Breast Cancer Risk in the WHI Estrogen-Progestin Trial Arm

Abstract & Commentary

By Leon Speroff, MD, Editor, Professor of Obstetrics and Gynecology, Oregon Health and Science University, Portland, is Editor for OB/GYN Clinical Alert.

Synopsis: The WHI reports an increase in breast cancer is concentrated in prior hormone users, but the overall adjusted risk of breast cancer is not statistically significant.

Source: Anderson GL, et al. Prior hormone therapy and breast cancer risk in the Women's Health Initiative randomized trial of estrogen plus progestin. Maturitas. 2006 Jun 29; [Epub ahead of print];

Anderson and colleagues from the WHI performed subgroup analyses focusing on how prior hormone therapy use influenced the risk of breast cancer found in the estrogen-progestin trial arm.1 Prior hormone users totaled 4311 participants (26%), with 42% reporting less than 2 years of use (17% used hormones 5 to 10 years previously, and 26% more than 10 years before enrolling in the WHI study). Prior users had an increased hazard ratio compared to placebo (1.96; CI = 1.17-3.27) in contrast to no increase among never users (1.02; CI = 0.77-1.36). The WHI concluded that this difference could reflect an increasing risk with cumulative exposure to hormone therapy. The subgroup analysis suggested that no increase in breast cancer was seen in never users, perhaps because of insufficient duration of exposure.


Many of the factors associated with a reduced risk of breast cancer were slightly but significantly more prevalent in the group of prior hormone users, such as younger age, more education, lower body mass, and more physically active. On the other hand, some factors associated with an increased risk of breast cancer were more common in prior users (smoking, alcohol use, vasomotor symptoms, and lower bone density). The overall risk of breast cancer in the treated estrogen-progestin group was the same as previously reported by the WHI (1.24; CI = 1.02-1.50).1 However, after adjusting for the multiple factors recognized to influence the risk of breast cancer, the hazard ratio was 1.20, and no longer statistically significant, CI = 0.94-1.53). Remarkably, the authors comment that the adjustment "did not substantially alter this risk estimate." Is it not substantial if the risk goes from significant to nonsignificant? Is it appropriate for the WHI in its conclusion to say "the significant increase in breast cancer risk found in the trial overall . . . ?"

A year-by-year analysis of prior users and never users is provided in a Figure. Every single line in this figure, with one exception, crosses 1.0, is not statistically significant, and the confidence intervals are very wide. The only statistically significant line is for prior users at year 5 of the study, and this confidence interval is the widest of all, 1.18-10.73. When the adjusted overall risk is no longer statistically significant, how confident can we be in the results of subgroup analyses with smaller numbers?

This report from the WHI is promoting the idea that increasing duration of exposure is necessary for an increasing risk. Yet, they provide this result: "Duration of prior hormone therapy use, and specifically duration of prior combined hormone use, did not significantly modify the risk of breast cancer."

How does all this fit with the idea that the data reflect the effect of hormone therapy on pre-existing tumors. Interestingly, the prior users who ended up in the placebo group had a lower incidence of breast cancer per year compared to the women without prior exposure. After adjustment for the various risk factors, this reduction was not statistically significant (0.66; CI = 0.41-1.05). The WHI recognized that this was a "puzzle." It seems to me that this is tantalizing, a result consistent with early detection of pre-existing tumors. The WHI concludes that the results are consistent with the hypothesis that the risk of breast cancer increases with longer exposure; however, the data do not answer the question: are we seeing effects on pre-existing tumors.

Most importantly, the overall result of an increased risk of breast cancer in the estrogen-progestin arm was no longer statistically significant after adjusting for risk factors. This is good news! The WHI results are not consistent with a large effect, and the findings are finding it hard to escape the influence of differences in risk factors and personal characteristics.


  1. Chlebowski RT, et al. Influence of estrogen plus progestin on breast cancer and mammography in healthy postmenopausal women. The Women's Health Initiative Randomized Trial. JAMA. 2003;289:3243-3253.