Evidence Matters

Aromatase Inhibitors and Breast Cancer Prevention: Does Anastrozole Continue to Reduce Risk Following Treatment Completion?

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

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

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

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

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