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J Natl Cancer Inst. 2013 Oct 2;105(19):1496-503. doi: 10.1093/jnci/djt243. Epub 2013 Sep 16.

Sex hormone levels and risk of breast cancer with estrogen plus progestin.

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Affiliations of authors: San Francisco Coordinating Center, California Pacific Medical Center Research Institute, San Francisco, CA (GNF, NP, SRC); Faculty of Health Sciences, University of Balamand, Beirut, Lebanon (GNF); Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA (RTC); Division of Preventive Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (JEM); Fred Hutchinson Cancer Research Center, Seattle, WA (GA, AZL); Department of Internal Medicine, University of California-San Francisco, San Francisco, CA (AH, DG); Department of Epidemiology and Biostatistics, University of California-San Francisco, San Francisco, CA (EV); Department of Internal Medicine, University of California-Davis, Sacramento, CA (JSL); Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA (JAC); Department of Internal Medicine, Ohio State University, Columbus, OH (RJ); Department of Preventive Medicine, Stony Brook University, Stony Brook, NY (DL); Department of Medicine, Emory University, Atlanta, GA (LP); Karmanos Cancer Institute, Wayne State University, Detroit, MI (MSS).



Although high endogenous sex hormone levels and estrogen plus progestin (E+P) therapy are associated with increased breast cancer risk, it is unknown whether pretreatment levels of sex hormones modify E+P effect on breast cancer.


We conducted a nested case-control study within the Women's Health Initiative randomized clinical trial of E+P. The trial enrolled 16608 postmenopausal women aged 50 to 79 years with 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 year 1 (estrogens and SHBG) using sensitive assays. All statistical tests were two-sided.


Statistically significant elevations in breast cancer risk were seen with greater pretreatment levels of total estradiol (P trend = .04), bioavailable estradiol (P trend = .03), estrone (P trend = .007), and estrone sulfate (P trend = .007). E+P increased all measured estrogens and SHGB at year 1 (all P < .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 to 4.79) in the lowest total estradiol quartile, compared with 0.96 (95% CI = 0.44 to 2.09) in the highest total estradiol quartile; P interaction = .04).


Women with lower pr-treatment endogenous estrogen levels were at greater risk of breast cancer during E+P therapy compared with those with higher levels. Further studies are warranted to confirm these findings.

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