How does Anastrozole (aromatase inhibitor) work?

How Anastrozole (Aromatase Inhibitor) Works

Anastrozole works by selectively inhibiting the aromatase enzyme, which converts androgens to estrogens in postmenopausal women, thereby significantly reducing estrogen levels that can stimulate hormone receptor-positive breast cancer growth.

Mechanism of Action

Anastrozole is a selective non-steroidal aromatase inhibitor that targets the specific pathway of estrogen production in postmenopausal women:

1. Estrogen Production in Postmenopausal Women:

   • In postmenopausal women, estrogens are mainly derived from the conversion of adrenal androgens (primarily androstenedione and testosterone) to estrone and estradiol 1
   • This conversion occurs in peripheral tissues and potentially within breast cancer tissue itself
   • The aromatase enzyme is responsible for catalyzing this final step of estrogen biosynthesis

2. Inhibition Mechanism:

   • Anastrozole specifically inhibits the cytochrome P-450 component of the aromatase enzyme complex 1
   • At the recommended daily dose of 1 mg, anastrozole reduces serum estradiol by approximately:
     • 70% within 24 hours of administration
     • 80% after 14 days of daily dosing 1

3. Selectivity:

   • Anastrozole is highly selective for the aromatase enzyme
   • It does not affect cortisol or aldosterone secretion at therapeutic doses
   • It does not possess direct progestogenic, androgenic, or estrogenic activity 1

Pharmacokinetic Properties

• Absorption: Rapid absorption with maximum plasma concentrations typically occurring within 2 hours under fasted conditions 1
• Distribution: 40% bound to plasma proteins in the therapeutic range
• Metabolism: Occurs primarily through N-dealkylation, hydroxylation, and glucuronidation
• Elimination: 85% of anastrozole is recovered in feces and urine, with a mean elimination half-life of 50 hours 1

Clinical Efficacy

Anastrozole's efficacy as an aromatase inhibitor has been demonstrated in several clinical settings:

• Advanced Breast Cancer: Superior to megestrol acetate in second-line therapy for postmenopausal women with hormone receptor-positive advanced breast cancer, with a significant survival advantage (26.7 vs 22.5 months) 2

• Early Breast Cancer: In the ATAC trial, anastrozole demonstrated fewer recurrences compared to tamoxifen in postmenopausal women with hormone receptor-positive early breast cancer 3

Important Distinctions

1. Not Effective in Premenopausal Women:

   • Aromatase inhibitors are not active in women with functioning ovaries 3
   • Should not be used in premenopausal women or those whose ovarian function cannot be reliably assessed due to treatment-induced amenorrhea 3

2. Comparison with Tamoxifen:

   • Different mechanism: Tamoxifen works as a selective estrogen receptor modulator (SERM) that blocks estrogen receptors
   • Anastrozole prevents estrogen production altogether
   • Different side effect profiles: Anastrozole is more associated with musculoskeletal symptoms and bone loss, while tamoxifen is associated with increased risk of uterine cancer and deep venous thrombosis 3, 4

Clinical Implications

• Anastrozole is specifically indicated for postmenopausal women with hormone receptor-positive breast cancer
• Bone health monitoring is essential during treatment due to increased risk of osteoporosis and fractures 3, 4
• Common side effects include hot flashes, musculoskeletal symptoms, and asthenia 4

Understanding anastrozole's mechanism of action is crucial for appropriate patient selection and management of potential side effects in the treatment of hormone receptor-positive breast cancer in postmenopausal women.