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Menopausal hormone therapy (MHT) was tied to increased breast cancer risk in a global study -- but implications for individual patients are less clear.

In a meta-analysis of 58 studies including more than 100,000 women, those who reported ever using MHT had a 26% higher relative risk for developing breast cancer compared with never-users (RR 1.26, 95% CI 1.24-1.28), reported the Collaborative Group on Hormonal Factors in Breast Cancer. The four members of the writing committee were all from the Nuffield Department of Population Health at the University of Oxford, England.

In the study, online in , estrogen-progestogen and estrogen-only preparations both were tied to a significant excess risk for developing breast cancer -- albeit higher for combination estrogen-progestogen preparations -- with risk also dependent on the duration of use. This increased risk was also higher among current users of hormone therapy versus past users. Estrogen-only preparations included estradiol and equine estrogen, while estrogen-progestogen preparations included levonorgestrel, norethisterone acetate, and medroxyprogesterone acetate.

For current users on hormone therapy for 1-4 years, those on estrogen-progestogen preparations saw a higher relative risk versus women on estrogen-only preparations (RR 1.60, 95% CI 1.52-1.69 vs RR 1.17, 95% CI 1.10-1.26). The magnitude of this increased relative risk for breast cancer was even higher among current users of hormonal therapy for 5-14 years, particularly for combination preparations (estrogen-progestogen RR 2.08, 95% CI 2.02-2.15; estrogen-only RR 1.33, 95% CI 1.28-1.37).

This excess risk was not only associated with duration of use, but was also dependent on the frequency of hormone use, the researchers noted. Women who were daily users of menopausal hormones for 5-14 years had a significantly higher risk for breast cancer incidence compared with less frequent users (RR 2.30, 95% CI 2.21-2.40 vs RR 1.93, 95% CI 1.84-2.01).

Both oral and transdermal methods of administration showed an elevated breast cancer risk for current users on hormones for 5-14 years (oral RR 1.33, 95% CI 1.27-1.38; transdermal RR 1.35, 95% CI 1.25-1.46). Vaginal estrogen preparations, however, were not tied to an excess breast cancer risk -- likely due to their limitation of systemic exposure, the investigators suggested (RR 1.09, 95% CI 0.97-1.23 for 5-14 years of use).

In addition, the researchers said, it was not possible to quantify breast cancer risk in women who ceased menopausal hormone therapy more than 15 years previously.

In terms of specific tumor characteristics, current users of estrogen-progestogen hormones for 5-14 years saw a higher degree of risk for all variations related to estrogen-receptor status, tumor histology, and tumor spread versus estrogen-only users, with the results as follows:

• ER positive: RR 2.44 (95% CI 2.35-2.54) vs 1.45 (95% CI 1.38-1.53)

• ER negative: RR 1.42 (95% CI 1.30-1.55) vs 1.25 (95% CI 1.13-1.38)

• Lobular: RR 2.72 (95% CI 2.51-2.95) vs 1.58 (95% CI 1.43-1.75)

• Ductal: RR 1.89 (95% CI 1.82-1.97) vs 1.25 (95% CI 1.20-1.31)

• Localized to the breast: RR 2.07 (95% CI 1.97-2.17) vs 1.31 (95% CI 1.23-1.39)

• Spread beyond the breast: RR 1.89 (95% CI 1.78-2.02) vs 1.35 (95% CI 1.25-1.46)

The researchers noted that when estrogen-only hormone use among women with obesity was broken down by body mass index, there was no added excess breast cancer risk beyond their already elevated risk. There was also only a slightly increased risk for developing breast cancer for women with obesity on combination preparations.

"The clinical relevance of the main findings lies in the magnitude of the absolute risks during and after MHT use for women who start MHT at ages 40-59 years, but the public health relevance depends additionally on the numbers of women previously and currently exposed," the researchers wrote.

Even though "use of either type of MHT for less than 1 year was associated with little subsequent risk, for women of average weight in developed countries 5 years of use, starting at age 50 years, would cause an appreciable increase in the probability of developing breast cancer at ages 50-69 years."

Writing in an , however, Joanne Kotsopoulos, PhD, of the University of Toronto in Canada, said that when interpreting this study, it is important to keep in mind that the analysis was limited only to prospective studies, many of which included unavoidable biases. She also pointed out that MHT use frequently isn't continuous, and women may change the type of preparation used.

But the findings are definitely concerning, Kotsopoulos said. "Clinicians must heed the message of this study but also take a rational and comprehensive approach to the management of menopausal symptoms, with careful consideration of the risks and benefits of initiating MHT for each woman."

"This might be dependent on severity of the symptoms, contraindications for MHT (i.e., breast cancer, cardiovascular disease, and stroke), and BMI, and could take into account patient preference," she continued. "For likely candidates, MHT (preferably estrogen alone) should be initiated around the time of natural menopause and ideally limited to 5 years of use."

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