What is the recommended treatment regimen for HER2 (Human Epidermal growth factor Receptor 2) positive breast cancer based on the Aphinity trial?

APHINITY Trial in HER2-Positive Breast Cancer

For patients with HER2-positive early breast cancer who have node-positive disease, adding pertuzumab to trastuzumab plus chemotherapy for one year of adjuvant therapy significantly reduces recurrence risk and should be strongly considered based on the APHINITY trial results. 1

Key APHINITY Trial Findings

The APHINITY trial demonstrated that adding pertuzumab to standard trastuzumab-based adjuvant therapy provides meaningful clinical benefit, particularly in higher-risk populations:

Overall Population Results

• After 6 years of follow-up, pertuzumab plus trastuzumab reduced the relative risk of recurrence by 24% compared to trastuzumab alone (HR 0.76; 95% CI 0.64-0.91). 1
• The 6-year invasive disease-free survival (IDFS) improved from 87.8% with trastuzumab alone to 90.6% with dual HER2 blockade. 1
• At 3 years, IDFS was 94.1% with pertuzumab versus 93.2% with placebo (HR 0.81; 95% CI 0.66-1.00; P=0.045). 2

Node-Positive Disease (Where Benefit is Strongest)

• In patients with node-positive disease, the absolute benefit was 4.5% at 6 years, with IDFS of 87.9% versus 83.4% (HR 0.72; 95% CI 0.59-0.87). 1
• At 3 years, node-positive patients had IDFS of 92.0% with pertuzumab versus 90.2% with placebo (HR 0.77; 95% CI 0.62-0.96; P=0.02). 2
• This represents a 23% relative reduction in recurrence risk for node-positive patients. 1

Node-Negative Disease (Limited Benefit)

• In node-negative disease, pertuzumab showed no statistically significant benefit (HR 1.02; 95% CI 0.69-1.53). 1
• The 3-year IDFS was actually slightly higher in the placebo group: 98.4% versus 97.5% with pertuzumab (HR 1.13; 95% CI 0.68-1.86; P=0.64). 2

Current Guideline Recommendations

NCCN 2024 Guidelines Position

• The NCCN panel recommends up to 1 year of HER2-targeted therapy with trastuzumab, and based on updated APHINITY data, the addition of pertuzumab may be considered with trastuzumab in those with node-positive disease. 1
• For patients who were node-positive at initial staging and received neoadjuvant therapy, trastuzumab plus pertuzumab is Category 1 recommendation for completing up to 1 year of HER2-directed therapy. 1
• The guidelines explicitly note that updated APHINITY results with 8.4 years median follow-up have confirmed the benefit of adding pertuzumab to trastuzumab plus chemotherapy in preventing recurrences. 1

Treatment Regimen Options

The NCCN panel includes several chemotherapy backbone options for use with dual HER2 blockade:

• Anthracycline-based regimens: AC (doxorubicin/cyclophosphamide) followed by docetaxel plus trastuzumab and pertuzumab. 1
• Non-anthracycline regimens: Paclitaxel/carboplatin plus trastuzumab and pertuzumab (based on TRAIN-2 data showing similar efficacy with less toxicity). 1
• Duration: Complete up to 1 year (18 cycles every 3 weeks) of HER2-targeted therapy. 1

Hormone Receptor Status Considerations

HR-Positive Disease

• With longer follow-up, pertuzumab's benefit became apparent in HR-positive disease: 6-year IDFS HR 0.73 (95% CI 0.59-0.92). 1
• These patients should receive adjuvant endocrine therapy (Category 1) in addition to HER2-directed therapy. 1

HR-Negative Disease

• In HR-negative disease, the between-group difference favored pertuzumab but was not statistically significant (HR 0.83; 95% CI 0.63-1.10). 1
• However, this subgroup still benefits from dual HER2 blockade, particularly when node-positive. 1

Safety Profile

Cardiac Monitoring

• Heart failure, cardiac death, and cardiac dysfunction were infrequent in both treatment groups. 2
• No primary cardiac events occurred in Chinese patients in either arm of APHINITY. 3
• LVEF should be evaluated prior to initiation and every 3 months during therapy per FDA recommendations. 1
• Anthracycline and taxane-based regimens with HER2-targeted agents carry increased cardiac toxicity risk. 1

Gastrointestinal Toxicity

• Diarrhea of grade 3 or higher occurred in 9.8% with pertuzumab versus 3.7% with placebo, occurring almost exclusively during chemotherapy. 2
• The incidence of diarrhea was higher in the pertuzumab arm across all populations studied. 3
• Most diarrhea cases were not severe and manageable. 4

Clinical Decision Algorithm

For HER2-positive early breast cancer patients:

1. Node-positive disease: Add pertuzumab to trastuzumab plus chemotherapy for 1 year (strong recommendation based on 4.5% absolute IDFS benefit at 6 years). 1

2. Node-negative disease with high-risk features (tumor >1 cm with grade 3, HR-negative, or age <35): Consider pertuzumab, though benefit is less clear; trastuzumab alone is reasonable. 1, 2

3. Node-negative disease without high-risk features: Trastuzumab plus chemotherapy alone is appropriate; pertuzumab adds no demonstrated benefit. 1, 2

4. Post-neoadjuvant setting: If node-positive at initial staging, use trastuzumab plus pertuzumab to complete 1 year of therapy (Category 1). 1

Important Caveats

• The APHINITY trial enrolled patients with node-positive disease or high-risk node-negative disease; extrapolation to very low-risk populations is not supported. 2
• Cost-effectiveness analyses suggest pertuzumab may not be cost-effective in all eligible patients, particularly those with node-negative disease. 4
• The survival benefit (overall survival) has not yet reached statistical significance (HR 0.85; 95% CI 0.67-1.07, P=0.170), though fewer deaths occurred in the pertuzumab arm (5.2% vs 6.1%). 1
• Data remain immature with only 43% of events required for final OS analysis; final results are pending. 1