What is the first line systemic therapy for a patient with newly diagnosed HER2 (human epidermal growth factor receptor 2) positive metastatic breast cancer and brain metastases?

First-Line Systemic Therapy for HER2-Positive Metastatic Breast Cancer with Brain Metastases

For newly diagnosed HER2-positive metastatic breast cancer with brain metastases, the first-line systemic therapy is trastuzumab plus pertuzumab plus a taxane (docetaxel or paclitaxel), which remains the standard of care regardless of the presence of brain metastases. 1

Standard First-Line Regimen

The combination of trastuzumab, pertuzumab, and a taxane should be offered as first-line therapy for at least 6 cycles, followed by maintenance with trastuzumab and pertuzumab (with or without endocrine therapy if hormone receptor-positive). 1 This recommendation is based on:

• ESMO guidelines (2025) designate this triplet as the preferred first-line therapy with the highest evidence grade (MCBS 1A) for patients who are candidates for chemotherapy, irrespective of brain metastases status. 1
• ASCO guidelines (2022) recommend offering HER2-targeted therapy according to standard algorithms for HER2-positive metastatic breast cancer, even in the presence of brain metastases. 1
• This regimen demonstrated superior outcomes in the CLEOPATRA and PERUSE trials, establishing it as the foundation of first-line therapy. 1

Critical Considerations for Brain Metastases

When Standard First-Line Therapy Applies

• Patients with asymptomatic or stable brain metastases should receive standard first-line trastuzumab-pertuzumab-taxane therapy. 1
• Patients whose systemic disease is progressive at the time of brain metastasis diagnosis should follow standard HER2-positive metastatic breast cancer treatment algorithms. 1
• The presence of brain metastases alone does not change the first-line systemic therapy choice. 1

Important Caveats About CNS-Penetrant Agents

While tucatinib plus trastuzumab plus capecitabine (TTC) demonstrates superior intracranial activity with median intracranial PFS of 9.9 months versus 4.2 months (HR 0.32, P<0.00001) 2, 3, this regimen is:

• Reserved for second-line or later therapy after progression on trastuzumab-pertuzumab-based treatment. 2, 4, 3
• Specifically indicated for patients who have received prior HER2-directed therapy including trastuzumab, pertuzumab, and T-DM1. 3
• Not appropriate as first-line therapy in treatment-naive patients, despite its excellent CNS penetration. 4, 5

Similarly, trastuzumab deruxtecan (T-DXd) achieved a pooled ORR of 64% in patients with brain metastases 6, but is:

• Preferentially used in second-line after trastuzumab-pertuzumab-taxane progression. 1, 7
• Not the standard first-line choice for newly diagnosed metastatic disease. 4, 5

Treatment Algorithm for Newly Diagnosed Patients

Step 1: Assess Local Therapy Needs

• Patients with 1-4 brain metastases should be considered for stereotactic radiosurgery (SRS) prior to or concurrent with systemic therapy. 4
• Patients with symptomatic brain metastases or significant mass effect require local therapy (surgery or radiation) before or alongside systemic treatment. 1
• Patients with asymptomatic, small brain metastases (<2-3 cm) may proceed directly to systemic therapy with close monitoring. 1

Step 2: Initiate First-Line Systemic Therapy

• Trastuzumab loading dose: 8 mg/kg IV on Day 1 of Cycle 1, then 6 mg/kg IV every 21 days (or 600 mg subcutaneously every 21 days). 3
• Pertuzumab loading dose: 840 mg IV on Day 1 of Cycle 1, then 420 mg IV every 21 days. 1
• Taxane: Docetaxel or paclitaxel for at least 6 cycles. 1

Step 3: Maintenance Therapy

• Continue trastuzumab plus pertuzumab indefinitely until progression or unacceptable toxicity. 1
• Add endocrine therapy to trastuzumab-pertuzumab maintenance if hormone receptor-positive (ESMO MCBS 1A). 1

Step 4: Monitoring

• Brain MRI every 2-4 months (initially every 6 weeks for first 24 weeks, then every 9 weeks) to detect intracranial progression. 4, 3
• Systemic imaging per standard protocols. 3

Common Pitfalls to Avoid

• Do not use tucatinib-based therapy as first-line treatment in newly diagnosed patients, even with brain metastases—it is reserved for second-line or later after progression on trastuzumab-pertuzumab. 4, 3, 5
• Do not withhold standard first-line therapy due to presence of brain metastases—trastuzumab-pertuzumab-taxane remains appropriate. 1
• Do not use T-DM1 as first-line therapy—while it showed OS benefit (HR 0.38, P=0.008) in patients with baseline CNS metastases, it had no PFS benefit (HR 1.00) and is inferior to standard first-line therapy. 1, 4
• Do not delay local therapy indefinitely in patients with symptomatic or large (>3-4 cm) brain metastases—these require prompt radiotherapy or surgical intervention. 1

Special Scenarios

Patients with Contraindications to Taxanes

• Use trastuzumab plus pertuzumab without chemotherapy (ESMO MCBS 2B). 1
• Add endocrine therapy if hormone receptor-positive. 1

Patients with Recent Adjuvant Therapy

• If metastatic recurrence occurs ≥12 months after completing adjuvant trastuzumab (without pertuzumab), proceed with standard first-line trastuzumab-pertuzumab-taxane. 1
• If recurrence occurs within 6-12 months of adjuvant trastuzumab-pertuzumab, consider moving directly to second-line therapy (T-DXd preferred). 1
• If recurrence occurs <6 months after adjuvant trastuzumab-pertuzumab, treat according to second-line recommendations. 1