What is the recommended treatment for a patient with hormone-receptor–positive, HER2-positive advanced breast cancer?

Treatment for Hormone-Receptor–Positive, HER2-Positive Advanced Breast Cancer

For patients with hormone-receptor–positive, HER2-positive advanced breast cancer, first-line treatment should be trastuzumab plus pertuzumab plus a taxane, NOT palbociclib, as HER2-targeted therapy with chemotherapy provides survival benefit and is the established standard of care. 1

First-Line Treatment Algorithm

Standard First-Line Therapy (Preferred)

• Administer trastuzumab + pertuzumab + taxane as first-line treatment for all patients with HER2-positive advanced breast cancer, regardless of hormone receptor status, unless contraindications to taxanes exist. 1
• This regimen is supported by high-quality evidence with strong recommendation strength from ASCO guidelines. 1
• Continue chemotherapy for approximately 4-6 months or until maximal response, depending on toxicity and absence of progression. 1
• After stopping chemotherapy, continue HER2-targeted therapy (trastuzumab + pertuzumab) until disease progression or unacceptable toxicity. 1

Alternative for Highly Selected Patients Only

• Endocrine therapy alone OR endocrine therapy plus HER2-targeted therapy may be considered only for highly selected patients with: 1
  • Low disease burden
  • No visceral crisis
  • Long disease-free interval
  • Significant comorbidities precluding chemotherapy
• The addition of HER2-targeted therapy to first-line aromatase inhibitors should be offered to patients with HR-positive, HER2-positive metastatic breast cancer in whom chemotherapy is not immediately indicated. 1

Role of Palbociclib in This Population

Emerging Evidence for Maintenance Therapy

• Palbociclib added to maintenance HER2-targeted and endocrine therapies after initial chemotherapy plus HER2-targeted therapy significantly improves progression-free survival (median 44.3 months vs. 29.1 months; HR 0.75; 95% CI 0.59-0.96; P=0.02). 2
• This represents a maintenance strategy after completing 4-8 cycles of chemotherapy plus HER2-targeted therapy, not a replacement for first-line chemotherapy. 2
• Grade 3-4 adverse events, predominantly neutropenia, occurred in 79.7% of patients receiving palbociclib versus 30.6% with standard therapy. 2

When Palbociclib Should NOT Be Used

• Palbociclib should NOT replace first-line trastuzumab + pertuzumab + taxane, as this would compromise survival outcomes demonstrated with HER2-targeted chemotherapy combinations. 1
• Palbociclib is FDA-approved and guideline-recommended for HR-positive, HER2-negative advanced breast cancer, not HER2-positive disease. 1, 3
• The ASCO 2016 guideline specifically recommends palbociclib for HER2-negative disease only. 1

Treatment Sequencing After Progression

Second-Line Therapy

• Trastuzumab emtansine (T-DM1) or trastuzumab deruxtecan (T-DXd, preferred if available) should be offered after progression on first-line HER2-targeted therapy. 1, 4
• T-DXd demonstrates superior progression-free survival compared to T-DM1 (median 28.8 months vs. 6.8 months; HR 0.28; P<0.001). 4

Third-Line and Beyond

• Continue HER2-targeted therapy beyond progression, as multiple studies demonstrate benefit from continuing HER2 blockade. 4
• Options include lapatinib plus capecitabine, tucatinib + trastuzumab + capecitabine, or lapatinib plus trastuzumab. 1, 4

Critical Pitfalls to Avoid

• Do not use palbociclib as first-line therapy in place of chemotherapy plus HER2-targeted therapy, as this would deviate from evidence-based guidelines and compromise survival outcomes. 1
• Do not stop HER2-targeted therapy when chemotherapy is discontinued—continue trastuzumab and pertuzumab until progression. 1
• Do not combine trastuzumab with anthracyclines concurrently, as this increases cardiac dysfunction risk (27% vs. 8% with sequential therapy). 5
• Monitor left ventricular ejection fraction (LVEF) prior to treatment and every 3 months during HER2-targeted therapy. 5

Endocrine Therapy Integration

• Add endocrine therapy (aromatase inhibitor or fulvestrant) concurrently with HER2-targeted maintenance therapy after completing chemotherapy for hormone-receptor–positive disease. 1, 5
• For premenopausal patients, add ovarian suppression (LHRH agonist) to aromatase inhibitor therapy. 1, 5
• Endocrine therapy can be given concurrently with trastuzumab/pertuzumab but should be given sequentially after chemotherapy completion, not during active chemotherapy. 5