Study: Estrogen without progesterone for hormone replacement may lower breast cancer risk

Relevance: Medium-High

Strength of Science: Medium-High

Research Timeline: Post Approval

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What is this study about?

This study combines data from one large and nine small studies to determine how estrogen-only hormone replacement therapy after menopause affects the risk of developing breast cancer.

Why is this study important?

Prior research has shown that estrogen plus progesterone hormone therapy after menopause increases the risk of breast cancer.  However, while some studies have shown that taking estrogen without progesterone increased the risk of breast cancer, others reported that it decreased breast cancer risk.

This new study looks at the results of multiple past studies; it included only high-quality research known as randomized controlled trials. These types of trials help researchers compare multiple groups of people who received different types of medical care to determine whether their outcomes differed.

The large Women’s Health Initiative (WHI) study compared the outcomes of women who took estrogen without progesterone to those who did not did not take any hormone replacement. Participants who took estrogen alone were less likely to develop breast cancer and less likely to die of breast cancer than those who did not take any hormone replacement. In contrast, two other large studies found that estrogen alone increased a woman’s risk of developing breast cancer.

Study findings

Women who took estrogen-only hormone therapy after menopause have lower rates of breast cancer than those who did not take hormone therapy. These results come from an analysis of 10 randomized control trials. The largest—the Women’s Health Initiative—had the most (10,739) participants. Together, the nine smaller studies included 3,500 participants.

Researchers found that:

• In the combined 10 studies, women who took estrogen were 33% less likely to develop breast cancer than those who did not take hormone therapy.
  • At 10-year follow-up; results from the WHI study showed that estrogen alone compared to no hormone therapy decreased breast cancer risk by 37%.
  • Results for the 9 smaller studies were similar to the early results from the Women’s Health Initiative data. Together, the results from these studies showed that participants who took estrogen alone had a 35% lower risk of developing breast cancer.
• Women who started estrogen earlier saw a stronger protective effect, according to the data from the WHI.
• The type of estrogen taken (conjugated equine estrogen, Estradiol or estrone sulfate) did not affect the study results.

At the time of enrollment, all participants in the Women’s Health Initiative study:

• were postmenopausal
• had a hysterectomy
• had never been previously diagnosed with breast cancer
• had a normal mammogram

The other studies had similar criteria. However, some studies included women with a history of breast cancer, although no conclusions were made about this group.

Participants took estrogen for varying amounts of time, ranging from an average of two years in some studies to over seven years in the WHI study. WHI participants were followed for more than 20 years.

What does this mean for me?

If you are postmenopausal, have an average risk for breast cancer and are taking, or thinking of taking estrogen-only hormone replacement, you do not need to worry about it increasing your risk of breast cancer. These results do not recommend estrogen to prevent breast cancer. Dr. Pamela Goodwin of the University of Toronto, who commented on these results at the 2023 San Antonio Breast Cancer Symposium, made these points:

• This study included women who had hysterectomies. Other approved drugs are available for them to prevent breast cancer, some of which may be more effective than estrogen-only hormone replacement.
• Doctors still do not understand why estrogen appears to protect against breast cancer, since blocking estrogen can prevent a recurrence.

This study is unlikely to change clinical practice, although it may be reassuring to women who choose to take hormone replacement with estrogen alone. Importantly, other risks are associated with estrogen-only hormone replacement therapy, including an increased risk of stroke and blood clots.

For women with a uterus, progestogen must be prescribed along with estrogen to protect against uterine cancer.

This study did not specifically look at women with inherited mutations linked to breast cancer or women who had early-onset menopause due to risk-reducing surgery. A study by Joanne Kotosopolous and colleagues in 2018 suggest that women with BRCA1 mutations may safely take estrogen alone as hormone therapy. However, data is lacking for women with BRCA2 mutations – more research is needed to understand how taking estrogen as hormone therapy would impact women with a BRCA2 mutation.

If you are struggling with symptoms of menopause, experts trained in menopause management, such as members of the North American Menopause Society, can help you understand your options.

Reference

Chlebowski R, Aragaki A, Pan K, Mortimer J, et al. Randomized trials of estrogen-alone and breast cancer incidence: A meta-analysis. Poster Spotlight Session 7: Panel Discussion 1 Moderated by P. Goodwin. 2023 San Antonio Breast Cancer Symposium. Presented by J. Mortimer.

Chlebowski RT, Anderson GL, Aragaki AK, Manson JE, et al. Association of menopausal hormone therapy with breast cancer incidence and mortality during long-term follow-up of the Women's Health Initiative randomized clinical trials. JAMA. 2020 Jul 28;324(4):369-380.

Collaborative Group on Hormonal Factors in Breast Cancer. Type and timing of menopausal hormone therapy and breast cancer risk: individual participant meta-analysis of the worldwide epidemiological evidence. Lancet. 2019 Sep 28;394(10204):1159-1168.

Kotosopolous J, Gronwald J, Karlan BY, et al. Hormone replacement therapy after oophorectomy and breast cancer risk among BRCA1 mutation carriers. JAMA Oncology. 2018;4(8):1059–1065.

Disclosure: FORCE receives funding from industry sponsors, including companies that manufacture cancer drugs, tests and devices. All XRAYS articles are written independently of any sponsor and are reviewed by members of our Scientific Advisory Board prior to publication to assure scientific integrity.

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posted 2/13/24