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

  • aminoglutethimide

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
Generation Steroidal (type 1) Nonsteroidal (type 2)
First (nonselective) Aminoglutethimide
Second (selective) Formestane Fadrozole
Third (super selective) Exemestane (Aromasin) Anastrozole, Letrozole

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.

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