Is combination therapy of hormone therapy and HER2-targeted therapy the standard of care for HR+HER2+ MBC patients, or is sequential therapy preferred?

Treatment Approach for HR+HER2+ Metastatic Breast Cancer

For HR+HER2+ metastatic breast cancer patients, HER2-targeted therapy combined with chemotherapy is the preferred first-line approach in most cases, as this combination has demonstrated overall survival benefits. 1

First-Line Treatment Options

• HER2-targeted therapy combined with chemotherapy is the standard of care and preferred first-line approach for most HR+HER2+ MBC patients, as this has demonstrated improvements in overall survival 1

• For patients in whom chemotherapy is not immediately indicated (less aggressive disease, minimal symptoms), the addition of HER2-targeted therapy to first-line aromatase inhibitors can be considered as this improves progression-free survival (PFS), although without demonstrated improvement in overall survival 1

• The choice between chemotherapy plus HER2-targeted therapy versus endocrine therapy plus HER2-targeted therapy should be driven by clinical and biological characteristics of the disease, with chemotherapy plus HER2-targeted therapy preferred for:

  • Patients with de novo metastatic disease 1
  • Visceral dominant disease 1
  • Rapidly progressive disease 1
  • Immediately life-threatening disease 1

Evidence for Combination Approaches

• In randomized trials evaluating HER2-targeted agents with first-line AI therapy, both trastuzumab plus anastrozole and lapatinib plus letrozole showed significant improvement in PFS compared to AI alone 1

• However, PFS was notably short (2.4-3 months) for patients treated with AI alone in these trials, highlighting the importance of HER2-targeted therapy 1

• The eLEcTRA trial demonstrated that letrozole plus trastuzumab improved median time to progression (14.1 months vs 3.3 months) and clinical benefit rate (65% vs 39%) compared to letrozole alone in HR+HER2+ MBC patients 2

• For patients receiving HER2-targeted therapy with chemotherapy, endocrine therapy can be added as maintenance treatment after completion of chemotherapy, although evidence supporting benefit in this specific setting is limited 1

Treatment Duration and Sequencing

• Optimal duration of chemotherapy is at least 4-6 months or until maximum response, depending on toxicity and in the absence of progression 1

• HER2-targeted therapy should continue until time of progression or unacceptable toxicities 1

• Sequential hormonal therapy should be offered to patients with endocrine-responsive disease after progression on initial therapy 1

Special Considerations

• Complex molecular crosstalk between HR and HER2 pathways may affect sensitivity to both HER2-targeted and endocrine therapies in HR+HER2+ breast cancer 3

• For patients with HR+HER2+ MBC who have completed chemotherapy, continuing HER2-targeted therapy with the addition of endocrine therapy is a reasonable approach 1

• The CLEOPATRA trial, which established pertuzumab plus trastuzumab plus docetaxel as a standard first-line therapy for HER2+ MBC, showed consistent benefit across hormone receptor status subgroups, though the hazard ratio was slightly better in the hormone receptor-negative subgroup (HR 0.55) compared to the hormone receptor-positive subgroup (HR 0.72) 4

Common Pitfalls and Caveats

• Avoid using endocrine therapy alone in HR+HER2+ MBC patients, as PFS is significantly shorter compared to combination approaches 1, 2

• Do not use combined endocrine therapy and chemotherapy simultaneously, as this is not recommended in guidelines 1

• When using HER2-targeted therapy plus endocrine therapy without chemotherapy, careful patient selection is crucial as this approach is not appropriate for patients with aggressive or symptomatic disease 1, 3

• For patients with disease limited to non-visceral metastasis, the benefit of HER2-targeted therapy may be less pronounced (HR=1.11 in CLEOPATRA trial) 4