOSAGE AND ADMINISTRATION For patients receiving AROMASIN with a potent CYP 3A4 inducer such as rifampicin or phenytoin, the recommended dose of AROMASIN is 50 mg once daily after a meal. In patients with moderate or severe hepatic or renal impairment: has not been studied. Based on experience with exemestane at repeated doses up to 200 mg daily that demonstrated a moderate increase in non-life threatening adverse events, dosage adjustment does not appear to be necessary

SIDE EFFECTS Incidence (%) of Adverse Events of all Grades1 and Illnesses Occurring in ( ≥ 5%) of Patients in Any Treatment Group in Study IES in Postmenopausal Women with Early Breast Cancer Body system and Adverse Event by MedDRA dictionary % ofpatients AROMASIN 25 m g daily (N=2252) Tamoxifen 20 mg daily2 (N=2280) Eye   Visual disturbances 3 5.0 3.8 Gastrointestinal   Nausea3 8.5 8.7 General Disorders   Fatigue3 16.1 14.7 Musculoskeletal   Arthralgia 14.6 8.6   Pain in limb 9.0 6.4   Back pain 7.2   Osteoarthr it is 5.9 4.5

SIDE EFFECTS Incidence (%) of Adverse Events of all Grades1 and Illnesses Occurring in ( ≥ 5%) of Patients in Any Treatment Group in Study IES in Postmenopausal Women with Early Breast Cancer Body system and Adverse Event by MedDRA dictionary % of patients AROMASIN 25 m g daily (N=2252) Tamoxifen 20 mg daily2 (N=2280) Nervous System   Headache3 13.1 10.8   Dizziness3 9.7 8.4 Psychiatric   Insomnia3 12.4 8.9   Depression 6.2 5.6 Skin & Subcutaneous Tissue   Increased sweating3 11.8 10.4 Vascular   Hot flushes 3 21.2 19.9   Hypertension 9.8

Exemestane N=73 (% incidence) Placebo N=73 (% incidence) Incidence of Selected Treatment-Emergent Adverse Events of all CTC Grades* Occurring in ≥ 5% of Patients in Either Arm on Study 027 Adverse Event Exemestane N=73 (% incidence) Placebo N=73 (% incidence) Hot flushes 32.9 24.7 Alopecia 15.1 4.1 Hypertension 6.9 Depression 9.6 Diarrhea 1.4 Dermatitis 8.2 Headache Myalgia 5.5 Edema * Most events were CTC grade 1–2

The most common side effects: Hot flashes fast breathing aching/painful joints and muscles headache unusual sweating weight gain nausea, diarrheaand vomiting may occur. tiredness Dizziness trouble sleeping Some researches proved that “Vitamin E Lowers Breast Cancer Risk and Moderates Hot Flashes”

Control of Bone Remodeling: Androgens and Estrogens Osteoblasts Estrogens Bone formation Bone resorption Bone Osteoclast Androgens (–) (+) Aromatase © American Society for Bone and Mineral Research Contributed by Katherine Weilbaecher

DRUG INTERACTIONS Exemestane is extensively metabolized by CYP 3A4 However, coadministration of ketoconazole, a potent inhibitor of CYP 3A4, has no significant effect on exemestane pharmacokinetics. Co-medications that induce CYP 3A4 (e.g., rifampicin, phenytoin, carbamazepine, or phenobarbital) may significantly decrease exposure to exemestane. Dose modification is recommended for patients who are also receiving a potent CYP 3A4 inducer

WARNINGS Pregnancy Category D AROMASIN Tablets may cause fetal harm when administered to a pregnant woman {The concentration of exemestane and its metabolites was approximately equivalent in maternal and fetal blood.} There are no studies in pregnant women using AROMASIN. AROMASIN is indicated for postmenopausal women. If there is exposure to AROMASIN during pregnancy, the patient should be apprised of the potential hazard to the fetus and potential risk for loss of the pregnancy.

PRECAUTIONS AROMASIN Tablets should not be administered to premenopausal women. AROMASIN should not be coadministered with estrogen-containing agents; as these could interfere with its pharmacologic action. aromasine

PRECAUTIONS Before taking exemestane, tell your doctor or pharmacist if you are allergic to it; or if you have any other allergies. Before using this medication, tell your doctor or pharmacist your medical history, especially of: high blood fats (cholesterol), bone problems (e.g., osteopenia, osteoporosis), heart problems (e.g., angina, coronary artery disease), high blood pressure, liver problems. This drug may make you dizzy or drowsy; use caution engaging in activities requiring alertness such as driving or using machinery. Limit alcoholic beverages. It is not known whether this drug passes into breast milk. Consult your doctor before breast-feeding.

Carcinogenesis, Mutagenesis, Impairment of Fertility Increased incidence of hepatocellular adenomas and/or carcinomas in both genders at the high dose level. An increased incidence of renal tubular adenomas was observed in male mice at the high dose of 450 mg/kg/day. Exemestane was not mutagenic in vitro in bacteria (Ames test) or mammalian cells (V79 Chinese hamster lung cells). Exemestane showed no effects on ovarian function, mating behavior, and conception rate in rats given doses up to 20 mg/kg/day (approximately 8 times the recommended human dose on a mg/m² basis), however, decreases in mean litter size and fetal body weight

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