The evidence from this clinical trial should be put into context of evidence from observational studies. The Million Women Study  observed no increased risk of breast cancer among women whose first use of estrogen-only therapy was 5 or more years after menopause, but the risk was statistically significantly higher among women initiating therapy within 5 years of menopause (RR = 1.43; 95% CI, 1.36-1.49). Among that group, the risk increased with duration of hormone use. Overall, risks associated with estrogen-only HT were lower than those observed for combined estrogen-progestin HT. Estrogen-only therapy, even for more than 25 years duration, was not associated with invasive breast cancer in a case-control study of women aged 65 years and older. The Collaborative Group on Hormonal Factors in Breast Cancer, a reanalysis of data from 52 observational studies of HT and breast cancer, had information on specific hormonal preparations for 39% of eligible women and most of these women reported use of estrogen-alone preparations. The combined analysis showed no marked variation between estrogen-only preparations and combined HT. However, the collaborative analysis, overall, provided limited information on estrogen-only versus combination estrogen-progestin therapy.
Following publication of the WHI results, HT use dropped dramatically in the United States and elsewhere. Follow-up of participants on the combined HT arm demonstrated a rapid decrease in the elevated breast cancer risk of therapy within 2 years, despite similar rates of mammography screening. Analysis of changes in breast cancer rates in the United States observed a sharp decline in breast cancer incidence rates from 2002 to 2003, following the release of the WHI trial data among women aged 50 years and older.[42,43] The decreased incidence is primarily the result of changes in the incidence of ER-positive breast cancer , which provides additional support for the causal association between combined HT and the risk of breast cancer. Similarly, in multiple countries where the prevalence of HT use was high, breast cancer rates decreased in a similar time frame, coincident with changes in prescribing patterns and/or reported prevalence of use. [44,45,46] A study among women receiving regular mammography screening supports that the observed sharp decline from 2002 to 2003 in breast cancer incidence was primarily caused by withdrawal of HT rather than declines in mammography rates. Since the decline in breast cancer incidence noted from 2002 to 2003, rates in the United States have stabilized.[48,47] These observations support the causal effect of combined HT on breast cancer incidence and modification of breast cancer risk through either withdrawal of HT or never having used HT.
Ionizing radiation exposure
A well-established relationship exists between exposure to ionizing radiation and the risk of developing breast cancer. Excess breast cancer risk is consistently observed in association with a variety of exposures such as fluoroscopy for tuberculosis and radiation treatments for acne, tinea, thymic enlargement, postpartum mastitis, or Hodgkin lymphoma. Although risk is inversely associated with age at radiation exposure, the manifestation of breast cancer risk occurs according to the usual age-related pattern. An estimate of the risk of breast cancer associated with medical radiology puts the figure at less than 1% of the total. However, it has been theorized that certain populations, such as AT heterozygotes, are at an increased risk of breast cancer from radiation exposure. A large cohort study of women who carry mutations of BRCA1 or BRCA2 concluded that chest x-rays increase the risk of breast cancer still further (RR = 1.54; 95% CI, 1.1-2.1), especially for women who were x-rayed before age 20 years.