What is the recommended treatment with aromatase inhibitors (AIs) for hormone receptor-positive breast cancer in postmenopausal women?

Aromatase Inhibitor Treatment for Hormone Receptor-Positive Breast Cancer in Postmenopausal Women

Postmenopausal women with hormone receptor-positive breast cancer should receive a third-generation aromatase inhibitor (anastrozole, letrozole, or exemestane) as part of their adjuvant endocrine therapy, either as initial treatment for 5 years, sequentially after 2-3 years of tamoxifen to complete 5 years total, or as extended therapy following 5 years of tamoxifen. 1

Treatment Strategies

There are three evidence-based approaches for incorporating aromatase inhibitors into adjuvant therapy:

Initial Adjuvant Therapy (Upfront AI)

• Start with anastrozole or letrozole for 5 years as first-line adjuvant therapy instead of tamoxifen 1
• This approach provides superior disease-free survival compared to tamoxifen alone, with the ATAC trial showing 4-year DFS of 86.9% on anastrozole versus 84.5% on tamoxifen 2
• Letrozole demonstrated better overall clinical response and breast-conserving surgery rates than tamoxifen in neoadjuvant settings 3

Sequential Therapy (Switch Strategy)

• Switch to an AI (anastrozole or exemestane) after 2-3 years of tamoxifen to complete 5 years total endocrine therapy 1
• The IES trial showed 3-year DFS of 91.5% with exemestane versus 86.8% with continued tamoxifen after switching 2
• This strategy is particularly valuable for women already partway through tamoxifen treatment 1

Extended Adjuvant Therapy

• Offer letrozole for 5 years after completing 5 years of tamoxifen 1
• The MA-17 trial demonstrated 4-year estimated DFS of 93% with letrozole versus 87% with placebo 2
• In node-positive disease, extended letrozole showed overall survival benefit (HR 0.61,95% CI 0.38-0.98) 1
• This benefit persists even when letrozole is started after a treatment-free interval following tamoxifen completion 1

Agent Selection

All three third-generation aromatase inhibitors (anastrozole, letrozole, exemestane) are considered equivalent in efficacy and toxicity, with no compelling evidence favoring one over another. 1

• Nonsteroidal AIs: Anastrozole 1 mg daily or letrozole 2.5 mg daily 4
• Steroidal AI: Exemestane 25 mg daily 5
• Letrozole demonstrates superior estrogen suppression in head-to-head studies 4
• Exemestane binds irreversibly to aromatase enzyme, offering a distinct mechanism that may provide benefit after nonsteroidal AI failure 4

Metastatic Disease Treatment

First-Line Therapy

Third-generation aromatase inhibitors are recommended over tamoxifen as first-line treatment for postmenopausal women with hormone receptor-positive metastatic breast cancer. 1

• Letrozole showed superiority to tamoxifen in objective response rate and time to progression across all subgroups 1
• Exemestane demonstrated superiority to tamoxifen in response rate and time to progression 1
• Tamoxifen remains a valuable option for those who decline or have contraindications to AIs 1

Second-Line and Beyond

• After tamoxifen failure, use a third-generation AI or fulvestrant 1
• After nonsteroidal AI failure, consider switching to steroidal exemestane due to incomplete cross-resistance 1, 4
• Exemestane plus everolimus improves progression-free survival in women who progressed on nonsteroidal AIs, though with substantially greater toxicity 6
• Sequential endocrine therapies include fulvestrant, megestrol acetate, high-dose estrogen, or androgens 1, 4

Critical Safety Considerations

Bone Health

• AIs cause reductions in bone mineral density and increased fracture risk compared to tamoxifen 1, 5
• Monitor bone mineral density regularly during AI therapy 7
• Assess 25-hydroxy vitamin D levels before starting AI treatment 5
• Bone density appears to return to baseline after treatment cessation 6

Cardiovascular Effects

• Increased cardiovascular events compared to tamoxifen (myocardial infarction, angina: 1.6% with exemestane vs 0.6% with tamoxifen) 5
• Monitor cardiovascular disease risk factors during treatment 7

Other Adverse Effects

• Common side effects include arthralgias, myalgias, hot flashes, and increased sweating 6, 5
• Decreased risk of endometrial cancer and thromboembolic events compared to tamoxifen 1
• Quality of life is reasonably preserved despite ongoing menopausal symptoms 1

Absolute Contraindications

Aromatase inhibitors must NEVER be used in premenopausal women outside clinical trials. 1

• AIs do not adequately suppress ovarian estrogen synthesis in women with functioning ovaries 1
• Women who become amenorrheic with chemotherapy may still have ovarian estrogen production despite absent menses 1
• Serial assessment of luteinizing hormone, follicle-stimulating hormone, and estradiol is mandatory to confirm true postmenopausal status before AI initiation 1
• In premenopausal women requiring AI therapy, ovarian function suppression with LHRH agonists is absolutely required 1, 4

Common Pitfalls to Avoid

• Do not assume chemotherapy-induced amenorrhea equals menopause - verify with hormonal testing 1
• Do not use AIs interchangeably without considering the clinical context - select the agent with the most relevant data for each situation 1
• Do not delay switching to AI if already on tamoxifen - benefits persist even after 2-3 years of tamoxifen 1
• Do not overlook bone health monitoring - fracture risk is real and requires proactive management 5, 7