Action Points
- Explain that women who begin using hormone therapy close to the time of menopause are at greater risk for breast cancer than those who wait five years or more.
- Note that for women who stop hormone therapy, the risk for breast cancer falls to the level of nonusers after two years.
Women who begin using hormone therapy close to the time of menopause are at greater risk for breast cancer than those who wait five years or more, a large prospective study found.
Among current users of estrogen-only hormone formulations who began the therapy soon after menopause, the risk of breast cancer was significantly higher than in nonusers (RR 1.43, 95% CI 1.35 to 1.51, P<0.001), according to Valerie Beral, MBBS, and colleagues from the University of Oxford in England.
But for those who deferred the therapy for five years or more, the relative risk was not increased (RR 1.05, 95% CI 0.89 to 1.24, P=0.6) the researchers reported online in the Journal of the National Cancer Institute.
The risk among women currently taking estrogen-progestin formulations was greater than for those taking estrogen alone, with relative risks of 1.53 (95% CI 1.38 to 1.70, P<0.001)) and 2.04 (95% CI 1.95 to 2.14, P<0.001) among those beginning more and less than five years after menopause, respectively.
Data from the Women's Health Initiative (WHI) in the U.S. suggested that there was little risk of breast cancer associated with estrogen-only hormone therapy, but in that study most women in the estrogen arm began treatment more than five years after menopause.
To clarify whether the timing of starting treatment influences breast cancer risk, Beral and her collaborators from the Million Women Study recruited almost 1.3 million women from the U.K. between 1996 and 2001, obtaining information on sociodemographic and health factors, as well as their history of hormone use.
Participants' average age was 56.6 years at enrollment.
A total of 55% had used hormone therapy at some point, and 35% were current users.
During more than four million woman-years of follow-up, 15,759 breast cancers were diagnosed, 61% in women who had ever used hormone therapy and 45% in women currently using the hormones.
Beral and her co-investigators found increased adjusted risks for both estrogen-only and estrogen-progestin formulations in both current and past users (P for heterogeneity <0.001).
Risk remained elevated for two years after cessation of therapy (RR 1.16, 95% CI 1.08 to 1.24, P<0.001) but subsequently fell to the level seen in women who never used hormones (RR 0.99, 95% CI 0.93 to 1.05), the researchers reported.
The researchers also calculated standardized incidence rates for women on hormone therapy ages 50 to 59:
- Never users, 0.30% per year (95% CI 0.29 to 0.31)
- Estrogen-alone beginning less than five years after menopause, 0.43% per year (95% CI 0.42 to 0.45)
- Estrogen-alone beginning at or after five years, 0.32% (95% CI 0.27 to 0.37)
- Estrogen-progestin beginning less than five years after menopause, 0.61% (95% CI 0.59 to 0.64)
- Estrogen-progestin beginning at or after five years, 0.46% (95% CI 0.41 to 0.51)
Greater risks also were seen for estrogen receptor-positive tumors in estrogen-alone users (RR 1.76, 95% CI 1.59 to 1.94, P for heterogeneity =0.005) and in estrogen-progestin users (RR 3.10, 95% CI 2.86 to 3.36, P for heterogeneity <0.001).
When the researchers looked at potential confounders, they found that incidence rates among women who never used hormone therapy increased with greater body mass index, but rates among users were not affected by body mass index.
Adjustment for other factors such as having a first-degree relative with breast cancer and age at menarche did not affect the results.
In discussing their findings, Beral and colleagues observed, "In this large prospective study we found substantial and clinically important heterogeneity in the effects of hormonal therapy on breast cancer incidence among postmenopausal women."
A limitation of their study was possible residual misclassification, with information on hormone use being obtained about 1.4 years before the detection of breast cancers, which could slightly attenuate relative risk estimates.
In an accompanying editorial, Rowan T. Chlebowski, MD, PhD, of Harbor-UCLA Medical Center in Torrance, Calif., and Garnet L. Anderson, PhD, from the Fred Hutchinson Cancer Research Center in Seattle, compared the findings from this study with those from the WHI.
"Given the considerable methodological differences between these studies, the similarity of results is remarkable and increases confidence in the validity of the conclusions," they commented.
However, they noted that the discrepant results in the two studies regarding risk associated with estrogen-alone hormone therapy represents an unresolved question.
"Additional post-intervention follow-up of the WHI estrogen-only clinical trial currently under way should lead to further clarification of this issue," Chlebowski and Anderson wrote.
The study was funded by Cancer Research UK and the UK Medical Research Council.
All authors declared no financial conflicts of interest.