What is the treatment regimen for patients with HER2-positive and hormone receptor-positive invasive ductal carcinoma using Femara (letrozole)?

Treatment Regimen for HER2-Positive and Hormone Receptor-Positive Invasive Ductal Carcinoma Using Femara (Letrozole)

For patients with HER2-positive and hormone receptor-positive invasive ductal carcinoma, letrozole (Femara) 2.5 mg daily should be combined with HER2-targeted therapy (trastuzumab or lapatinib), not used as monotherapy, as this combination significantly improves progression-free survival compared to letrozole alone. 1

First-Line Treatment Approach

The preferred first-line treatment is chemotherapy plus dual HER2 blockade (trastuzumab and pertuzumab) with a taxane, as this provides overall survival benefit. 1 However, when chemotherapy is not immediately indicated due to indolent disease, low disease burden, significant comorbidities, or patient preference, endocrine therapy combined with HER2-targeted therapy is an acceptable alternative. 1

Letrozole-Based Regimen (When Chemotherapy Not Indicated)

Letrozole 2.5 mg orally once daily combined with trastuzumab is the evidence-based regimen for postmenopausal women. 1 The TAnDEM trial demonstrated that anastrozole plus trastuzumab improved progression-free survival from 2.4 months to 4.8 months (HR 0.63, P=0.0016) compared to anastrozole alone. 1 The eLEcTRA trial showed letrozole plus trastuzumab extended median time to progression from 3.3 months to 14.1 months compared to letrozole alone. 1

Alternatively, letrozole 2.5 mg daily combined with lapatinib can be used. 1 A phase III study showed lapatinib plus letrozole reduced risk of disease progression compared to letrozole alone (median PFS 8.2 vs 3.0 months; HR 0.71, P=0.019). 1

Premenopausal Patients

Premenopausal women must receive ovarian suppression (goserelin or other LHRH agonist) in addition to letrozole and HER2-targeted therapy. 1, 2 A case report demonstrated effectiveness of goserelin, letrozole, trastuzumab, and abemaciclib combination in a premenopausal patient with HER2/HR-positive metastatic disease. 2

Dosing and Administration

• Letrozole: 2.5 mg orally once daily, taken without regard to meals 3
• Trastuzumab: Standard dosing per protocol (loading dose 4 mg/kg IV, then 2 mg/kg weekly OR 8 mg/kg loading, then 6 mg/kg every 3 weeks) 1
• Lapatinib: 1500 mg orally once daily when combined with letrozole 1

For patients with cirrhosis or severe hepatic impairment, reduce letrozole to 2.5 mg every other day. 3

Monitoring Requirements

Cardiac function must be monitored before and every 3 months during HER2-targeted therapy due to risk of cardiotoxicity, particularly left ventricular ejection fraction (LVEF) decline. 4, 3

Bone mineral density monitoring should be considered as letrozole decreases bone density. 3

Cholesterol monitoring is recommended as letrozole increases total cholesterol. 3

Duration of Therapy

Continue letrozole plus HER2-targeted therapy until disease progression or unacceptable toxicity. 1 If chemotherapy was initiated first and then stopped after 4-6 months or maximal response, continue HER2-targeted therapy with addition of letrozole as maintenance. 1

Critical Pitfalls to Avoid

Do NOT use letrozole monotherapy without HER2-targeted therapy in HER2-positive disease – this ignores the HER2-driven resistance mechanism and results in inferior outcomes (median PFS only 2.4-3.3 months). 1

Do NOT give letrozole concurrently with chemotherapy – endocrine therapy and chemotherapy must be sequential, with endocrine therapy starting after chemotherapy completion. 5

Do NOT use letrozole in premenopausal women without ovarian suppression – aromatase inhibitors are ineffective without eliminating ovarian estrogen production. 1

Do NOT assume normal HER2 ECD levels – elevated circulating HER2 extracellular domain levels (present in 19% of patients) predict significantly shorter time to progression with letrozole (4 vs 14 months, P=0.0004) and lower response rates (14% vs 30%, P<0.036). 6

Advanced Options

For patients who have received prior trastuzumab, consider dual HER2 blockade with lapatinib plus trastuzumab combined with an aromatase inhibitor. 1 The ALTERNATIVE trial showed this combination significantly increased PFS compared to trastuzumab plus AI alone (11 vs 5.7 months; HR 0.62, P=0.0064). 1

Adding pertuzumab to trastuzumab plus letrozole may be considered based on the PERTAIN trial, which showed improved PFS (18.9 vs 15.8 months; HR 0.65) with the three-drug combination plus AI. 1

Expected Outcomes

With letrozole plus trastuzumab, expect objective response rates of 22-26% and median time to progression of 8.9-14.1 months. 1 With letrozole plus lapatinib, expect objective response rates of approximately 28% and median PFS of 8.2 months. 1 These outcomes are inferior to chemotherapy plus HER2-targeted therapy but appropriate for selected patients with contraindications to chemotherapy or indolent disease. 1