How Exemestane Works in Hormone Receptor-Positive Breast Cancer
Exemestane is an irreversible steroidal aromatase inhibitor that blocks the conversion of androgens to estrogens in peripheral tissues, thereby depriving hormone receptor-positive breast cancer cells of the estrogen they need to grow. 1
Mechanism of Action
Exemestane functions through "suicide inhibition" of the aromatase enzyme 1:
- Acts as a false substrate that structurally mimics androstenedione (the natural substrate for aromatase) 1
- Binds irreversibly to the active site of the aromatase enzyme, permanently inactivating it 1
- Suppresses circulating estrogens by 85-95% at the standard 25 mg daily dose in postmenopausal women 1, 2
- Reduces whole body aromatization by 98% as measured by radiolabeled androstenedione studies 1
The maximal estrogen suppression occurs 2-3 days after dosing and persists for 4-5 days 1.
Why This Matters in Breast Cancer Treatment
In postmenopausal women, the ovaries no longer produce significant estrogen—instead, peripheral tissues convert adrenal and ovarian androgens into estrogens via the aromatase enzyme 1. Since approximately 70% of breast cancers are hormone receptor-positive and depend on estrogen for growth 3, blocking this conversion starves the cancer cells.
Clinical Applications
Adjuvant Treatment (Early Breast Cancer)
Exemestane is FDA-approved for postmenopausal women with estrogen receptor-positive early breast cancer who have completed 2-3 years of tamoxifen, switching to exemestane to complete a total of 5 consecutive years of hormonal therapy 1. This sequential approach (tamoxifen followed by exemestane) is superior to continuing tamoxifen alone for disease-free survival 3.
Advanced/Metastatic Disease
Exemestane is FDA-approved for treating advanced breast cancer in postmenopausal women whose disease has progressed following tamoxifen therapy 1. In the metastatic setting:
- First-line option: Aromatase inhibitors including exemestane are preferred over tamoxifen for postmenopausal women with HR-positive metastatic breast cancer 3
- Second-line therapy: Sequential hormone therapy should be offered after progression on initial endocrine therapy 3
- Combination with everolimus: Exemestane plus everolimus may be offered to postmenopausal women who progressed on nonsteroidal aromatase inhibitors (anastrozole or letrozole), as this combination improves progression-free survival compared to exemestane alone, though with significantly increased toxicity 3
Potential Lack of Cross-Resistance
Because exemestane is a steroidal aromatase inactivator (Type 1) while anastrozole and letrozole are nonsteroidal inhibitors (Type 2), there may be partial lack of cross-resistance 4, 5. This means exemestane can still provide clinical benefit in 40-47% of patients who have progressed on nonsteroidal aromatase inhibitors 5.
Important Caveats
- Postmenopausal status only: Exemestane is only effective in postmenopausal women because it does not suppress ovarian estrogen production 1
- Selective for aromatase: Does not affect cortisol, aldosterone, or other adrenal steroid production, so no replacement therapy is needed 1
- Common side effects: Arthralgias, myalgias, hot flashes, and bone mineral density loss with increased fracture risk (though bone density appears to return to baseline after treatment cessation) 3, 6
- More toxicity with combinations: The combination of exemestane and everolimus has substantially greater toxicity than exemestane alone, including stomatitis (56%), rash (36%), and noninfectious pneumonitis (12%) 3