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More Evidence Linking Estrogen Plus Progestin Therapy to Breast Cancer
Laurie Barclay, MD
June 24, 2003 — Two studies in the June 25 issue of The Journal of the American Medical Association provide more evidence against the use of combined hormone therapy (CHT) in postmenopausal women. The first study, from the Women's Health Initiative (WHI), shows that not only is the incidence of breast cancer increased with CHT, but that it is diagnosed at a more advanced stage. The second study again shows that progestin, not estrogen, is primarily responsible for the increase in breast cancer risk.
"Relatively short-term combined estrogen plus progestin use increases incident breast cancers, which are diagnosed at a more advanced stage compared with placebo use, and also substantially increases the percentage of women with abnormal mammograms," write Rowan T. Chlebowski, MD, PhD, from Harbor-UCLA Research and Education Institute in Torrance, California, and colleagues from the WHI Randomized Trial. "These results suggest estrogen plus progestin may stimulate breast cancer growth and hinder breast cancer diagnosis."
The WHI was a randomized, placebo-controlled trial of CHT in 16,608 postmenopausal women. As Medscape has reported previously, the WHI was stopped early, on July 9, 2002, when interim analysis revealed that the overall health risks associated with CHT, including breast cancer, exceeded the benefits. The present analysis determined the association of CHT with breast cancer characteristics and annual mammography findings.
Based on intent-to-treat analysis, number of breast cancer cases was 245 in the CHT group and 185 in the placebo group (hazard ratio [HR], 1.24; weighted P < .001)). Number of cases of invasive breast cancer was 199 in the CHT group vs. 150 in the placebo group (HR, 1.24; weighted P = .003). Compared with the placebo group, invasive breast cancers in the CHT group were larger (1.7 ± 1.1 cm vs. 1.5 cm ± 0.9 cm; P = .04) and were diagnosed at a more advanced stage (25.4% vs. 16.0% regional/metastatic; P = .04).
After one year, the percentage of women with abnormal mammograms was 9.4% (716 of 7,656) in the CHT group and 5.4% (398 of 7,310) in the placebo group (P < .001). Throughout the study, more women receiving CHT had abnormal mammograms than did women receiving placebo.
According to the authors, about 3 million postmenopausal women in the U.S. currently use CHT, so the absolute increase in abnormal mammograms of about 4% per year with CHT is equivalent to approximately 120,000 otherwise avoidable abnormal mammograms annually in these women.
"The breast cancers diagnosed in women in the [CHT] group had similar histology and grade but were more likely to have advanced stage vs. women in the placebo group," the authors write. "These results suggest that invasive breast cancers developing in women receiving estrogen plus progestin therapy may have an unfavorable prognosis.... Consideration for use of estrogen plus progestin for any duration by postmenopausal women should incorporate the current findings into established and emerging risks and benefits of these agents."
The National Heart, Lung, and Blood Institute funded this study. Wyeth supplied the active study drug and placebo. Several of the authors have financial arrangements with Wyeth and/or other pharmaceutical companies.
In a separate study, CHT was associated with increased risk of breast cancer regardless of whether the progestin component was prescribed as continuous or sequential CHT. A previous analysis of 51 studies showed that current users of CHT or progestin alone for at least five years had a 53% increase in breast cancer risk.
"Evidence is mounting regarding the adverse impact on breast cancer risk of adding progestin to [hormone therapy]," write Christopher I. Li, MD, PhD, from the Fred Hutchinson Cancer Research Center in Seattle, Washington, and colleagues. "This adverse impact appears to be manifest within several years of initiating use of CHT, and to be similar in magnitude irrespective of the pattern of CHT use."
This population-based case-control study compared 975 women, aged 65 to 79 years, diagnosed with invasive breast cancer between April 1, 1997, and May 31, 1999, with 1,007 women without breast cancer.
Women using estrogen therapy for 25 years or longer had no significant increase in risk of breast cancer. However, women who used CHT, with or without a history of estrogen therapy, had a 1.7-fold increased risk of breast cancer, a 2.7-fold increased risk of invasive lobular carcinoma, a 1.5-fold increased risk of invasive ductal carcinoma, and a 2-fold increase in estrogen receptor–positive breast cancers.
Risk of breast cancer was related to duration of CHT use. Risk for invasive ductal carcinoma was increased 1.5-fold in users for 5 to 14.9 years and 1.6-fold in users for 15 or more years. Increased risk for invasive lobular carcinoma was 3.7-fold and 2.6-fold, respectively. Continuous vs. sequential CHT did not appear to affect these risk patterns.
"At least for the forms of CHT used most commonly by US women in the latter part of the 20th century, including both sequential CHT and continuous CHT, an increased incidence of breast cancer must be tallied as a possible consequence," the authors write.
The National Cancer Institute supported this study through a contract with Fred Hutchinson Cancer Research Center. Wyeth has financial arrangements with two of the authors.
In an accompanying editorial, Peter H. Gann, MD, ScD, and Monica Morrow, MD, from the Feinberg School of Medicine at Northwestern University in Chicago, Illinois, refer to CHT as "a single-edged sword."
Commenting on the WHI trial, they note that "alteration of a woman's basic hormonal physiology over decades in the interest of long-term disease prevention is fraught with hazard." They point out that CHT increases the risk of developing breast cancer while decreasing mammographic sensitivity and thereby delaying detection of the cancer.
They recommend additional research, but they suggest that the WHI trial of CHT "is as close to definitive as can be expected.... In the meantime, the message for physicians caring for menopausal patients is clear. The increased risk of breast cancer and the mammographic abnormalities among women in the WHI study provide further compelling evidence against the use of combination estrogen plus progestin hormone therapy."
JAMA. 2003;289:3243-3253, 3254-3263, 3304-3306
Reviewed by Gary D. Vogin, MD
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