Study: Hormone therapy and breast cancer risk after ovary removal in women with a BRCA1 mutation


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Women with BRCA1 mutations who have had risk-reducing ovary removal and have never been diagnosed with breast cancer

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Checked People with a genetic mutation linked to cancer risk

Checked Previvors

Checked Women under 45

Checked Women over 45

Checked Special populations: BRCA1 previvors who have or are considering removal of their ovaries


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Does hormone therapy (HT) alter the risk of breast cancer for woman carrying a BRCA1 mutation who have never been diagnosed with cancer? In this study, researchers showed that among women with BRCA1 mutations, HT use did not increase breast cancer rates for 10 years after ovary removal. More women taking combined estrogen plus progesterone developed breast cancer compared to those taking estrogen only, though this difference was not statistically significant. (9/7/18)

Contents

At a glance Media coverage
Findings     In-depth               
Clinical trials Limitation
Questions for your doctor             Resources and references                               


STUDY AT A GLANCE

This study is about:

Whether hormone therapy (HT) started after removal of the ovaries is associated with increased breast cancer risk among women with BRCA1 mutations who have never been diagnosed with cancer.

Why is this study important?

HT alleviates symptoms of menopause associated with removal of the ovaries (oophorectomy). Although retrospective review of medical records show that HT does not appear to change the risk of breast cancer for women with BRCA mutations who had their ovaries removed, no prospective study has examined this issue. Knowing how HTs affect breast cancer risk may be helpful for decision making by women with BRCA1 mutations.

Study findings: 

This study followed 872 women with BRCA1 mutations who had risk-reducing oophorectomy. Among these women, 43% chose to use HTs and 57% did not. During the study period, 92 (10.6%) of the participants were diagnosed with breast cancer:

  • There was no increase in breast cancer between those who used HT compared to those who did not.
  • The rate of breast cancer differed by the type of HT used:
    • 12% of women who used estrogen-only HT were diagnosed with breast cancer.
    • 22% of women who used progesterone-estrogen combination HTs were diagnosed with breast cancer.
    • While this difference was seen, it did not reach statistical significance. However, the number of women taking progesterone-estrogen HT was small, so subtle differences may be undetectable.
    • Of note, this study suggests that estrogen alone could be associated with some benefit. For every year on estrogen-only HT, there was a relative reduction of risk compared to women who took no hormones. This same protective effect was not seen in the estrogen-progesterone combination HT. More research is needed to determine the long term benefits of estrogen-only HT.

What does this mean for me?

National guidelines recommend that all women with a BRCA1 mutation have their ovaries and fallopian tubes removed between the ages of 35-40 to lower their risk for ovarian cancer. If you are a BRCA1 previvor who has had or will have your ovaries removed, this study showed that using hormone replacement therapy for 10 years will not increase your risk of breast cancer.

Although not statistically significant, breast cancer rates were higher in women who took HT that contains progesterone compared with women who took estrogen-only HT. It’s important to note that estrogen-only HT can increase the risk for uterine cancer. Progesterone is often given to women who have had risk-reducing ovary removal but who have not removed their uterus. Progesterone can lower the risk for uterine cancer in women who take estrogen. Women who are planning risk-reducing removal of their ovaries should speak with their health care provider about whether or not they should remove their uterus at the time of surgery.

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Expert Guidelines

The National Comprehensive Cancer Network (NCCN) creates guidelines for the management of risk in women at high risk for cancer. 

Guidelines for oophorectomy in high risk women

  • NCCN recommends risk-reducing salpingo-oophorectomy for women with BRCA1 and BRCA2 mutations.
    • For women with BRCA1 mutations the surgery is recommended between age 35 and 40 and upon completion of child bearing.
    • For women with BRCA2 mutations they state that delaying risk-reducing removal of ovaries and fallopian tubes until age 40-45 is “reasonable."
  • NCCN suggests that women with Lynch Syndrome, BRIP1 or RAD51C or RAD51D consider undergoing the surgery.

Guidelines for hormone replacement after salpingo-oophorectomy in high risk women

In their guidelines NCCN also states that hormone replacement therapy in women who have RRSO does not negate the reduction in breast cancer risk associated with the surgery. However they do highlight the limitations of the existing research .

The North American Menopause Society is a professional society of experts in the field of menopause. In 2017 they released a position statement on hormone replacement therapy, which includes the following: 

  • Menopause symptoms and a variety of symptoms and diseases are more likely to occur in women who have surgical menopause from ovary removal. These symptoms can have a major effect on quality of life and potential adverse effects on the cardiovascular system, bone, mood, sexual health and cognition, which have been shown in observational studies to be lessened by estrogen therapy. 
  • Unless contraindications are present, estrogen therapy is indicated for women who have removed both ovaries, to reduce their risk of sexual side effects, bone loss, heart disease and cognitive decline. For women who retain their uterus, endometrial protection (eg-progesterone) is indicated.

Specific to women with BRCA1 or BRCA2 mutations who have removed their ovaries to lower their risk for cancer, they include the following:

  • For women with BRCA1 or BRCA2 mutations who have not be diagnosed with breast there is some evidence suggesting that that hormone therapy use after oophorectomy does not increase the risk for breast cancer any further.
  • Considerations should be made about the benefits of estrogen to prevent health risks caused by surgical menopause.
  • Considerations should be made (based on a limited amount of data) about hormone therapy until age 52 with discussions about longer use based on the individual patient.

Questions To Ask Your Health Care Provider

  • Should I consider using HT after risk-reducing ovary removal? After menopause?
  • What kind of HT would be most appropriate for me?
  • What are other options for managing menopause without HT?
  • What risks are associated with taking or not taking HT after removal of my ovaries?
  • Can you refer me to a menopause expert?

 

Open Clinical Trials

NCT03815929: Oophorectomy, Estrogen Therapy and Cardiovascular Disease Risk in Young Women. Researchers are trying to assess the best dose of estrogen for decreasing heart disease in women who have removed their ovaries before the age of 46.

NCT02760849: Surgery in Preventing Ovarian Cancer in Patients With Genetic Mutations (WISP Study). The goal of the WISP Study is to compare whether removal of fallopian tubes only, delaying removal of the ovaries can safely improve sexual functioning and menopausal symptoms compared to standard risk-reducing removal of the ovaries and fallopian tubes (also known as risk-reducing salpingo-oophorectomy or RRSO).

IN-DEPTH REVIEW OF RESEARCH
Study background:

Women with BRCA1 mutations have a greater risk of ovarian and breast cancers: about 44% risk of ovarian cancer and 72% risk of breast cancer by age 80. The ovaries are a natural source of estrogen and progesterone; risk-reducing removal of the ovaries (oophorectomy) and fallopian tubes reduces the risk of ovarian cancer by 80%, but also causes surgical menopause. To reduce menopause symptoms, some women elect to use hormone therapy (HT). HT usually contains estrogen and/or progesterone.

How HT use affects breast cancer risk in women with BRCA1 and BRCA2 mutations has been unclear. Several studies have shown contradictory results among women in the general population who took hormones after natural menopause. In the Women's Health Initiative (WHI)—a very well designed and large study—women using progesterone plus estrogen (versus placebo) had increased rates of breast cancer and heart disease. The estrogen-only group of the WHI had an increased risk of stroke but a decreased risk of breast cancer.

The researchers of this study showed in a prior case-control study that women with BRCA1 mutations who used HT did not have an increase in breast cancer rates. Here they conduct a prospective study following 872 women with BRCA1 mutations who had risk-reducing removal of their ovaries.

Researchers of this study wanted to know:

Whether hormone therapy (HT) started after removal of the ovaries increases breast cancer risk among women with BRCA1 mutations who have never been diagnosed with cancer.

Populations looked at in this study:

Participants in this study were women from over 80 centers in 17 countries who have BRCA1 mutations and had bilateral oophorectomies (both ovaries removed). Women were excluded if they had a prior cancer, did not have a bilateral oophorectomy during the study period, had bilateral mastectomy (breast removal) during the study period or did not complete survey questionnaires.

Study findings:  

This study followed 872 women with BRCA1 mutations who had had risk-reducing ovary removal (oophorectomy). Participants filled out questionnaires every 2 years about their history of cancer, reproductive and medical history, and HT use.

  • Among the 872 women with BRCA1 mutations, 43% chose to use HTs after ovary removal and 57% did not. 

Participants were asked if they had been diagnosed with invasive breast cancer. Study researchers looked at whether the women who reported a breast cancer diagnosis had used HTs or not.

  • 10.9% (92 women of all participants) had been diagnosed with breast cancer.

No statistical difference in breast cancer rates was found between women who did or did not use HTs. This indicates that HT use in general is not associated with increased breast cancer risk.

  • 10.3% of women who used HTs were diagnosed with breast cancer.
  • 10.7% of women who did not use HTs were diagnosed with breast cancer.

Researchers looked at the type of HT used by women. The rate of breast cancer differed by the type of HT used. This difference was greater for women who had ovary removal before age 45.

  • 12% of women who used estrogen-only HT were diagnosed with breast cancer.
  • 22% of women who used progesterone-estrogen combination HTs were diagnosed with breast cancer.
  • While this difference was seen, it did not reach statistical significance. Only 66 women used progesterone-estrogen combination HTs. Because the number of women taking progesterone-estrogen HT was small, subtle differences may be undetectable.
  • The potential benefit of estrogen-only HT over estrogen plus progesterone HT needs further study.
  • Of note, breast cancer risk was reduced by 8% for each year of estrogen-only HT use (for example, a 10.6% baseline risk would be reduced to 9.7% after one year of estrogen only HT use and 8.9% in 2 years of estrogen only HT use).

Limitations:

One limitation of this study is that the data came from self-reported questionnaires. However, researchers pointed out that prior studies suggest self-reported and medical records generally correspond.

This study assessed breast cancer rates for a 10-year period after ovary removal. It is unknown what results would be for HT use for longer periods of time.

This study examined the risk of breast cancer associated with HT use after ovary removal only for women with BRCA1 mutations. Women with BRCA2 mutations and other mutations are at high risk for breast and ovarian cancer as well. Researchers recruited women with BRCA2 mutations for this study but too few participants with BRCA2 were available to reach any direct conclusions. Whether results would be similar for women with BRCA2 mutations or other breast cancer predisposing mutations is an important question that is not addressed by this study. Because women with BRCA2 mutations, like women with BRCA1 mutations, often have hormone receptor-positive tumors, study researchers speculate that the results may be similar. This idea needs to be tested in future studies.

The impact of HTs on women who have not removed their ovaries was not examined; only women who had undergone risk-reducing ovarian removal were evaluated. However, a case-control study by the same researchers previously showed that women with BRCA1 mutations without ovary removal who took HTs did not have increased rates of breast cancer as compared to women with BRCA1 mutations without ovary removal who did not take HTs.

The differences in breast cancer rates among women who used different types of HTs indicated that estrogen-only HT use may be beneficial. It is possible that estrogen-progesterone HTs may be detrimental (based on trends in this study and data in other studies). However, not enough study participants used estrogen-progesterone HTs to adequately assess this specific HT.

Conclusions:

If you are a previvor who has had or will have ovarian removal, this study suggests that your risk of breast cancer is not increased if you choose to use hormone replacement therapy. Estrogen-only HT is associated with less breast cancer risk than HT which contains progesterone.

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Posted 9/7/18

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