New-Onset Breast Tenderness During Hormone Therapy Linked to Increased Breast Cancer Risk

From Medscape Medical News CME
Laurie Barclay, MD
Charles P. Vega, MD

October 21, 2009 — New-onset breast tenderness during conjugated equine estrogens plus medroxyprogesterone acetate (CEE+MPA) hormonal therapy is linked to increased breast cancer risk, according to an analysis of data from a randomized controlled trial reported in the October 12 issue of the Archives of Internal Medicine.

"To our knowledge, no prior published studies have addressed whether there is an association between CEE+MPA–induced new-onset breast tenderness and breast cancer risk," lead author Carolyn J. Crandall, MD, MS, from the David Geffen School of Medicine at University of Southern California, Los Angeles, said in a news release.

In the Women's Health Initiative (WHI) Estrogen Plus Progestin Trial, postmenopausal women with an intact uterus were randomly assigned to receive daily CEE+MPA (0.625/2.5 mg; n = 8506) or placebo (n = 8102). Mammography and clinical breast examination were performed at baseline and once yearly, and self-reported breast tenderness was evaluated at baseline and at 12 months. During follow-up (mean duration, 5.6 years), medical record review allowed confirmation of invasive breast cancer incidence.

Among 14,538 women who did not report breast tenderness at baseline, new-onset breast tenderness after 12 months occurred in 36.1% of those randomly assigned to CEE+MPA vs 11.8% of those in the placebo group (P < .001). Among women receiving CEE+MPA, those with new-onset breast tenderness had significantly higher breast cancer risk vs those without self-reported tenderness (hazard ratio, 1.48; 95% confidence interval, 1.08 - 2.03; P = .02).

"Is it because the hormone therapy is causing breast-tissue cells to multiply more rapidly, which causes breast tenderness and at the same time indicates increased cancer risk?" Dr. Crandall said. "We need to figure out what makes certain women more susceptible to developing breast tenderness during hormone therapy than other women."

Breast cancer risk was not significantly associated with new-onset breast tenderness in the placebo group (P = .97).

Limitations of this study include annual vs more frequent assessment of breast tenderness, relatively high rates of discontinuation of combination therapy and of crossover from placebo to active therapy, and lack of generalizability to other types of hormonal therapy.

"New-onset breast tenderness during conjugated equine estrogens plus medroxyprogesterone therapy was associated with increased breast cancer risk," the study authors write. "The sensitivity and specificity of the association between breast tenderness and breast cancer were similar in magnitude to those of the Gail model."

The National Heart, Lung, and Blood Institute, National Institutes of Health, US Department of Health and Human Services supported the WHI. Dr. Crandall's work was supported by the National Institute on Aging, National Institutes of Health, and the Tarlow-Eisner-Moss Research Endowment of the Iris Cantor–UCLA Women's Health Center. Wyeth-Ayerst Research Laboratories supplied the active study drug and placebo. One of the study authors (Dr. Chlebowski) has disclosed various financial relationships with Astra-Zeneca, Eli Lilly & Co, Novartis International AG, Wyeth Pharmaceuticals, and Pfizer Inc.

Arch Intern Med. 2009;169:1684-1691.

Additional Resources

More information on breast cancer and hormone therapy is available on the Women's Health Inititaive's Web site and also on the National Cancer Institute's Web site.

Clinical Context

Women with increased breast density on mammography results have a higher risk for breast cancer, and a previous study suggests that breast symptoms in women during menopause may predict the degree of breast density. In another study by Crandall and colleagues, which was published in the August 14-28 issue of the Archives of Internal Medicine, middle-aged and older women with new-onset breast discomfort had a significant 3.9% increase in total breast density vs women who did not have discomfort. Although participants in this research were enrolled in a trial of postmenopausal hormone therapy, the positive relationship between breast density and breast discomfort was present whether they were receiving active treatment or placebo.

Postmenopausal hormone therapy can increase breast density, and breast discomfort as a marker may be useful to identify women with a higher risk for breast cancer. The current study examines the relationship between breast discomfort and breast cancer using data from the WHI.