When is upfront surgery recommended in HER2 (Human Epidermal growth factor Receptor 2)-enriched breast cancer?

Upfront Surgery in HER2-Enriched Breast Cancer

Upfront surgery is recommended for HER2-positive breast cancer patients with stage I T1a/b N0 disease, while neoadjuvant systemic therapy is preferred for clinical stage II-III disease. 1, 2

Patient Selection for Upfront Surgery

Recommended for upfront surgery:

• Stage I T1a/b N0 HER2-positive disease 1
• Small tumors with clinically negative nodes
• Patients with lower risk features

Risk stratification factors to consider:

1. Tumor size:

   • T1a/b (≤1 cm): Upfront surgery preferred
   • T1c (>1 cm but ≤2 cm): Consider individual risk factors
   • T2 or larger (>2 cm): Neoadjuvant therapy preferred 3, 2

2. Nodal status:

   • Clinically node-negative (cN0): May consider upfront surgery for smaller tumors
   • Any nodal involvement (≥cN1): Neoadjuvant therapy preferred 3, 2

3. Additional factors favoring upfront surgery:

   • Older age (>50 years) 4, 5
   • Absence of lymphovascular invasion 5
   • Unifocal disease 5
   • Normal axillary ultrasound 5

Caution Points for Upfront Surgery

Upfront surgery should be carefully considered in patients with cT1cN0 disease as they have a 32.5% likelihood of pathologic nodal metastases 5. This risk increases to 47.1% in patients under 50 years of age 5.

Risk factors for nodal involvement in early HER2-positive disease include:

• Age under 50 years 4, 5
• Triple-positive status (ER+/PR+/HER2+) 4
• Lymphovascular invasion (strongest predictor with 73.3% vs 22.6% risk) 5
• Multifocal/multicentric disease 5
• Abnormal lymph nodes on axillary ultrasound 5

Neoadjuvant Approach Benefits

For patients with higher-risk features, neoadjuvant therapy offers several advantages:

• Downstaging of tumor, potentially reducing surgical extent 2
• In vivo assessment of treatment efficacy 2
• Improved breast conservation rates 2
• Risk stratification to guide subsequent adjuvant therapy 2
• Dual HER2 blockade (trastuzumab + pertuzumab) achieves higher pathologic complete response rates (50-70%) 2

Treatment Algorithm

1. For stage I T1a/b N0 HER2-positive disease:

   • Proceed with upfront surgery
   • Follow with appropriate adjuvant therapy based on final pathology

2. For cT1c N0 disease:

   • Assess risk factors: age, lymphovascular invasion, multifocality
   • If low risk (>50 years, no LVI, unifocal): Consider upfront surgery
   • If high risk (<50 years, LVI present, multifocal): Consider neoadjuvant therapy

3. For stage II-III (≥cT2 or ≥cN1):

   • Neoadjuvant chemotherapy + dual HER2 blockade is preferred 3, 2

Common Pitfalls

• Underestimating nodal involvement in cT1cN0 disease, particularly in younger patients
• Failing to recognize that triple-positive tumors have higher rates of nodal involvement (24.8%) compared to HER2-enriched (19.6%) 4
• Not considering age as a significant factor (younger patients have higher rates of nodal involvement)
• Overlooking the importance of lymphovascular invasion in predicting nodal status

By carefully assessing these risk factors, clinicians can make more informed decisions about the optimal treatment sequence for patients with HER2-positive breast cancer.