What is the recommended treatment for a patient with estrogen receptor (ER) negative, progesterone receptor (PR) negative, and human epidermal growth factor receptor 2 (HER2) positive breast cancer?

Treatment of ER-Negative, PR-Negative, HER2-Positive Breast Cancer

For ER-negative, PR-negative, HER2-positive breast cancer, the standard treatment is HER2-targeted therapy combined with chemotherapy—specifically trastuzumab plus pertuzumab plus a taxane as first-line therapy—and endocrine therapy has no role because hormone receptors are absent. 1

First-Line Treatment for Metastatic Disease

The combination of trastuzumab, pertuzumab, and a taxane represents the evidence-based standard for first-line treatment unless contraindications to taxanes exist. 2, 1

• Chemotherapy should continue for approximately 4-6 months or until maximal response, while trastuzumab and pertuzumab must continue until disease progression or unacceptable toxicity. 2, 1
• The taxane component is typically docetaxel 75-100 mg/m² every 3 weeks or weekly paclitaxel 80 mg/m² for 12 weeks. 3
• Do not discontinue HER2-targeted therapy when chemotherapy is completed—this is a critical error that compromises outcomes. 2, 3

Timing Considerations After Adjuvant Therapy

• If the patient completed trastuzumab-based adjuvant treatment more than 12 months before recurrence, follow first-line HER2-targeted therapy recommendations (trastuzumab + pertuzumab + taxane). 2, 1
• If the patient completed trastuzumab-based adjuvant treatment 12 months or less before recurrence, proceed directly to second-line HER2-targeted therapy recommendations. 2, 1

Second-Line Treatment After Progression

Trastuzumab deruxtecan (T-DXd) is the preferred second-line agent based on the most recent evidence. 2

• If T-DXd is unavailable, trastuzumab emtansine (T-DM1) should be offered as the alternative second-line treatment. 2, 1, 4
• T-DM1 is dosed at 3.6 mg/kg intravenously every 3 weeks until disease progression or unacceptable toxicity. 4

Third-Line and Beyond

For patients with disease progression after second-line therapy, tucatinib plus trastuzumab plus capecitabine is the preferred third-line regimen, particularly for patients with CNS involvement. 1, 5, 6

• If the patient has not received T-DM1, it should be offered at this stage. 2
• If the patient has not received pertuzumab, it may be considered, though evidence for this approach is limited. 2
• Other options include lapatinib plus capecitabine, other chemotherapy combinations with trastuzumab, or lapatinib plus trastuzumab. 2

Early-Stage Disease (Neoadjuvant/Adjuvant Setting)

For locally advanced or high-risk early-stage disease, neoadjuvant chemotherapy with trastuzumab, pertuzumab, and a taxane for 3-6 cycles, followed by surgery, is the standard approach. 1, 3

• Postmastectomy radiation therapy is mandatory for locally advanced presentations (such as T3N1 disease) and can be given concurrently with HER2-targeted therapy. 1, 3
• Trastuzumab plus pertuzumab should be continued to complete one year of HER2-targeted therapy from the start of neoadjuvant treatment. 1, 3
• For patients with residual disease after neoadjuvant therapy, switching to trastuzumab deruxtecan as adjuvant therapy is recommended, or continuing trastuzumab plus pertuzumab if trastuzumab deruxtecan is unavailable. 3

Why Endocrine Therapy Is NOT Recommended

ER-negative/PR-negative/HER2-positive breast cancer lacks hormone receptor expression, making endocrine therapy ineffective and inappropriate—treatment must focus exclusively on HER2-targeted therapy combined with chemotherapy. 1

• This is a fundamental distinction from ER-positive/HER2-positive disease, where endocrine therapy plays a role. 2
• Even in patients with bone-only or asymptomatic visceral metastases, endocrine therapy alone is not appropriate for ER-negative/PR-negative disease. 7, 1

Critical Monitoring and Safety Considerations

Cardiac Monitoring

• Assess left ventricular ejection fraction (LVEF) prior to initiation of trastuzumab and at regular intervals during treatment. 8
• Discontinue trastuzumab in patients receiving adjuvant therapy and withhold in patients with metastatic disease for clinically significant decrease in LVEF. 8
• Trastuzumab given in combination with an anthracycline is associated with significant cardiac toxicity. 7

Hepatotoxicity with T-DM1

• Monitor hepatic function prior to initiation and prior to each dose of T-DM1, as hepatotoxicity, liver failure, and death have occurred. 4

Pulmonary Toxicity

• Monitor for dyspnea or signs of interstitial lung disease or pneumonitis, which can be serious and fatal with trastuzumab products. 8, 4

Thrombocytopenia

• Monitor platelet counts prior to each T-DM1 dose and institute dose modifications as appropriate. 4

Common Pitfalls to Avoid

• Omitting pertuzumab from the initial regimen—the combination of trastuzumab plus pertuzumab plus taxane is the evidence-based standard with high-quality evidence. 2, 1, 3
• Stopping HER2-targeted therapy when chemotherapy is completed—HER2-targeted therapy must continue until disease progression or unacceptable toxicity. 2, 1, 3
• Failing to re-biopsy accessible metastatic lesions to confirm HER2 status, as receptor status can change during disease progression. 2
• Omitting radiation therapy in locally advanced disease (T3N1)—postmastectomy radiation is mandatory for locoregional control. 3
• Attempting endocrine therapy in ER-negative/PR-negative disease—this is ineffective and delays appropriate HER2-targeted treatment. 1