What are the pros and cons of letrozole (aromatase inhibitor) for hormone receptor-positive breast cancer treatment?

Letrozole for Hormone Receptor-Positive Breast Cancer: Benefits and Side Effects

Letrozole is superior to tamoxifen for postmenopausal women with hormone receptor-positive breast cancer, offering improved disease-free survival and reduced risk of recurrence, though with different side effect profiles that must be carefully considered. 1

Indications and Efficacy

Letrozole is FDA-approved for:

• Adjuvant treatment of postmenopausal women with hormone receptor-positive early breast cancer
• Extended adjuvant treatment after 5 years of tamoxifen therapy
• First and second-line treatment of advanced hormone receptor-positive breast cancer 1

Evidence of Benefit

The BIG 1-98 trial demonstrated that letrozole as initial adjuvant therapy provided superior disease-free survival compared to tamoxifen (HR 0.81; 95% CI 0.70-0.93; p=0.003) in postmenopausal women with hormone receptor-positive breast cancer 2.

The MA-17 trial showed significant benefits when letrozole was used as extended therapy after 5 years of tamoxifen:

• Improved disease-free survival at 4 years (94.4% vs 89.8%; HR 0.58; p<0.001)
• Significant overall survival improvement specifically in node-positive patients (HR 0.61; 95% CI 0.38-0.98; p=0.04) 2

Advantages of Letrozole

1. Superior efficacy: Consistently demonstrates better disease-free survival compared to tamoxifen 2

2. Reduced risk of certain adverse events compared to tamoxifen:

   • Lower incidence of thromboembolic events
   • Fewer gynecologic symptoms (5.8% vs 9.0%)
   • Less vaginal bleeding (4.0% vs 5.5%)
   • Fewer muscle cramps (2.8% vs 4.4%) 2

3. Effective in multiple treatment scenarios:

   • As initial adjuvant therapy
   • After 2-3 years of tamoxifen (switching strategy)
   • As extended adjuvant therapy after completing 5 years of tamoxifen 2

Disadvantages and Side Effects

1. Musculoskeletal issues:

   • Increased risk of arthralgia compared to tamoxifen
   • Higher rates of myalgia 2, 3

2. Bone health concerns:

   • Higher risk of osteoporosis (5.7% vs 7.4% compared to tamoxifen)
   • Increased bone fracture risk (requires bone density monitoring) 2, 3

3. Other side effects:

   • Visual disturbances (more common than with tamoxifen)
   • Diarrhea (2.3% vs 4.3%)
   • Hot flashes (though less frequent than with tamoxifen) 2

4. Contraindications:

   • Not effective in premenopausal women
   • Contraindicated in pregnancy (can cause fetal harm)
   • Requires dose adjustment in severe hepatic impairment 3, 1

Treatment Algorithm for Postmenopausal Women

1. Early-stage hormone receptor-positive breast cancer:

   • Initial adjuvant therapy: Letrozole 2.5mg daily for 5 years
   • OR Sequential approach: Tamoxifen for 2-3 years followed by letrozole to complete 5 years
   • OR Extended therapy: After completing 5 years of tamoxifen, add letrozole for additional 5 years 2, 1

2. Advanced/metastatic hormone receptor-positive breast cancer:

   • First-line: Letrozole 2.5mg daily (preferred over tamoxifen due to superior time to progression)
   • Second-line: After tamoxifen failure, letrozole is recommended based on favorable side effect profile 2, 1

Important Clinical Considerations

• Verify postmenopausal status before initiating letrozole. In women with chemotherapy-induced amenorrhea, confirm postmenopausal status through hormone levels (FSH, LH, estradiol) 3

• Monitor bone health during treatment with letrozole due to increased risk of osteoporosis and fractures 3

• Duration of therapy: In adjuvant setting, optimal duration is 5 years; in extended adjuvant setting after tamoxifen, treatment for 5 years is recommended; in advanced disease, continue until disease progression 1

• Hepatic impairment: Reduce dose by 50% in patients with cirrhosis and severe hepatic dysfunction 1

Letrozole represents a significant advancement in hormone receptor-positive breast cancer treatment, offering improved outcomes compared to tamoxifen but requiring careful monitoring of bone health and management of musculoskeletal side effects.