What is the role of Letrazole (letrozole) in treating postmenopausal women with hormone receptor-positive breast cancer?

Letrozole in Postmenopausal Hormone Receptor-Positive Breast Cancer

Letrozole is a highly effective aromatase inhibitor that should be used preferentially over tamoxifen alone in postmenopausal women with hormone receptor-positive breast cancer, as it consistently demonstrates superior disease-free survival and reduced recurrence rates across multiple treatment settings. 1, 2

Primary Treatment Strategies

The evidence supports three distinct approaches for incorporating letrozole into treatment:

Initial Adjuvant Therapy (First-Line)

• Letrozole 2.5 mg daily for 5 years as initial adjuvant therapy is a Category 1 recommendation for postmenopausal women with hormone receptor-positive early breast cancer 1, 3
• In the BIG 1-98 trial, letrozole significantly prolonged disease-free survival compared to tamoxifen (HR 0.81; 95% CI 0.70-0.93; P=0.003) at median follow-up of 25.8 months 1, 4
• Letrozole demonstrated superior time to progression (9.9 months vs 6.2 months, P=0.0001) and objective response rate (32% vs 21%, P=0.0003) compared to tamoxifen in metastatic disease 5

Sequential Therapy After Tamoxifen

• Switching to an aromatase inhibitor after 2-3 years of tamoxifen to complete 5 years total endocrine therapy is equally acceptable 1
• This strategy allows patients to benefit from both drug classes while potentially reducing cumulative toxicities 1

Extended Adjuvant Therapy

• Letrozole 2.5 mg daily for up to 5 years after completing 4.5-6 years of tamoxifen is FDA-approved for extended adjuvant treatment 3
• The MA.17 trial demonstrated that letrozole significantly improved disease-free survival (HR 0.58; 95% CI 0.45-0.76; P<0.001) and distant disease-free survival (HR 0.60; 95% CI 0.43-0.84; P=0.002) 1, 6
• In node-positive patients specifically, letrozole improved overall survival (HR 0.61; 95% CI 0.38-0.98; P=0.04) 1, 6

Patient Selection for Extended Therapy

Node-positive patients derive the most consistent benefit from extended therapy and should be offered letrozole for up to 10 years total endocrine treatment 7:

• Women with ≥4 positive lymph nodes have higher risk of late recurrence and warrant extended therapy 7
• Node-negative patients may be offered extended therapy based on additional risk factors, but benefits are narrower 7
• Low-risk node-negative tumors should not routinely receive extended therapy 7

Metastatic Disease Treatment

For first-line treatment of hormone receptor-positive metastatic breast cancer, letrozole is recommended as preferred therapy 1:

• Letrozole showed superior time to progression and overall response rate compared to tamoxifen in all subgroups according to dominant site of metastatic disease, receptor status, or prior adjuvant endocrine treatment 1
• Following tamoxifen failure, third-generation aromatase inhibitors (including letrozole) are recommended for second-line treatment based on favorable side-effect profile 1
• Modern combination therapy with letrozole plus CDK4/6 inhibitors (such as ribociclib) represents current standard-of-care first-line treatment for HR+/HER2- metastatic breast cancer 8

Safety Profile and Toxicity Comparison

Advantages Over Tamoxifen

Letrozole demonstrates significantly lower rates of:

• Endometrial carcinoma (0.2% vs 0.8%; P=0.02) 2
• Venous thromboembolic events (2.8% vs 4.5%; P=0.0004) 2, 4
• Cerebrovascular events (2.0% vs 2.8%; P=0.03) 2
• Gynecologic symptoms, vaginal bleeding, hot flushes, and night sweating 1, 4

Disadvantages Compared to Tamoxifen

Letrozole has higher rates of:

• Bone fractures (11.0% vs 7.7%; P<0.0001) 2
• Arthralgias (35.6% vs 29.4%; P<0.0001) 2
• Osteoporosis 1

Critical Clinical Caveats

Menopausal Status Verification

Aromatase inhibitors are absolutely contraindicated in premenopausal women 2, 3:

• Letrozole does not adequately suppress ovarian estrogen synthesis in women with functioning ovaries 2
• For women who become amenorrheic with chemotherapy, serial assessment of luteinizing hormone, follicle-stimulating hormone, and estradiol is mandatory to confirm true postmenopausal status 2
• If aromatase inhibitors are considered in premenopausal patients, they must be given with ovarian function suppression 1

Bone Health Management

Baseline bone mineral density assessment and aggressive bone protection are essential 2:

• Patients with pre-existing osteoporosis or history of fragility fractures require baseline DEXA scanning 2
• Bisphosphonates or denosumab should be initiated before starting letrozole in high-risk patients 2
• Baseline DEXA scan is recommended for patients >65 years, with family history of osteoporosis, or on chronic steroids 2

Duration Considerations

Total endocrine therapy duration should not exceed 10 years 7:

• AI therapy alone should not exceed 5 years in the primary adjuvant setting 7
• Extended therapy beyond 10 years is not supported by current evidence 7
• Treatment should be discontinued at tumor relapse 3

Dosing and Administration

The recommended dose is letrozole 2.5 mg orally once daily, without regard to meals 3:

• No dosage adjustment required for renal impairment if creatinine clearance ≥10 mL/min 3
• For patients with cirrhosis and severe hepatic dysfunction, reduce dose by 50% (2.5 mg every other day) 3
• No adjustment needed for mild to moderate hepatic impairment 3

Equivalence Among Aromatase Inhibitors

The NCCN panel finds no compelling evidence that anastrozole, letrozole, and exemestane have meaningful differences in efficacy or toxicity 2:

• All three third-generation aromatase inhibitors are considered equally effective 1
• Selection should be based on patient-specific factors such as tolerability, cost, and insurance coverage rather than perceived efficacy differences 2
• Switching between steroidal and non-steroidal AIs may be considered before abandoning AI therapy entirely if tolerability issues arise 2

Overall Survival Data

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 MA.17 trial remains the only major study showing overall survival advantage, specifically in node-positive disease 1
• To date, none of the extended therapy studies have shown improvement in overall survival with longer-duration AI therapy, with benefits primarily in disease-free survival and prevention of second breast cancers 7
• Longer follow-up is expected to reveal overall survival differences as trials mature 1