PRIME II Trial

Breast-Conserving Surgery with or without Irradiation in Early Breast Cancer

Kunkler et al., New England Journal of Medicine 2023

Background

• Whole breast radiotherapy (WBRT) after breast-conserving surgery (BCS) reduces local recurrence
• Benefit may be less pronounced in older women with low-risk disease
• Previous studies (e.g., CALGB 9343) suggested omission of RT in select patients ≥70 years
• PRIME II investigates RT omission in a broader age group (≥65 years)

Study Objective

To determine whether whole breast radiotherapy could be omitted in older women with low-risk early breast cancer treated with breast-conserving surgery and adjuvant endocrine therapy

Study Design

• Phase 3 randomized controlled trial
• 1326 women aged ≥65 years with early breast cancer
• Randomized 1:1 to:
  • Whole breast radiotherapy (40-50 Gy)
  • No radiotherapy
• All patients received adjuvant endocrine therapy

Patient Population

Key Inclusion Criteria:

• Age ≥65 years
• Hormone receptor-positive
• Node-negative
• T1-T2 tumors ≤3 cm
• Clear excision margins (≥1 mm)

Key Exclusion Criteria:

• High-grade tumors
• Lymphovascular invasion

Demographic and Clinical Characteristics

Methods

• Primary endpoint: Ipsilateral breast tumor recurrence (IBTR)
• Secondary endpoints: Regional recurrence, contralateral breast cancer, distant metastases, disease-free survival, overall survival
• Median follow-up: 9.1 years
• Statistical analysis: Kaplan-Meier estimates, hazard ratios with 95% CIs

Methods: Detailed

• Randomization: 1:1 ratio using computerized randomization service
• Stratification: By radiotherapy treatment centre
• Radiotherapy:
  • Dose: 40 to 50 Gy in total
  • Fractionation: 2.66 to 2.00 Gy per fraction
  • Duration: 3 to 5 weeks
  • Optional boost: 10 to 15 Gy (electrons) or 20 Gy (iridium implant)
• Endocrine therapy: Tamoxifen 20 mg daily for 5 years (recommended)
• Follow-up: Annual clinical visits for at least 5 years, then clinic visits or telephone calls
• Mammography: Annual for both breasts (recommended)

Kaplan-Meier Curve: Local Breast Cancer Recurrence-free Survival

Kaplan-Meier Curve: Overall Survival

Kaplan-Meier Curve: Breast Cancer-Specific Survival

Kaplan-Meier Curve: Distant Recurrence-free Survival

Results: IBTR

Results: Secondary Outcomes

Results: Overall Survival

Subgroup Analysis: Age

Key Findings

• Omission of RT associated with increased IBTR (HR 10.4, 95% CI 4.1-26.1)
• No significant difference in overall survival (80.8% vs 80.7% at 10 years)
• No significant difference in distant recurrence, regional recurrence, or breast cancer-specific survival
• Lower IBTR rates in both groups compared to historical data

Discussion: Context with Other Trials

• CALGB 9343 (≥70 years): Similar findings, but in an older population
• BASO II: Supported omission of RT in select patients
• PRIME II extends findings to a broader age group (≥65 years)
• Consistent with trend towards de-escalation of treatment in low-risk older patients

Strengths and Limitations

• Strengths:
  • Large sample size
  • Long-term follow-up (median 9.1 years)
  • Multicenter design
• Limitations:
  • Open-label design
  • Limited data on very long-term outcomes (>10 years)
  • Evolving landscape of endocrine therapy

Clinical Implications

• Supports omission of RT in select older patients with low-risk breast cancer
• Emphasizes importance of shared decision-making
• Potential for reduced treatment burden and improved quality of life
• Highlights need for careful patient selection

Future Directions

• Refining patient selection criteria
• Investigating biomarkers for recurrence risk
• Exploring partial breast irradiation in this population
• Longer-term follow-up studies

Conclusions

• Omission of RT associated with increased IBTR but no difference in overall survival
• Absolute increase in IBTR at 10 years: 9.5% vs. 0.9%
• Consider omitting RT in carefully selected older patients with low-risk breast cancer
• Importance of individualized treatment decisions
• Further research needed on very long-term outcomes and patient selection