Aromatase Inhibitors

Aromatase Inhibitors

Androgens are converted to estrogen in the peripheral tissue of post-menopausal females with the help of an enzyme, aromatase.
The drugs inhibiting this enzyme will decrease the formation of estrogen
beneficial in the treatment of breast carcinoma.

First-generation

second generation

letrozole, anastrozole, vorozole, fadrozole à nonsteroidal or type II à reversible inhibitors of aromatase
formestane, and exemestane à steroidal or type I à irreversible (suicide) inhibitor

Letrozole

orally active nonsteroidal (type 2) compound
reversibly inhibits aromatization including that within the breast cancer cells, resulting in nearly total estrogen deprivation in postmenopausal women
Als are not recommended in premenopausal women unless ovaries are removed, or Gn secretion from pituitary is suppressed
The proliferation of estrogen-dependent breast carcinoma cells is suppressed to a greater extent than with tamoxifen.
rapidly absorbed à 100% oral bioavailability, a large volume of distribution, t½ of ~40 hours.

Uses

Early breast cancer:

first-line drug for adjuvant therapy after mastectomy in ER+ postmenopausal women.
Extended adjuvant therapy with letrozole beyond the standard 5-year tamoxifen treatment continues to afford protection.
Replacement of tamoxifen by an Al is now recommended after 2 years (sequential therapy) because Als do not predispose to thromboembolism and endometrial cancer.
Survival is prolonged in patients who have positive axillary lymph nodes.

Advanced breast cancer:

Current guidelines recommend letrozole as first-line therapy because of a longer time to disease progression and higher response rate obtained with it compared to tamoxifen.
also, effective as a second-line treatment when tamoxifen has failed.

Adverse effects

Hot flashes, vaginal dryness, nausea, diarrhea, dyspepsia and thinning of hair are the side effects.
Joint pain and stiffness are common; bone loss may be accelerated.
However, there is no endometrial hyperplasia or an increased risk of endometrial carcinoma.
The risk of venous thromboembolism is also not increased, and there is no deterioration of the lipid profile.
Dose: 2.5 mg OD oral.
The use of letrozole for inducing ovulation in infertile women has been banned in India since Oct. 20 11.

Anastrozole

Another nonsteroidal and reversible (Type 2) AI.
more potent than letrozole and suitable for single daily dosing.
Accumulates in the body to produce peak effect after 7- 10 days.
useful as adjuvant therapy in early ER+ breast cancer as well as for palliation of advanced cases in postmenopausal women.
The risk of a new tumor appearing in the contralateral breast was also lower with anastrozole.
longer time to disease progression compared to tamoxifen has been obtained in advanced ER+ive breast cancer.
Many tamoxifen-resistant cases responded with increased survival.
Like letrozole. it is also a first-line drug for early as well as advanced breast carcinoma in postmenopausal women. Side effects are similar to those with letrozole.
Dose: 1 mg OD.

Exemestane:

This steroidal and irreversible (Type I) inhibitor of aromatase acts like a suicide substrate by covalent binding to the enzyme.
As a result, >90% suppression of estradiol production is obtained.
However, it has a weak androgenic activity similar to androstenedione.
found beneficial in early breast cancer by reducing the risk of disease progression when it was substituted for tamoxifen as adjuvant therapy.
In advanced breast cancer, longer survival, increased time to disease progression and fewer treatment failures have been obtained with exemestane.
It is administered orally and is well tolerated.
Adverse effects are similar to other Als.
Dose: 25 mg OD oral after meals; those receiving CYP3A4 inducer 50 mg OD.