What is the recommended treatment for a postmenopausal woman with hormone receptor-positive breast cancer, specifically regarding aromatase inhibitors (AIs)?

Aromatase Inhibitors for Postmenopausal Hormone Receptor-Positive Breast Cancer

Postmenopausal women with hormone receptor-positive breast cancer should receive an aromatase inhibitor (anastrozole, letrozole, or exemestane) as their primary adjuvant endocrine therapy, as these agents demonstrate superior disease-free survival and reduced recurrence rates compared to tamoxifen monotherapy. 1

Initial Treatment Strategy

The NCCN explicitly recommends aromatase inhibitors preferentially over tamoxifen alone in postmenopausal women with hormone receptor-positive breast cancer. 1 You have three equivalent Category 1 treatment approaches 1, 2:

• Initial AI therapy: Start with an aromatase inhibitor (anastrozole, letrozole, or exemestane) for 5 years 1, 2
• Sequential therapy: Give tamoxifen for 2-3 years, then switch to an AI to complete 5 total years 1, 2
• Extended therapy: After completing tamoxifen, add letrozole for additional years 1, 2

The NCCN panel finds no compelling evidence that anastrozole, letrozole, and exemestane differ meaningfully in efficacy or toxicity among the aromatase inhibitors. 1

Extended Therapy Duration

Women with node-positive breast cancer should be offered extended AI therapy for up to a total of 10 years of adjuvant endocrine treatment. 3 The absolute benefit is substantial enough in this population to justify the extended duration despite ongoing side effects. 3

For node-negative disease, the decision is more nuanced 3:

• Many women with node-negative breast cancer are candidates for extended AI therapy up to 10 years total based on recurrence risk using established prognostic factors 3
• Women with low-risk node-negative tumors should not routinely receive extended therapy, as the absolute benefits are narrower 3
• A substantial portion of the benefit from extended AI therapy comes from prevention of second breast cancers, not just recurrence prevention 3

No patient should receive more than 10 years total of adjuvant endocrine treatment. 3

Critical Menopausal Status Verification

Aromatase inhibitors are absolutely contraindicated in premenopausal women and should not be used outside clinical trials in this population. 1 This is a critical safety issue that cannot be overlooked.

For women who become amenorrheic with chemotherapy, you must perform serial assessment of luteinizing hormone, follicle-stimulating hormone, and estradiol to confirm true postmenopausal status before starting an AI. 1 Do not rely on amenorrhea alone.

Efficacy Evidence

The BIG 1-98 trial demonstrated that letrozole for 5 years was superior to tamoxifen for 5 years in disease-free survival (HR 0.81; 95% CI 0.70-0.93; P=0.003) in postmenopausal women with hormone receptor-positive breast cancer. 1

While disease-free survival consistently favors aromatase inhibitors, overall survival differences have not been demonstrated in most trials comparing initial AI therapy versus tamoxifen alone. 1 The exception is the MA.17 trial, which showed a survival advantage with extended letrozole in node-positive disease (HR 0.61; 95% CI 0.38-0.98; P=0.04). 1

Side Effect Profile Comparison

Advantages of AIs Over Tamoxifen

Aromatase inhibitors have a more favorable profile for several serious adverse events 1:

• Significantly lower endometrial carcinoma rates (0.2% vs 0.8%; P=0.02) 1
• Reduced venous thromboembolic events (2.8% vs 4.5%; P=0.0004) 1
• Fewer cerebrovascular events (2.0% vs 2.8%; P=0.03) 1
• Lower rates of hot flushes, vaginal bleeding, and vaginal discharge 1

Disadvantages of AIs

The primary concerns with aromatase inhibitors are musculoskeletal 1, 2:

• Higher bone fracture rates (11.0% vs 7.7%; P<0.0001) compared to tamoxifen 1
• Increased arthralgias (35.6% vs 29.4%; P<0.0001) compared to tamoxifen 1
• Increased risk of osteoporosis 2

Baseline bone mineral density assessment is mandatory before initiating aromatase inhibitor therapy. 4 Consider upfront zoledronic acid throughout AI therapy to preserve bone mineral density and improve disease-free survival. 4

FDA-Approved Indications

All three third-generation aromatase inhibitors have FDA approval for postmenopausal hormone receptor-positive breast cancer 5, 6:

• Letrozole: Adjuvant treatment, extended adjuvant treatment after tamoxifen, and first/second-line advanced disease 5
• Exemestane: Adjuvant treatment after 2-3 years of tamoxifen (switching to complete 5 years total), and advanced disease after tamoxifen failure 6
• Anastrozole: Similar indications across the treatment spectrum 1

Key Qualifying Statement

To date, none of the studies have shown improvement in overall survival with longer-duration AI therapy. 3 The recommendations for extended adjuvant AI therapy are based on benefits that include prevention of distant recurrence and prevention of second breast cancers, not mortality reduction. 3 This distinction must be communicated clearly when discussing extended therapy with patients, weighing ongoing risks and side effects against these specific benefits. 3