Effect of Hormone Replacement Therapy on Breast Cancer Risk: Estrogen Versus Estrogen Plus Progestin

In contrast to the unopposed estrogen used for some time as hormone replacement therapy (HRT) in the United States, combination regimens (CHRT) are becoming increasingly popular. With this approach, a progestin is added to estrogen for either the entire monthly cycle or sequentially. Because reassessment of the relationship between HRT and breast cancer seemed to be in order, a population-based, case-control study was planned. Women diagnosed with incident breast cancer in Los Angeles County were enrolled over a 4.5-year period starting in mid-1987. Cases included 1897 postmenopausal women ranging in age from 55 to 76 years; there were 1637 control women. No subject had undergone simple hysterectomy. HRT was used by 54 percent of breast cancer patients and 52 percent of control subjects. The average number of months of use was 46 and 43, respectively. A majority of users had received unopposed estrogen, most often relatively low doses (≤0.625 mg daily) of conjugated equine estrogen. CHRT was most often used sequentially; the progestin used was nearly always medroxyprogesterone acetate. The risk of breast cancer increased 10 percent for every 5 years of HRT use, for an odds ratio (OR) of 1.10. The findings suggested a steady rise in risk with an increasing duration of HRT use, to a level of 36 percent after 15 years of use. Estrogen replacement was not associated with the risk of breast cancer except in women using it for 15 years or longer (OR = 1.24). Thin women seemed to be more at risk than those who were heavy. The risk of breast cancer increased much more with the use of CHRT; the OR associated with 10 or more years of use was 1.51, and the estimated risk per 5 years of use was 1.24. Sequential CHRT carried a higher risk than a continuous regimen, but the difference was not statistically significant. With estrogen-only therapy, the excess risk was almost exclusively limited to in situ disease, but with CHRT, risk levels were comparable for all stages of cancer at presentation. The increased risk associated with CHRT was not restricted to current users; those who had stopped using this therapy 2 or more years earlier had a similar risk. These findings are evidence that adding a progestin to HRT substantially increases the risk of breast cancer compared with estrogen-only therapy. Women who are candidates for CHRT, in part to protect against endometrial cancer, should be aware that the increased risk of breast cancer may outweigh this benefit. J Natl Cancer Inst 2000;92:328–332