Can Tamoxifen (tamoxifen citrate) be used together with Herceptin (trastuzumab) and Perjeta (pertuzumab) in the treatment of HER2-positive, hormone receptor-positive breast cancer?

Can Tamoxifen Be Used with Herceptin and Perjeta in HER2+/HR+ Breast Cancer?

For patients with HER2-positive, hormone receptor-positive metastatic breast cancer, endocrine therapy (including tamoxifen) combined with dual HER2 blockade (trastuzumab plus pertuzumab) is a guideline-supported treatment option, particularly as maintenance therapy after initial chemotherapy or in highly selected patients who cannot tolerate chemotherapy. 1

First-Line Treatment Approach

The preferred first-line treatment for HER2+/HR+ metastatic breast cancer is chemotherapy (taxane) plus trastuzumab plus pertuzumab for at least 6 cycles, followed by maintenance therapy. 1

Maintenance Strategy After Chemotherapy

• Following completion of chemotherapy with trastuzumab and pertuzumab, maintenance therapy should consist of trastuzumab plus pertuzumab plus endocrine therapy (which can include tamoxifen) for patients with HR-positive disease. 1
• This approach is supported by ESMO guidelines with MCBS 1A rating, representing the highest level of clinical benefit. 1
• The NCCN panel specifically notes that if treatment was initiated with chemotherapy plus trastuzumab plus pertuzumab and chemotherapy is stopped, endocrine therapy may be added to the dual HER2 blockade. 1

Endocrine Therapy Plus Dual HER2 Blockade Without Chemotherapy

For highly selected patients with contraindications to chemotherapy, the combination of trastuzumab plus pertuzumab plus endocrine therapy (including tamoxifen) can be used as initial treatment. 1

Patient Selection Criteria

This chemotherapy-free approach should be reserved for patients with: 1

• Strong contraindications to chemotherapy
• Long disease-free interval
• Minimal disease burden, particularly limited visceral involvement
• Strong ER/PgR expression

Supporting Evidence

• The TAnDEM trial demonstrated borderline overall survival benefit when excluding crossover patients treated with anastrozole plus trastuzumab versus anastrozole alone (median PFS: 4.8 vs 2.4 months; HR 0.63). 1
• The PERTAIN trial showed improved PFS with pertuzumab plus trastuzumab plus aromatase inhibitor versus trastuzumab plus aromatase inhibitor (18.9 vs 15.8 months; HR 0.65), though approximately half received induction taxane therapy. 1
• The eLEcTRA trial demonstrated median time to progression of 14.1 months with trastuzumab plus letrozole versus 3.3 months with letrozole alone. 1

Important Caveats and Considerations

Potential Drug Interactions

There is conflicting preclinical evidence regarding tamoxifen and trastuzumab interactions that warrants awareness, though clinical trials have not demonstrated harm. 2, 3, 4

• Laboratory studies show antagonistic interactions at lower levels of cell kill when tamoxifen is combined with trastuzumab, potentially related to tamoxifen upregulating HER2 expression and phosphorylation. 2
• However, other in vitro studies demonstrate synergistic growth inhibition and enhanced G0-G1 cell cycle arrest with the combination. 4
• Clinical trial data (TAnDEM, eLEcTRA, PERTAIN) demonstrate clinical benefit with endocrine therapy plus HER2-targeted therapy combinations, superseding the preclinical concerns. 1

Reimbursement and Regulatory Considerations

• In several countries, trastuzumab can only be used once in the metastatic setting or is not reimbursed beyond progression. 1
• In such settings, preference should be given to chemotherapy plus anti-HER2 therapy to maximize the benefit from HER2-targeted treatment. 1

Ongoing Clinical Trials

• Direct comparisons of chemotherapy plus anti-HER2 therapy versus endocrine therapy plus anti-HER2 therapy are ongoing (DETECT V/CHEVENDO, SYSUCC-002, PERNETTA trials). 1
• Results from these trials will provide more definitive guidance on optimal sequencing and patient selection. 1

Practical Algorithm for Decision-Making

Step 1: Confirm HER2-positive and HR-positive status. 1

Step 2: Assess candidacy for chemotherapy:

• If chemotherapy candidate: Use taxane + trastuzumab + pertuzumab for 6+ cycles, then switch to trastuzumab + pertuzumab + endocrine therapy (tamoxifen or aromatase inhibitor based on menopausal status) as maintenance. 1
• If chemotherapy contraindicated: Use trastuzumab + pertuzumab + endocrine therapy from the start, ensuring patient meets selection criteria (minimal visceral disease, strong hormone receptor expression, long disease-free interval). 1

Step 3: Monitor for cardiac toxicity with trastuzumab and pertuzumab (baseline and periodic LVEF monitoring every 3-4 months). 1

Step 4: Continue dual HER2 blockade plus endocrine therapy until disease progression. 1