Breast Cancer and HRT: The Million Women Study

Abstract & Commentary

Synopsis: Current users of estrogen or estrogen-progestin combinations were shown to have a significantly higher risk of developing and dying from breast cancer. The findings confirm and extend those published last year by the Women’s Health Initiative.1

Source: Million Women Study Collaborators. Breast cancer and hormone replacement therapy in the Million Women Study. Lancet. 2003;362:419-427.

The Million Women Study was undertaken between the years 1996 and 2001, during which time 1,084,110 UK women provided information about their use of hormone replacement therapy (HRT), as well as other personal details, and were then followed for cancer incidence and death. The participants in the study represent approximately 25% of the UK women in this age group. Approximately half of the women reported current or past use of HRT. During the 5 years of study there were 9364 incident invasive breast cancers and 637 breast cancer deaths after an average of 2.6 and 4.1 years of follow-up, respectively. Current-users of HRT at recruitment were more likely than never-users to develop breast cancer (adjusted relative risk, 1.66 [95% CI, 1.58-1.75; P < .0001) and die from it (1.22 [1.00-1.48]; P = .05). However, past-users of HRT were not at an increased risk of incident or fatal disease (1.01 [0.94-1.09] and 1.05 [0.82-1.34], respectively). Incidence was significantly increased for current-users both of preparations containing estrogen only (1.30 [1.21-1.40]; P < .0001) or estrogen-progestin (2.0 [1.88-2.12]; P < .0001), but the magnitude of the associated risk was substantially and significantly greater for estrogen-progestin than for other types of HRT (P < .0001). When looked at separately, relative risks were significantly increased for users of oral, transdermal, and implanted estrogen formulations (P < .0001). In current-users of each type of HRT the risk of breast cancer increased with increasing total duration of use. Ten years use of HRT was estimated to result in 5 (95% CI, 3-7) additional cancers per 1000 users of estrogen-only preparations, and 19 (15-23) additional cancers per 1000 users of estrogen-progestin combinations.

Comment by William B. Ershler, MD

This large epidemiologic study confirms the association of HRT and breast cancer. Furthermore it demonstrates an increased risk for all types of HRT, including estrogen alone or transdermal formulations. The estro gen-progestin combinations seem to be the most dangerous with regard to the development of breast cancer. The duration of HRT use appears to be important, and those current users having been treated for a decade or more were at particularly high risk. To put these findings in perspective, among women from developed countries who never used HRT the incidence of invasive breast cancer is estimated to be typically 32 in every 1000 between the ages of 50 and 65.2 The cumulative incidence of breast cancer per 1000 associated with different patterns of use of HRT, calculated by applying the relative risk estimates determined in this study to the estimated incidence rates in never-users of HRT, showed that by 5 years use of HRT, beginning at the age of 50, it would be estimated to result in 1.5 additional breast cancers by the age of 65 among 1000 users of estrogen-only preparations, and 6 (CI, 5-7) additional cancers per 1000 users of estrogen-progestin combinations. By 10 years the use is estimated to result in 5 (CI, 3-7) additional cancers in 1000 users of estrogen only, and 19 (CI, 18-20) additional cancers in 1000 users of combined HRT. Looked at another way, use of HRT by UK women, age 50-64 years, in the most recent decade is estimated to have resulted in an extra 20,000 incident breast cancers.

Thus, the cumulated data from this and other well-constructed studies1, 3-5 indicate an irrefutable association between breast cancer and HRT use. The estimated increased numbers are of great consequence, and physicians need to be aware and to discuss these increased risks if patients are to undertake such treatment approach. The new evidence of breast cancer mortality dictates an explicit position for general practitioners—HRT should be discouraged and, for women presenting with new postmenopausal related health problems, general practitioners should seek alternative solutions. With the current data, it is difficult to find fault with that recommendation.


1. Women’s Health Initiative. JAMA. 2002;288:321-333.

2. Parkin DM, et al. Cancer incidence in five continents, vol VIII. Lyon: International Agency for Research on Cancer Scientific Publications, 2002.

3. Chlebowski RT, et al. JAMA. 2003;289:3243-3253.

4. Beral V, et al. Lancet. 2002;360:942-944.

5. Beral V, et al. J Epidemiol Biostat. 1999;4:191-215.

Dr. Ershler is an Oncologist at the INOVA Fairfax Hospital Cancer Center, Fairfax, VA; Director, Institute for Advanced Studies in Aging, Washington, DC.