In an analysis from the IBIS-II prevention trial reported in The Lancet Oncology, Jack Cuzick, PhD, and colleagues found that increasing the ratio of baseline estradiol level to sex hormone–binding globulin (SHBG) was associated with an increased risk of breast cancer in high-risk postmenopausal women treated with placebo, but not in those treated with anastrozole.
Jack Cuzick, PhD
Study Details
In the double-blind trial, 3,864 women enrolled from sites in 16 countries between February 2003 and January 2012 were randomly assigned to receive anastrozole at 1 mg/d (n = 1,920) or placebo daily (n = 1,944) for 5 years. Breast cancer risk per estradiol-SHBG ratio quartile (1 = lowest, 4 = highest) was determined for the anastrozole group and the placebo group. In addition, case-control sets were derived that consisted of 72 cases and 140 controls matched for age and follow-up in the anastrozole group and 142 cases and 274 matched controls in the placebo group. A multinominal logistic regression likelihood-ratio trend test was used to assess what change in the proportion of cases was associated with a one-quartile change in estradiol-SHBG ratio, with controls used only to determine quartile cutoffs.
Key Findings
Median follow-up was 131 months (interquartile range = 106–156 months). Among all patients, breast cancer was observed in 85 patients (4.4%) in the anastrozole group and in 165 (8.5%) in the placebo group. Overall, the relative benefit of anastrozole in preventing breast cancer was 0.49 (95% confidence interval [CI] = 0.32–0.62, P < .0001).
A trend of increasing breast cancer risk with increasing estradiol-SHBG ratio was observed in the placebo group, with an increase in risk per quartile of 1.25 (95% CI = 1.08–1.45, P = .0033). No such effect was observed in the anastrozole group, with an increase in risk per quartile of 1.06 (95% CI = 0.86–1.30, P = .60).
A weaker—but significant—effect was observed for testosterone-SHBG ratio in the placebo group, with an increase in risk per quartile of 1.21 (95% CI = 1.05–1.41, P = .011). The relationship in the anastrozole group was not significant, with an increased risk per quartile of 1.18 (95% CI = 0.96–1.46, P = .11).
Among 72 breast cancer cases in the anastrozole group vs 142 cases in the placebo group derived from the case-control sets, analysis by quartile of estradiol-SHBG ratio showed a relative benefit of anastrozole in quartile 2 (19% vs 22% of cases, relative benefit = 0.55, 95% CI = 0.13–0.78), quartile 3 (29% vs 32% of cases, relative benefit = 0.54, 95% CI = 0.22–0.74), and quartile 4 (22% vs 31% of cases, relative benefit = 0.56, 95% CI = 0.23–0.76), but not in quartile 1 (25% vs 16% of cases, relative benefit = 0.18, 95% CI = –0.60 to 0.59).
The investigators concluded, “These results suggest that serum hormones should be measured more routinely and integrated into risk-management decisions. Measuring serum hormone concentrations is inexpensive and might help clinicians differentiate which women will benefit most from an aromatase inhibitor.”
Dr. Cuzick, of the Wolfson Institute of Population Health, Queen Mary University of London, is the corresponding author for The Lancet Oncology article.
Disclosure: The study was funded by Cancer Research UK, the National Health and Medical Research Council (Australia), the Breast Cancer Research Foundation, and the DaCosta Fund. For full disclosures of the study authors, visit thelancet.com.
