Hormone Replacement Therapy (HRT)
CATEGORY: IARC known, NTP known
USED IN: Medications
Between 1995 and 2000, several epidemiological studies indicated that use of combined estrogen-progestin HRT treatments led to an increase in invasive breast cancer (Colditz, 1995; Magnusson,1999; Ross 2000; Schairer, 2000).
In 2002, a study designed to explore the benefits and risks of combined estrogen (conjugated equine estrogens) plus progestin (medroxyprogesterone acetate) HRT in post-menopausal women was halted three and half years before the intended end of the study period. This project, called the Women’s Health Initiative (WHI), enrolled more than 16,600 healthy women ages 50 to 79. The study was designed as a large randomized control trial, a method considered to be the most rigorous approach to studying clinical responses in human populations (Sibbald, 1998). Half the women took the combined estrogen-progestin HRT, while the other half took a placebo, and a number of health and disease outcomes were monitored. The WHI study was halted early because researchers observed a 26 percent increase in the relative risk of breast cancer (38 women with breast cancer versus 30 women per 10,000 person-years), in addition to significant increases in the risk of heart disease, stroke and blood clots (Rossouw, 2002). More recent analyses clarify that the increased risk of breast cancer in the WHI study is found in women taking the combined estrogen-progestin formula, but not in those women taking estrogen-only HRT supplements (Anderson, 2004).
Since the initial results of the WHI study were published, other large studies have supported its major conclusions. In 2003, Swedish researchers halted a study of HRT in women with a history of breast cancer. Originally planned as a five-year study, the Swedish trial was stopped after two years because women taking HRT had three times the rate of recurrence or new tumors compared to women who received other treatments for menopausal symptoms (Holmberg, 2004).
Also in 2003, researchers in the Million Women Study (MWS) in the United Kingdom reported that the use of all types of post-menopausal HRT significantly increased the risk of breast cancer (MWSC, 2003). Again, the risk was greatest among users of estrogen-progestin combination therapy. The study enrolled more than 1 million women ages 50 to 64. Researchers estimated that women who used estrogen-progestin HRT for 10 years were almost four times more likely to develop breast cancer than women who used estrogen-only HRT (19 additional breast cancers per 1,000 women compared to five per 1,000).
Other recent studies have confirmed the basic result that use of combined HRT increases risk of breast cancer in post-menopausal women. Examination of cancer histology in women taking combined HRT at the time of diagnosis reveals an increased presentation of breast cancer of lobular origin (Biglia, 2005; Borquist, 2007; Reeves, 2006) but also of cancers with low proliferation rates (mitotic indices) and favorable prognostic outcome (Reeves, 2006; Schuetz, 2007).
A follow-up study of the women in the WHI trial three years after all participants stopped taking either the HRT or placebo treatments demonstrated increases in invasive cancers of all sorts (grouped together) in women who had been in the HRT arm of the trial. While breast cancer rates remained elevated in this group, a trend over time toward rates similar to those found in the placebo group made these effects nonsignificant (Heiss, 2008). These data suggest that the increased risk for breast cancer that accompanies use of HRT is reversible within a fairly short period following discontinuation of the treatment. This finding is consistent with the rapid drop in post-menopausal breast cancer incidence rates since 2002, a decrease that has been attributed to the precipitous drop in HRT prescriptions following the release of the data from these large studies (Verkooijen, 2009).
