'Tis but a scratch: a critical review of the Women's Health Initiative evidence associating menopausal hormone therapy with the risk of breast cancer

Abstract

Use of menopausal hormone therapy (HT) fell precipitously after 2002, largely as a result of the Women's Health Initiative's report claiming that the combination of conjugated equine estrogen (CEE) and medroxyprogesterone acetate increased breast cancer risk and did not improve quality of life. More recently, Women's Health Initiative (WHI) publications acknowledge HT as the most effective treatment for managing menopausal vasomotor symptoms and report that CEE alone reduces the risk of breast cancer by 23% while reducing breast cancer death by 40%. Their sole remaining concern is a small increase in breast cancer incidence with CEE and medroxyprogesterone acetate (1 per 1,000 women per year) but with no increased risk of breast cancer mortality. This article closely examines evidence that calls even this claim of breast cancer risk into serious question, including the WHI's reporting of nonsignificant results as if they were meaningful, a misinterpretation of its own data, and the misleading assertion that the WHI's findings have reduced the incidence of breast cancer in the United States. A generation of women has been deprived of HT largely as a result of this widely publicized misinterpretation of the data. This article attempts to rectify this misunderstanding, with the goal of helping patients and physicians make informed joint decisions about the use of HT.

Response to letter to editor

“…(3) In the randomized trial phase of the WHI, the increase in the hazard rate of breast cancer for women on CEE + MPA, compared with women on placebo, is attributable to the unexplained extremely low rate of incident breast cancer in the women with prior HT assigned to placebo, not to an increased breast cancer risk among those randomized to CEE + MPA. 2,5,6 Chlebowski and Aragaki now argue that this finding "disappears" over nearly 15 yr of post-trial observational follow-up in the clinical trial participants. Yet because that assessment also lacked appropriate statistical adjustments, it compounds the analytic omissions in the clinical trial phase and does not contravene or undo the randomized clinical trial's statistically nonsignificant findings of breast cancer risk.…”

“…For years, we and others have challenged the WHI's failure to follow their protocol and basic statistical norms. [5][6][7] Although the WHI has consistently ignored these critiques, at worst these investigators claim a rare increase of 1 additional case of non-fatal breast cancer for every 1,000 women on CEE + MPA for 1 year. 8 Further, the WHI acknowledges that no increased risk occurs among women who had not taken HT before joining their study.…”

Letter to the Editor

“…Moreover, long-term influence of CEE plus MPA on breast cancer risk did not depend on prior hormone use, as women without prior hormone use and women with prior use had elevated risk that were statistically similar, when randomized to CEE plus MPA compared with placebo; HR (95% CI) = 1.21 (1.05–1.40) and HR (95% CI) = 1.52 (1.16–1.98), respectively, with P-interaction = 0.14 2 . Kaplan-Meier estimates of breast cancer incidence for women with and without prior hormone therapy use, as originally published 3 and republished, 1 were updated using long-term follow-up and illustrate excess breast cancer risk among those randomized to CEE plus MPA regardless of prior hormone use 4 …”

“…We find nothing humorous related to discussions regarding breast cancer risk associated with estrogen plus progestin use 1 . The most recent update of findings from the Women's Health Initiative (WHI) randomized, placebo-controlled clinical trial confirmed that the higher risk of breast cancer incidence associated with conjugated equine estrogen and medroxyprogesterone acetate (CEE plus MPA) persists years after discontinuation of use 2 .…”

“…To inform clinical decision making, details regarding the long-term influence of hormone therapy on breast cancer are available in the latest WHI update 2 and in the United States Preventive Services Task Force (USPSTF) summary 5 . Those interested in an assessment of Bluming et al's 1 “Personal Perspective” should refer to a recent narrative review, 4 which systematically addresses the contentions raised.…”