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Long-Term Follow-Up Suggests Estrogen-Only and Combination Hormone Replacement Therapy Have Opposite Effects on Breast Cancer Risk

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Estrogen-only hormone replacement therapy seems to lower breast cancer risk, while combination hormone replacement therapy increases risk, according to long-term data from the Women’s Health Initiative.

The research was presented on Dec. 13, 2019, at the San Antonio Breast Cancer Symposium. Read the abstract of “Long-term influence of estrogen plus progestin and estrogen alone use on breast cancer incidence: The Women's Health Initiative randomized trials.”

In the video below, Marisa Weiss, M.D., founder and chief medical officer, interviews Rowan T. Chlebowski, M.D., chief of the Division of Medical Oncology and Hematology at Harbor-UCLA Medical Center and an investigator at The Lundquist Institute, who presented the results.

The Women’s Health Initiative

This study is part of the very large Women’s Health Initiative Clinical Trial and the Women’s Health Initiative Observational Study. Both studies are commonly called the WHI. Together, the two studies include information from more than 161,608 postmenopausal women who were ages 50 to 79 when they joined between 1993 to 1998. The WHI wants to find any links between health, diet, and lifestyle factors and health problems such as cancer.

Hormone replacement therapy

Many postmenopausal women take hormone replacement therapy, also called HRT, to ease menopausal symptoms such as hot flashes, night sweats, and fatigue, and also to reduce bone loss.

There are two main types of HRT:

  • combination HRT contains the hormones estrogen and progesterone
  • estrogen-only HRT contains only estrogen

In 2002, a study found a link between HRT and an increase in breast cancer risk, which caused a number of women to stop taking HRT. Still, HRT was often the only effective treatment for troubling menopausal symptoms for many women.

Since that time, more studies have looked at the topic with longer follow-up. The results have suggested the relationship between HRT and breast cancer risk is more nuanced, and using HRT remains a controversial topic.

In June 2017, the North American Menopause Society updated its guidelines on using HRT. The guidelines say that for women younger than 60 or within 10 years of menopause who have no other contraindications (medical reasons to avoid HRT), the benefits of HRT outweigh the risks when treating menopausal symptoms, especially hot flashes, and for women who have a higher-than-average risk of bone loss or breaking a bone.

It is extremely important to know that being diagnosed with breast cancer is a contraindication for HRT. Women who have a history of breast cancer should not take HRT.

In 2015, an analysis of data from the WHI with about 13 years of follow-up found that the effect of HRT on breast cancer risk changed over time:

  • Women who were taking combination HRT had a higher risk of breast cancer, but that risk dropped about 3 years after the women stopped taking the combination HRT. Still, their risk stayed higher than average.
  • While taking estrogen-only HRT, women were about 20% less likely to be diagnosed with breast cancer compared to women not taking HRT. This decrease in risk lasted for a few years after the women stopped taking estrogen-only HRT. Still, a few years later, this decrease in risk seemed to go away.

This latest WHI analysis has about 5 more years of follow-up.

It’s also important to know that a meta-analysis of 58 studies published in 2019 found that both estrogen-only HRT and combination HRT increased the risk of breast cancer.

A meta-analysis combines and analyzes the results of many earlier studies.

About the study

The WHI started in 1993 and included 27,347 postmenopausal women ages 50 to 79. The 16,608 women who had a uterus were randomly assigned to get either:

  • combination HRT (combination HRT contains both estrogen and progesterone)
  • a placebo (a sugar pill that looked just like the combination HRT pill)

for nearly 6 years.

The 10,739 women who had had a hysterectomy and so didn’t have a uterus were randomly assigned to get either:

  • estrogen-only HRT
  • a placebo (a sugar pill that looked just liked estrogen-only HRT)

for about 7 years.

In 2002, the combination HRT part of the WHI was stopped after about 6 years of follow-up because an early analysis showed that the women taking combination HRT were much more likely to be diagnosed with breast cancer compared to women taking the placebo. In 2004, the estrogen-only HRT part of the study also was stopped because of concerns about the women’s risk of breast cancer.

When the two parts of the WHI study ended, more than 12,700 women who had been taking combination HRT and more than 7,640 women who had been taking estrogen-only HRT agreed to be followed for more time. Fewer than 4% of the women continued to take HRT (either combination or estrogen-only) after the WHI HRT trial officially ended.

After about 16 years of follow-up, 520 cases of breast cancer were diagnosed in the group of women treated with estrogen-only HRT. Compared to women who had been treated with placebo, women treated with estrogen-only HRT were 23% less likely to have been diagnosed with breast cancer and 44% less likely to die from the disease.

After about 18 years of follow-up, 1,003 cases of breast cancer were diagnosed in the group of women treated with combination HRT. Compared with women who had been treated with placebo, women treated with combination HRT were 29% more likely to be diagnosed with breast cancer. Women treated with combination HRT also were more likely to die from breast cancer compared to women treated with placebo, but this difference was not statistically significant, which means that it could have been due to chance and not because of the difference in treatment.

“In the two randomized, placebo-controlled WHI clinical trials involving 27,347 postmenopausal women, [combination HRT] significantly increased breast cancer incidence, with these adverse effects persisting over a decade after discontinuing use,” said Chlebowski. “And in contrast to decades of observational study findings, in the WHI trial, [estrogen-only HRT] significantly reduced breast cancer incidence and significantly reduced deaths from breast cancer, with these favorable effects persisting over a decade after discontinuing use.

“While there are differences in characteristics of participants in the observational studies compared with those in the WHI randomized trials, the discordance between the randomized clinical trial findings with respect to estrogen alone use and observational findings are difficult to reconcile,” he added.

What this means for you

While the WHI found that estrogen-only HRT reduced breast cancer risk, a number of other studies have found that both types of HRT increase breast cancer risk. So the issue is far from resolved.

Menopausal side effects can dramatically reduce quality of life for some women. These women have to weigh the benefits of HRT against the risks. If you're having severe hot flashes or other menopausal side effects and are considering HRT, talk to your doctor about all of your options. Ask how you can minimize your breast cancer risk and relieve your symptoms. Be sure to discuss the pros and cons of different types and doses of HRT.

If you’ve been diagnosed with breast cancer, you should not take any type of HRT.

If you do decide to take HRT, try to take the lowest dose possible that still meets your treatment goals. You may want to ask your doctor if estrogen-only HRT is a good option for you. You also may want to ask your doctor about vaginal or transdermal HRT.

To start the discussion with your doctor, you may want to review the North American Menopause Society HRT guidelines:

  • The risks of HRT are different for different women, depending on type, dose, duration of use, route of administration, timing of initiation, and whether progestogen is needed. Treatment should be individualized using the best available evidence to maximize benefits and minimize risks, with periodic reevaluation of the benefits and risks of continuing HRT.
  • For women younger than 60 or who are within 10 years of menopause and have no contraindications, the benefits outweigh the risks for treating bothersome hot flashes and for women with higher-than-average risk of bone loss or fracture. Based on results from the Women's Health Initiative study, women who need to take HRT for a longer period of time should take estrogen-only HRT rather than combination HRT, which contains both estrogen and progesterone.
  • For women who start HRT more than 10 or 20 years after menopause starts or when they’re age 60 or older, the risks of HRT are greater than the benefits because HRT is linked to a higher risk of heart disease, stroke, blood clots, and dementia.
  • Women older than 60 or 65 don’t automatically have to stop taking HRT and can consider continuing HRT beyond age 65 for persistent hot flashes, quality-of-life issues, or prevention of osteoporosis after appropriate evaluation and counseling of the benefits and risks of HRT.
  • Vaginal estrogen (and systemic if required) or other non-estrogen therapies may be used at any age for prevention or treatment of vaginal dryness and other vaginal symptoms.

Learn more about menopause and ways to manage side effects on the Managing Menopausal Symptoms pages.

Written by: Jamie DePolo, senior editor

Reviewed by: Brian Wojciechowski, M.D., medical adviser

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