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Hormone therapy affects breast cancer risk differently over time
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The risk for breast cancer associated with use of menopausal hormone therapy changes over time, according to an analysis of two Women’s Health Initiative clinical trials.
Menopausal hormone therapy usage — estrogen with or without progestin — decreased considerably after reports surfaced of an increased breast cancer risk associated with estrogen plus progestin, according to study background. However, data from the Women’s Health Initiative randomized trials indicated estrogen plus progestin increased the incidence of breast cancer and breast cancer-related death, whereas estrogen alone reduced these risks for women who previously had a hysterectomy. These findings raised questions about short-term and long-term effects of both treatment regimens, according to the researchers.
Rowan T. Chlebowski
Rowan T. Chlebowski, MD, PhD, chief of internal medicine at the Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center in Torrance, California, and colleagues sought to determine time-specific breast cancer incidence rates and examine breast cancer characteristics during the intervention and post-intervention phases in the two Women’s Health Initiative randomized clinical trials. Median follow-up was 13 years.
The analysis included 27,347 women aged 50 to 79 years who were enrolled at one of 40 U.S. clinical centers between 1993 and 1998.
Researchers randomly assigned 16,608 women who had a uterus to oral conjugated equine estrogens (0.625 mg daily) plus medroxyprogesterone acetate (2.5 mg daily) or placebo for a median intervention of 5.6 years. Researchers randomly assigned the 10,739 women who had undergone prior hysterectomy to the equine estrogen course alone or placebo for a median intervention of 7.2 years.
The HR for the risk for breast cancer associated with estrogen plus progestin was 0.71 (95% CI, 0.47-1.08) for 2 years and steadily increased during the intervention. The increase was significant for the entire intervention phase (HR = 1.24; 95% CI, 1.01-1.53).
In the early part of the post-intervention phase (within 2.75 years), there was a decline in breast cancer incidence in the combined hormone therapy group; however, the HR for breast cancer remained greater than 1 (HR = 1.23; 95% CI, 0.9-1.7). The HR remained greater than 1 during the later portion of the post-intervention phase for a median of 5.5 years of follow-up (HR = 1.37; 95% CI, 1.06-1.77).
In the estrogen alone trial, the HR for breast cancer was 0.79 (95% CI, 0.61-1.02) throughout the entire intervention phase and remained low in the early part of post-intervention (HR = 0.55; 95% CI, 0.34-0.89). However, the risk increased during the last follow-up post-intervention (HR = 1.17; 95% CI, 0.73-1.87).
The characteristics of breast cancer diagnosed during early and late post-intervention differed in both trials. Estrogen plus progesterone was associated with an increased risk for larger tumors (HR = 2.67; 95% CI, 1.19-6) and PR-negative tumors (HR = 2.67; 95% CI, 1.25-5.73) during early vs. late post-intervention, whereas estrogen alone was associated with HER-2–positive tumors (HR = 1.79; 95% CI, 0.43-7.49) and fewer moderately differentiated tumors (HR = 0.24; 95% CI, 0.96-4.1) during early vs. late post-intervention.
“The ongoing influences on breast cancer after stopping hormone therapy in the Women’s Health Initiative trials require recalibration of breast cancer risk and benefit calculation for both regimens, with greater adverse influence for estrogen and progestin use and somewhat greater benefit for use of estrogen alone,” Chlebowski and colleagues wrote.
In an accompanying editorial, Purna A. Joshi, MSc, PhD, a postdoctoral fellow at the Princess Margaret Cancer Centre in the University Health Network, Toronto, and colleagues called the results of this study “striking” and said they were important in the understanding of therapeutic intervention for breast cancer.
“Emerging detailed analysis from the Women’s Health Initiative trials such as those reported [in this study] reveal new, compelling evidence for the significance of progesterone in breast cancer where it has traditionally taken a backseat to estrogen,” Joshi and colleagues wrote. “Although the Women’s Health Initiative trials relate to the menopausal setting, lessons learned from them continue to provide additional value in appreciating a potential role of progesterone even in premenopausal breast cancer.” – by Anthony SanFilippo
Disclosure: Chlebowski reported consultant/advisory roles with Amgen, AstraZeneca, Genomic Health, Novartis and Novo Nordisk, research funding from Amgen and serving on the speakers bureau for Genentech and Novartis. The rest of the researchers and editorial authors reported no relevant financial disclosures.
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