What is Exemestane (Aromatase Inhibitor)?

Exemestane: An Aromatase Inhibitor for Breast Cancer Treatment

Exemestane is an irreversible steroidal aromatase inhibitor that works by permanently inactivating the aromatase enzyme, preventing the conversion of androgens to estrogens in postmenopausal women with hormone receptor-positive breast cancer. 1

Mechanism of Action

Exemestane functions as a "suicide inhibitor" of the aromatase enzyme:

• Acts as a false substrate for the aromatase enzyme
• Forms an intermediate that binds irreversibly to the active site
• Significantly lowers circulating estrogen concentrations (85-95% suppression at 25 mg dose)
• Reduces whole body aromatization by 98% in postmenopausal women 1

Unlike non-steroidal aromatase inhibitors (anastrozole and letrozole) that bind reversibly to the enzyme, exemestane:

• Is structurally related to androstenedione (the natural substrate)
• Binds irreversibly to aromatase
• Has a steroidal structure 2, 1

Clinical Indications

Exemestane is FDA-approved for:

1. Adjuvant treatment of postmenopausal women with estrogen receptor-positive early breast cancer:

   • After 2-3 years of tamoxifen therapy (switched to exemestane to complete 5 total years of hormonal therapy) 1

2. Advanced/metastatic breast cancer in postmenopausal women:

   • After disease progression following tamoxifen therapy 1
   • As second-line therapy following antiestrogen failure 2

3. Off-label use for breast cancer risk reduction:

   • In postmenopausal women ≥35 years with elevated breast cancer risk (≥1.66% 5-year projected risk)
   • Reduces invasive breast cancer incidence by 65% compared to placebo 3

Dosing and Administration

• Standard dose: 25 mg once daily orally 1
• Administered until disease progression in metastatic setting
• For adjuvant therapy, typically used to complete a total of 5 years of hormonal therapy 1

Efficacy

In metastatic breast cancer:

• Produces objective response rates of 15-28% in tamoxifen-refractory disease 4
• Shows similar clinical efficacy to megestrol acetate but with significantly prolonged duration of response, time to progression, and survival advantage 4
• Effective in patients with visceral metastases 4
• Maintains efficacy after multiple hormonal therapies, including after nonsteroidal aromatase inhibitors 4

In early breast cancer:

• Switching to exemestane after 2-3 years of tamoxifen improves disease-free survival compared to continuing tamoxifen 2

Side Effects and Safety Profile

Common adverse effects:

• Musculoskeletal: Myalgias and arthralgias 5
• Menopausal symptoms: Hot flashes, increased sweating 4
• Other: Fatigue, nausea, dizziness 4

Bone health:

• Associated with reduced bone mineral density and increased fracture risk
• These effects may not persist long-term, with potential return to pretreatment values 5
• Regular bone density monitoring recommended 2

Compared to tamoxifen:

• Reduced incidence of endometrial changes
• Lower risk of thromboembolic events
• Fewer hot flashes 5

Endocrine effects:

• No significant effect on cortisol or aldosterone secretion
• No glucocorticoid or mineralocorticoid replacement needed
• Minimal effect on circulating androgens at therapeutic doses 1

Clinical Considerations

• Exemestane is only effective in postmenopausal women or those with ovarian suppression
• Premenopausal women should not receive aromatase inhibitors without ovarian function suppression 2
• Verify postmenopausal status before initiating therapy, especially in women who become amenorrheic with chemotherapy 2
• Adherence is a concern, with studies showing nonadherence in 23-32% of patients 5

Comparison with Other Hormonal Therapies

• The NCCN Breast Cancer Guidelines Panel considers the three selective AIs (anastrozole, letrozole, exemestane) to have similar antitumor activity and toxicity profiles 2
• In sequential therapy after tamoxifen, exemestane has demonstrated superior efficacy to continuing tamoxifen 2
• In metastatic disease, exemestane is superior to megestrol acetate after progression on tamoxifen 4

Exemestane represents an important option in the hormonal treatment arsenal for postmenopausal women with hormone receptor-positive breast cancer, with proven efficacy in both early and advanced disease settings.