Letrozole for Postmenopausal Hormone Receptor-Positive Breast Cancer
For postmenopausal women with hormone receptor-positive breast cancer, letrozole 2.5 mg daily is a highly effective aromatase inhibitor that should be incorporated into treatment either as initial adjuvant therapy for 5 years, after 2-3 years of tamoxifen to complete 5 years total, or as extended therapy following 5 years of tamoxifen. 1
Treatment Strategies and Algorithms
The 2006 NCCN guidelines established three equally valid Category 1 treatment approaches for postmenopausal women with hormone receptor-positive breast cancer 1:
Option 1: Initial Adjuvant Therapy
- Letrozole 2.5 mg daily for 5 years as upfront treatment 1, 2
- The BIG 1-98 trial demonstrated superior disease-free survival with letrozole compared to tamoxifen (HR 0.81,95% CI 0.70-0.93, P=0.003) 1
- This approach is preferred for patients who want maximum estrogen suppression from the start 3
Option 2: Sequential Therapy After Tamoxifen
- Start with tamoxifen for 2-3 years, then switch to letrozole to complete 5 years total endocrine therapy 1
- This strategy is based on the IES trial showing superior disease-free survival when switching to an aromatase inhibitor after 2-3 years of tamoxifen (91.5% vs 86.8%, HR 0.68, P=0.00005) 1
- Consider this approach for patients already on tamoxifen or those with contraindications to initial aromatase inhibitor use 1
Option 3: Extended Adjuvant Therapy
- After completing 5 years of tamoxifen, continue with letrozole for up to 5 additional years 1, 2
- The MA.17 trial showed letrozole significantly improved 4-year disease-free survival (94.4% vs 89.8%, HR 0.58, P<0.001) 1
- Most importantly, this was the only strategy showing overall survival benefit in node-positive patients (HR 0.61,95% CI 0.38-0.98, P=0.04) 1
Patient Selection for Extended Therapy (Beyond 5 Years)
The 2019 ASCO guidelines provide specific recommendations for extending aromatase inhibitor therapy beyond 5 years 1:
- Node-positive patients should be offered extended therapy up to 10 years total 1
- Node-negative patients with higher recurrence risk may be offered extended therapy, but those with low-risk tumors should not routinely receive it 1
- Women with tumors ≤5 mm and node-negative disease do not require adjuvant hormonal therapy at all 1
- Prevention of contralateral breast cancer is a major benefit that should inform the decision 1
Critical Caveat on Extended Therapy
No study has demonstrated overall survival improvement with therapy extending beyond 5 years in the general population 1. The benefits are primarily in disease-free survival and prevention of second breast cancers, not mortality reduction 1.
Dosing and Administration
Standard dose: Letrozole 2.5 mg orally once daily, without regard to meals 2
Dose Modifications:
- Patients with cirrhosis or severe hepatic dysfunction: 2.5 mg every other day 2
- No adjustment needed for mild-to-moderate hepatic impairment 2
- No adjustment needed for renal impairment if creatinine clearance ≥10 mL/min 2
Duration:
- Continue until tumor relapse in adjuvant/extended adjuvant settings 2
- Continue until disease progression in advanced/metastatic disease 2
Monitoring Requirements
Bone Health
Letrozole causes decreases in bone mineral density 2. The FDA label specifically states consideration should be given to monitoring BMD, with median decreases of 4% in lumbar spine BMD at 24 months 2. All aromatase inhibitors increase fracture risk compared to tamoxifen 3.
Lipid Monitoring
Increases in total cholesterol may occur and cholesterol monitoring should be considered 2.
Safety Monitoring
- Monitor for fatigue, dizziness, and somnolence, which may impair ability to operate machinery 2
- Obtain pregnancy test in females of reproductive potential before initiating therapy 2
Adverse Effect Profile
The most common adverse reactions (>20%) include 2:
- Hot flashes
- Arthralgia
- Flushing
- Asthenia
- Edema
- Headache
- Dizziness
- Hypercholesterolemia
- Increased sweating
- Bone pain
- Musculoskeletal symptoms
Comparative Tolerability
When compared to tamoxifen, aromatase inhibitors have fewer gynecologic symptoms (5.8% vs 9.0%), less vaginal bleeding (4.0% vs 5.5%), fewer muscle cramps (2.8% vs 4.4%), and less thromboembolic disease (1.0% vs 1.9%) 1. However, they cause more visual disturbances (7.4% vs 5.7%), osteoporosis (7.4% vs 5.7%), arthralgias (5.4% vs 3.6%), and diarrhea (4.3% vs 2.3%) 1.
Alternatives When Letrozole Is Not Tolerated
If letrozole is not tolerated, switching to exemestane (steroidal AI) is the preferred next option 3. If both nonsteroidal AIs (letrozole, anastrozole) are poorly tolerated, exemestane offers a mechanistically distinct alternative 3. All three third-generation AIs have similar efficacy, so switching for tolerability does not compromise cancer outcomes 3.
Fulvestrant is a mechanistically distinct alternative if all three AIs are poorly tolerated 3. Tamoxifen remains valuable after AI failure as part of sequential endocrine therapy 3.
Advanced/Metastatic Disease
For first-line treatment of hormone receptor-positive metastatic breast cancer, letrozole is superior to tamoxifen 1, 4:
- Median time to progression: 9.9 months vs 6.2 months (HR 0.713, P=0.0001) 4
- Objective response rate: 32% vs 21% (P=0.0003) 4
In the modern era, letrozole should be combined with a CDK4/6 inhibitor (such as ribociclib or palbociclib) for first-line metastatic disease, as this combination significantly improves overall survival 5.
Contraindications
Absolute contraindications 2:
- Pregnancy (letrozole can cause fetal harm)
- Known hypersensitivity to letrozole or any excipients
Key Clinical Pitfalls to Avoid
Do not use letrozole in premenopausal women without ovarian suppression - aromatase inhibitors are ineffective without eliminating ovarian estrogen production 3
Do not continue therapy beyond 10 years total - no evidence supports benefit beyond this duration 1
Do not ignore bone health - proactive BMD monitoring and intervention are essential given the consistent bone loss seen with aromatase inhibitors 2
Do not assume all patients need extended therapy - low-risk node-negative patients derive minimal benefit and should not routinely receive therapy beyond 5 years 1
Do not forget that tamoxifen remains appropriate for women who decline, have contraindications to, or cannot tolerate aromatase inhibitors 1