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

Local Breast Cancer Recurrence-free Survival

Kaplan-Meier Curve: Overall Survival

Overall Survival

Kaplan-Meier Curve: Breast Cancer-Specific Survival

Breast Cancer-Specific Survival

Kaplan-Meier Curve: Distant Recurrence-free Survival

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