What treatment approach would be recommended for a middle-aged woman with newly diagnosed T1/T2 N0 breast cancer, who is estrogen receptor (ER) positive, progesterone receptor (PR) positive, and human epidermal growth factor receptor 2 (HER2) positive?

Treatment for ER/PR-Positive, HER2-Positive Early Breast Cancer

For a middle-aged woman with T1/T2 N0 ER/PR-positive, HER2-positive breast cancer, the standard treatment should include breast-conserving surgery or mastectomy, followed by adjuvant chemotherapy with dual HER2-targeted therapy (trastuzumab plus pertuzumab for high-risk features), radiation therapy, and endocrine therapy for 5-10 years. 1

Surgical Approach

• Breast-conserving surgery with sentinel lymph node biopsy is the preferred surgical approach for T1/T2 N0 disease, offering equivalent survival outcomes to mastectomy. 2
• Mastectomy remains an option based on patient preference, tumor location, or contraindications to radiation therapy. 1
• Sentinel lymph node biopsy is standard for axillary staging in clinically node-negative disease. 1, 2

Systemic Chemotherapy

• Adjuvant chemotherapy is indicated for HER2-positive breast cancer regardless of tumor size, given the aggressive biology of HER2-positive disease. 1
• Standard chemotherapy regimens include anthracycline and taxane-based combinations (such as doxorubicin-cyclophosphamide followed by paclitaxel or docetaxel). 1, 3
• Chemotherapy should be administered sequentially with endocrine therapy following chemotherapy completion. 1

HER2-Targeted Therapy

• All patients with HER2-positive breast cancer should receive trastuzumab for a total duration of 1 year (52 weeks), which can be administered concurrently with taxane chemotherapy and continued as monotherapy. 1, 3
• Dual HER2 blockade with trastuzumab plus pertuzumab should be considered for high-risk patients, defined as node-positive OR estrogen receptor-negative disease. 1, 4
• For T1/T2 N0 ER-positive disease, single-agent trastuzumab is standard, though dual blockade may be considered if other high-risk features are present. 1
• Trastuzumab may be administered concurrently with radiation therapy and endocrine therapy. 1

Important Caveat on HER2-Targeted Therapy

• The benefit of HER2-targeted therapy is somewhat attenuated in hormone receptor-positive compared to hormone receptor-negative HER2-positive disease, but remains clinically significant and should still be administered. 4, 5
• In the CLEOPATRA trial, the hazard ratio for progression-free survival was 0.72 in hormone receptor-positive patients versus 0.55 in hormone receptor-negative patients, but both showed significant benefit. 4

Radiation Therapy

• Whole breast radiation therapy is mandatory following breast-conserving surgery to reduce local recurrence risk. 2
• Radiation should be initiated after completion of chemotherapy. 1, 3
• Post-mastectomy radiation is not typically indicated for T1/T2 N0 disease unless additional high-risk features are present. 1

Endocrine Therapy

• Adjuvant endocrine therapy for 5-10 years is essential for all hormone receptor-positive breast cancers, regardless of HER2 status. 1, 2
• For premenopausal women with higher-risk features (such as requiring chemotherapy), ovarian function suppression combined with an aromatase inhibitor should be strongly considered. 1, 6
• For postmenopausal women, aromatase inhibitors are preferred over tamoxifen for higher-risk disease. 1
• Endocrine therapy should be administered sequentially after chemotherapy completion, not concurrently. 1
• Extended endocrine therapy beyond 5 years should be considered based on individual risk assessment. 1

Treatment Sequencing

The optimal treatment sequence is:

1. Surgery (breast-conserving surgery or mastectomy with sentinel lymph node biopsy) 2
2. Adjuvant chemotherapy (anthracycline and taxane-based regimen) with concurrent trastuzumab (± pertuzumab for high-risk features) starting with the taxane portion 1, 3
3. Continuation of trastuzumab to complete 1 year total 1
4. Radiation therapy (if breast-conserving surgery performed) 2
5. Endocrine therapy for 5-10 years 1

Alternative: Neoadjuvant Approach

• For tumors >2 cm, neoadjuvant chemotherapy with HER2-targeted therapy is preferred over adjuvant treatment, as it allows for assessment of pathological response and potential surgical downstaging. 1
• Neoadjuvant regimens should include trastuzumab, and pertuzumab may be added for T2 or greater tumors. 1, 4
• If residual invasive disease is present after neoadjuvant therapy, adjuvant trastuzumab emtansine (T-DM1) should replace standard trastuzumab where available. 1

Critical Considerations

• The presence of hormone receptor positivity does NOT negate the need for HER2-targeted therapy—both pathways must be addressed. 1, 7
• There is bidirectional cross-talk between ER and HER2 pathways that can lead to endocrine resistance, making dual targeting essential. 7
• Cardiac monitoring is essential during trastuzumab therapy, particularly when combined with anthracyclines, though sequential administration reduces cardiotoxicity risk. 3
• The combination of chemotherapy plus anti-HER2 therapy has demonstrated survival advantages in HER2-positive disease that outweigh the benefits of endocrine therapy alone, even in hormone receptor-positive patients. 1