What is the treatment plan for a patient with Her2 (Human Epidermal growth factor Receptor 2) positive, Estrogen Receptor (ER) positive, and Progesterone Receptor (PR) negative breast cancer?

Treatment of HER2+, ER+, PR- Breast Cancer

For HER2-positive, estrogen receptor-positive, progesterone receptor-negative breast cancer, you should treat with dual HER2-targeted therapy (trastuzumab plus pertuzumab) combined with chemotherapy as first-line treatment, followed by maintenance HER2-targeted therapy with the addition of endocrine therapy. 1, 2

First-Line Treatment Approach

Standard Regimen

• Administer trastuzumab plus pertuzumab plus a taxane as the first-line standard of care for HER2-positive advanced/metastatic disease, unless contraindications to taxanes exist 1, 2
• Continue chemotherapy for approximately 4-6 months or until maximal response, depending on toxicity and absence of progression 1, 2
• After completing chemotherapy, continue HER2-targeted therapy (trastuzumab plus pertuzumab) until disease progression or unacceptable toxicity 1, 2

Hormone Receptor-Positive Considerations

Since this tumor is ER-positive (despite being PR-negative), you have three evidence-based options, listed in order of strength 1, 2:

1. HER2-targeted therapy plus chemotherapy (strongest recommendation - this is what most patients should receive) 1, 2
2. Endocrine therapy plus trastuzumab or lapatinib (for selected cases only) 1, 2
3. Endocrine therapy alone (only in special circumstances: low disease burden, significant comorbidities like congestive heart failure contraindicating HER2-targeted therapy, or long disease-free interval) 1, 2

The vast majority of patients with HER2+/ER+ disease should still receive chemotherapy plus HER2-targeted therapy as first-line treatment, even though the tumor is hormone receptor-positive 1, 2

Maintenance Phase Strategy

Adding Endocrine Therapy

• When chemotherapy is completed, add endocrine therapy to the ongoing HER2-targeted therapy (trastuzumab plus pertuzumab) 1, 2
• This approach addresses both the HER2-driven and ER-driven components of tumor growth 3, 4
• The rationale is that bidirectional crosstalk between HER2 and ER pathways can drive treatment resistance, making dual pathway blockade essential 3, 4

Endocrine Therapy Options

• For premenopausal women: ovarian suppression plus aromatase inhibitor for high-risk disease 5
• For postmenopausal women: aromatase inhibitors are preferred 5
• Duration: 5-10 years 5

Timing Based on Prior Adjuvant Therapy

If this patient previously received adjuvant trastuzumab:

• If recurrence occurred ≤12 months after completing adjuvant trastuzumab: follow second-line HER2-targeted therapy recommendations (see below) 1, 2
• If recurrence occurred >12 months after completing adjuvant trastuzumab: follow first-line recommendations (trastuzumab plus pertuzumab plus taxane) 1, 2

Second-Line Treatment (If First-Line Fails)

• Trastuzumab deruxtecan (T-DXd) is the preferred second-line agent based on the most recent evidence 2
• If T-DXd is unavailable, use trastuzumab emtansine (T-DM1) 1, 2
• Continue HER2-targeted therapy until progression, and you may add or continue endocrine therapy during this phase 1, 2

Third-Line and Beyond

• If the patient has not received T-DM1, offer it 1, 2
• If the patient has not received pertuzumab, consider adding it (though evidence is limited) 1, 2
• Other options include lapatinib plus capecitabine, other chemotherapy combinations with trastuzumab, or lapatinib plus trastuzumab 1, 2

Critical Monitoring Requirements

Cardiac Function

• Evaluate left ventricular ejection fraction (LVEF) prior to initiating HER2-targeted therapy and every 3 months during treatment 6, 5, 7, 8
• Discontinue trastuzumab/pertuzumab for confirmed clinically significant decrease in left ventricular function 7, 8
• The risk of cardiac toxicity is highest when combining HER2-targeted therapy with anthracyclines - avoid concurrent use 6, 5, 7

Infusion Reactions

• Monitor for infusion reactions during and within 24 hours of trastuzumab or pertuzumab administration 7, 8
• Interrupt infusion for dyspnea or clinically significant hypotension 7, 8
• Discontinue permanently for anaphylaxis, angioedema, or pulmonary toxicity 7, 8

Common Pitfalls to Avoid

• Do not stop HER2-targeted therapy when chemotherapy ends - continue trastuzumab and pertuzumab until disease progression 1, 2
• Do not treat with endocrine therapy alone as first-line unless there are specific contraindications to HER2-targeted therapy or chemotherapy 1, 2
• Do not assume PR-negative status negates the benefit of endocrine therapy - ER-positivity alone is sufficient indication for adding endocrine therapy to HER2-targeted maintenance 1, 2, 5
• Consider re-biopsy of accessible metastatic lesions to confirm HER2 and hormone receptor status, as receptor status can change during disease progression 2