BACKGROUND AND PURPOSE:

• SERMs (tamoxifen and raloxifene) have been recommended to reduce risk of breast cancer in women at high risk
• Aromatase inhibitors (e.g., anastrozole) have similarly demonstrated benefit in the initial 5 years of follow-up studies
  • Anastrozole demonstrated a 58% reduction in incidence of invasive estrogen receptor-positive breast cancer and a 70% reduction in incidence of ductal carcinoma in situ
  • Usual side effects include fractures, joint-related effects, and menopausal symptoms related to anti-estrogenic effects
• Cuzick et al. (The Lancet, 2019) report
  • Long-term follow-up for the IBIS-II trial, which compared anastrozole with placebo
  • Efficacy of anastrozole for preventing breast cancer (both invasive and ductal carcinoma in situ) in the post-treatment period

METHODS:

• Randomized, double-blind, placebo-controlled trial (international)
  • International Breast Cancer Intervention Study II (IBIS-II)
  • Started in 2003
  • Postmenopausal women without breast cancer at high risk
    • 45–60 years who had a relative risk (RR) of breast cancer at least 2x as high as that in the general population
    • 60–70 years who had an RR at least 1.5x general population
    • 40–44 years who had a RR at least 4x general population
• Randomized groups
  • Anastrozole (1 mg per day, oral) for 5 years
  • Matching placebo daily for 5 years
• Study design
  • Women were randomly assigned to a group 1:1
  • After treatment completion, women were followed on a yearly basis
  • Data collection included: Breast cancer incidence | Death | Other cancers | Major adverse events (cardiovascular events and fractures)
• Primary outcome
  • All breast cancer

RESULTS:

• 3,864 women recruited
  • 1,920 women in anastrozole group | 1,944 women in placebo group
  • Median follow-up of 131 months (approx. 11 years)
• Primary outcome: 49% reduction in breast cancer observed for anastrozole
  • 85 vs 165 cases | Hazard ratio (HR) 0.51 (95% CI, 0.39 to 0.66, p<0.0001)
• The reduction was
  • Larger in the first 5 years
    • 35 vs 89 cases | HR 0.39 (95% CI, 0.27 to 0.58; p<0.0001)
  • Still significant after 5 years
    • 50 vs 76 cases | HR 0.64 (95% CI, 0.45 to 0.91; p=0.014)
    • Not significantly different vs the first 5 years (p=0.087)
• Invasive estrogen receptor-positive breast cancer
  • Reduced by 54%
  • Effect continued after 5 year treatment period
  • HR 0.46 (95% CI, 0.33 to 0.65; p<0.000)
• Ductal carcinoma in situ
  • Reduced by 59%  
  • HR 0.41 (95% CI, 0.22 to 0.79; p=0.0081)
  • Estrogen receptor-positive: HR 0.22 (95% CI, 0.78 to 0.65; p<0.0001)
• Deaths: No significant differences
  • Overall
    • 69 vs 70 cases | HR 0.96 (95% CI, 0.69 to 1.34; p=0.82)
  • Deaths due to breast cancer
    • 2 vs 3 (anastrozole vs placebo)
  • Non-breast cancer deaths: Reduced in anastrozole group, due to non-melanoma skin cancer
  • 147 vs 200 cases, odds ratio (OR) 0.72 (95% CI, 0.57 to 0.91; p=0.0042)
• Adverse events: No difference in fractures or cardiovascular disease

CONCLUSION:

• Anastrozole treatment in high-risk women leads to a reduction in breast cancer that continues into the post-treatment follow-up period
  • Initial reduction in breast cancer incidence in the first 5 years has been maintained in subsequent follow-up to 12 years
  • Greater prevention effect than tamoxifen that provides a “roughly constant 29% reduction for 20 years”
• Further follow-up will assess the effect on breast cancer mortality

Learn More – Primary Sources:

Use of anastrozole for breast cancer prevention (IBIS-II): long-term results of a randomised controlled trial

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