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The WHI database will probably provide an infinite number of publications. This time the focus of the analysis was to explore whether pretreatment levels of sex hormones modify the effect of estrogen + progestin (E+P) on breast cancer [1]. This was a nested case–control study within the WHI randomized clinical trial of E+P. The trial enrolled 16,608 postmenopausal women aged 50–79 years with an intact uterus and no breast cancer history. During a mean of 5.6 years of follow-up, 348 incident breast cancer case subjects were identified and matched with 348 control subjects. Case and control subjects had their sex hormone levels measured at baseline (estrogens, testosterone, progesterone and sex hormone binding globulin (SHBG)) and at year 1 (estrogens and SHBG) using sensitive assays. Statistically significant elevations in breast cancer risk were seen with greater pretreatment levels of total estradiol ([i]p[/i] trend = 0.04), bioavailable estradiol ([i]p[/i] trend = 0.03), estrone ([i]p[/i] trend = 0.007), and estrone sulfate ([i]p[/i] trend = 0.007). E+P increased all measured estrogens and SHGB at year 1 (all [i]p[/i] < 0.001). The effect of E+P on breast cancer risk was strongest in women whose pretreatment levels of total estradiol, bioavailable estradiol and estrone were in the lowest quartiles. For example, the odds ratio for E+P relative to placebo was 2.47 (95% confidence interval (CI) 1.28–4.79) in the lowest total estradiol quartile, compared with 0.96 (95% CI 0.44–2.09) in the highest total estradiol quartile; [i]p[/i] interaction = 0.04). The main conclusion was that women with lower pretreatment endogenous estrogen levels were at greater risk for breast cancer during E+P therapy compared with those with higher levels.


  • Amos Pines
    Department of Medicine T, Ichilov Hospital, Tel-Aviv, Israel


  1. Farhat GN, Parimi N, Chlebowski RT, et al. Sex hormone levels and risk of breast cancer with estrogen plus progestin. J Natl Cancer Inst 2013 Sep 16. Epub ahead of print.
  2. Hartz AJ, He T. Cohort study of risk factors for breast cancer in post menopausal women. Epidemiol Health 2013;35:e2013003.
  3. Baglietto L, English DR, Hopper JL, et al. Circulating steroid hormone concentrations in postmenopausal women in relation to body size and composition. Breast Cancer Res Treat 2009;115:1719.
  4. Kuhl H. Breast cancer risk in the WHI study: the problem of obesity. Maturitas 2005;51:83-97.
  5. Collaborative Group on Hormonal Factors in Breast Cancer. Breast cancer and hormone replacement therapy: collaborative reanalysis of data from 51 epidemiological studies with 52,705 women with breast cancer and 108,411 women without breast cancer. Lancet 1997;350:104759.
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