February 2020: Long-term follow-up results of the IBIS-II trial

In the randomized IBIS-II trial, postmenopausal women at increased risk of developing breast cancer were randomly assigned to either anastrozole or placebo for 5 years. After treatment completion, women were followed on a yearly basis to collect data on breast cancer incidence, death, other cancers, and major adverse events (cardiovascular events and fractures). The primary outcome was all breast cancer. Between February 2003 and January 2012, a total of 3864 women were randomized (1920 to anastrozole and 1944 to placebo) and included in this analysis. 3704 (95.9%) were still at risk of developing breast cancer after the 5-year treatment period (1866 anastrozole, 1838 placebo) and follow-up is ongoing.

The first analysis after a median follow-up of 60 months (IQR 36-85) demonstrated a significant reduction in incidence of 53% for all breast cancer (including ductal carcinoma in situ) (Cuzick et al. Lancet Oncol. 2015). Median follow-up for this updated analysis was 131 months (IQR 105–156). Median age at study entry was 59.4 years (IQR 55.0-63.4), 1893 patients (47.0%) had used hormone replacement therapy before entering the trial, and 2631 (68.1%) had a BMI of more than 25kg/m². 250 breast cancers were reported (85 anastrozole vs 165 placebo) with a statistically significant reduction of 49% for all breast cancer with anastrozole (hazard ratio [HR] 0.51 [95%CI 0.39-0.66], p<0.001). The reduction was larger in the first 5 years (35 vs 89, HR 0.39 [95%CI 0.27-0.58], p<0.001), but still significant after 5 years (50 vs 76 new cases, HR 0.64 [95%CI 0.45-0.91], p=0.014). The effects in the two periods were not significantly different (p=0.087). Invasive estrogen receptor-positive breast cancer was reduced by 54% (HR 0.46 [95%CI 0.33-0.65], p<0.001), with a continued significant effect in the period after treatment. A reduction of 59% was observed in ductal carcinoma in situ (HR 0.41 [95%CI 0.22-0.79], p=0.008), especially in estrogen receptor-positive patients (HR 0.22 [95%CI 0.78-0.65], p<0.001). Overall, there was no significant difference between anastrozole and placebo arms seen for deaths (69 vs 70, HR 0.96 [95%CI 0.69-1.34], p=0.82) or for breast cancer (2 anastrozole vs 3 placebo). A significant decrease in non-breast cancers was observed in anastrozole arm (147 vs 200, odds ratio 0.72 [95%CI 0.57-0.91], p=0.0042), owing primarily to non-melanoma skin cancer. No excess of fractures or cardiovascular disease was reported. In conclusion, these updated results show a continuing long-term effect of 5 years of anastrozole treatment in preventing breast cancer in high-risk postmenopausal women. No new major adverse events were identified. Further follow-up is needed to assess the effect on breast cancer mortality.

Cuzick J, Sestak I, Forbes JF, Dowsett M, Cawthorn S, Mansel RE, Loibl S, Bonanni B, Evans DG, Howell A; IBIS-II investigators. Use of anastrozole for breast cancer prevention (IBIS-II): long-term results of a randomised controlled trial. Lancet. 2020; 395:117–122.

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