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Study: Mutations in BRCA1 or BRCA2 may increase risk for endometrial cancer

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Contents

At a glance Clinical trials
Study findings Guidelines
Strengths and limitations Questions for your doctor
What does this mean for me? Resources
In-depth  

 

STUDY AT A GLANCE
What is this study about?

This study looked at whether women with an inherited 1 or mutation are at increased risk of developing endometrial cancer.

 

Why is this study important?

The exact risk for endometrial cancer in women with mutations is not clear. National guidelines recommend risk-reducing salpingo-oophorectomy (removal of the ovaries and ) for women with a or mutation. People with an inherited mutation should know their overall risk for endometrial cancer. When considering risk-reducing surgery to remove their ovaries and , knowing their risk for endometrial cancer can help women decide whether to also remove their uterus at the same time.

 

Study findings

This study looked at the endometrial cancer risk between women with an inherited mutation who were enrolled in the Hereditary Breast and Ovarian study in the Netherlands as compared to two groups:

  • The general population of Dutch women.
  • Women without a mutation who had family members with a known mutation.

Among women whose family had a mutation, those who had the mutation and those who did not were followed for up to 27 years or until they died or were diagnosed with cancer.

 

Lifetime risk for developing endometrial cancer

This study showed that Dutch women with a or mutation had a slightly increased lifetime risk of endometrial cancer: 2.0-3.4 percent depending on the mutation compared to 1.0-1.4 percent among women in the general Dutch population. (Women in the US have 3 percent risk.)

Women who do not have their family’s known mutation are an excellent comparison group because they are expected to share many genetic and environmental features (more than with the general population).

  • In this study, the lifetime risk of endometrial cancer for mutation carriers was 3.4 percent.
    • Women with a mutation were more than three times more likely to develop endometrial cancer compared with women in the general Dutch population.
    • Women with a mutation were also about three times more likely to develop endometrial cancer compared to women who did not have their family’s known mutation.
  • In this study, the lifetime risk of endometrial cancer for mutation carriers was 2 percent.
    • Women with a mutation were almost twice as likely to develop endometrial cancer than women in the general population. However, this result was barely significant (2.0% compared to 1.0-1.4%).
    • In a more direct comparison, women with a mutation did not have an increased risk of endometrial cancer when compared to women without their family’s known mutation.
      • This suggests that mutations may not increase endometrial cancer risk.

 

Type of endometrial cancer risk
Although the risks of developing endometrial cancer were low in women with a mutation, some differences were observed:

  • Women with a mutation, especially those with a mutation, were more likely to be diagnosed with a more aggressive form of endometrial cancer called serous-like endometrial cancer compared with women in the general population.
  • Women with an inherited mutation were more likely to develop serous-like endometrial cancer compared to women without their family’s known mutation (the better comparison group).
  • Women with a mutation did not have a greater risk for any form of endometrial cancer compared to women known to not have a mutation.

 

Strengths and limitations

Strengths

  • The study followed participants over a long period (average follow-up was 22.5 years), allowing researchers to evaluate long-term trends.
  • This study compared people with mutations to family members without mutations. This is stronger than a comparison to the general population because the number of people with a mutation in or in the general population is unknown.

Limitations

  • The study only looked at endometrial cancer risk in people with inherited and mutations. It did not look at inherited mutations in other genes that are known to increase cancer (e.g., , , , , ).
  • The researchers did not have access to additional participant health information, including other risk factors for endometrial cancer, making it impossible to account for these factors in the analysis.
  • The study only included women in the Netherlands. This limits its generalizability for women of other nationalities.
  • When people had risk-reducing removal of ovaries and (), researchers did not know whether they also had a hysterectomy (uterus removal). Because people with and an intact uterus are still be at risk for endometrial cancer, they did not exclude anyone with an surgery (include anyone without a uterus and therefore much decreased risk of endometrial cancer). However, they note that hysterectomy is not commonly done with surgery in the Netherlands so this may not include many participants.
     

What does this mean for me?

Women with a or mutation who are considering risk-reducing salpingo-oophorectomy () to remove their ovaries and may also want to consider hysterectomy (removal of the uterus) at the same time. For women with a uterus, estrogen plus progesterone hormone therapy is recommended after risk-reducing removal of the ovaries and . For pre-menopausal women, hormone replacement therapy has not been shown to increase the risk of breast cancer. However, there may be some risk for post-menopausal women. Removing the uterus allows for simplified hormone replacement therapy with estrogen alone, to avoid potential risk of breast cancer.

Although the lifetime risk for endometrial cancer is very low among individuals with mutations, some women whose risk is high due to personal risk factors or family history of endometrial cancer may choose to have risk-reducing hysterectomy.

Current guidelines recommend that women with an inherited mutation speak with their healthcare provider about the benefits and risks of hysterectomy at the time of risk-reducing salpingo-oophorectomy (removal of the ovaries and ). You can read more about the benefits and risks of these risk-reducing surgeries here.

If you have a mutation and you have had risk-reducing salpingo-oophorectomy but kept your uterus, you may still have increased risk for endometrial cancer. Currently, experts do not recommend hysterectomy to reduce endometrial cancer risk for women who did not remove their uterus at the time of their .

The most common sign of endometrial cancer is abnormal vaginal bleeding. Women who have additional risks, symptoms or concerns about endometrial cancer should speak with their surgeon about the benefits and risks of hysterectomy.

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posted 11/30/21

 

References

de Jong MM, de Kroon CD, Jenner DJ, et al. Endometrial cancer risk in women with germline or mutations: multicenter cohort study. Journal of the National Cancer Institute; 2021; 113 (9): djab036. Published online March 12, 2021.

Sherman ME, Foulkes WD. BRCA1/2 and endometrial cancer risk: implications for management. Journal of the National Cancer Institute; 2021; 113 (9): djab037. Published online March 12, 2021.

Nahshon C, Lavie O. RE: Endometrial cancer risk in women with germline or mutations: multicenter cohort study. Journal of the National Cancer Institute; 2021; 00 (0): djab154. Published online August 23, 2021.

de Kroon CD, de Jonge MM, Bosse T, van Asperen CJ. Response to Nahshon and Lavie. Journal of the National Cancer Institute; 2021; 00 (0): djab155. Published online August 23, 2021.

 

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.

This article is relevant for:

People with BRCA1 or BRCA2 mutations

This article is also relevant for:

People with breast cancer

People with endometrial cancer

People with ovarian cancer

Previvors

People with a family history of cancer

People with a genetic mutation linked to cancer risk

Be part of XRAY:

Expert Guidelines Expert Guidelines

The National Comprehensive Cancer Network (NCCN) provides guidelines for management of gynecologic cancer risk in people with and mutations. 

Prevention 

  • Risk-reducing removal of ovaries and , (known as salpingo-oophorectomy) is recommended between ages 35-40 for and 40-45 for and upon completion of childbearing.
    • Research studies have shown that removing the ovaries can increase how long women with  mutations live. 
    • Women should talk with their doctors about the effects of early menopause and options for managing them.
  • Women should talk with their doctors about the risks and benefits of keeping or removing their uterus (hysterectomy), including:
    • Women with a  mutation have an increased risk for a rare form of aggressive uterine cancer; hysterectomy removes this risk. 
    • For women considering hormone replacement after surgery, the presence or absence of a uterus can affect the choice of hormones used.
      • Estrogen-only hormone replacement is less likely to increase the risk for breast cancer. However, estrogen-only hormone replacement increases the risk for uterine cancer. Women who still have their uterus are typically given estrogent and progesterone hormone replacement.
      • Adding progesterone to estrogen hormone replacement can protect against uterine cancer. However, the combination of these hormones may increase the risk for breast cancer than estrogen alone. 
    • Any medical history of fibroids or other uterine or cervicak issues may justify a hysterectomy. 
  • Oral contraceptives (birth control pills) have been shown to lower the risk for ovarian cancer in women with  mutations. Research on the affect of oral contraceptives on breast cancer risk has been mixed. Women should discuss the benefits and risks of oral contraceptives for lowering ovarian cancer risk with their doctors. 
  • Removal of the  only () is being studied as an option for lowering risk in high-risk women who are not ready to remove their ovaries. Studies on the effects of  have not been completed. At this time it is not known if  lowers the risk for ovarian cancer in high risk women. 
    • Consider enrolling in a research study looking at this procedure to lower cancer risk.

Screening

  • Routine ovarian cancer screening using transvaginal  and a  blood test has not shown benefit. However, some doctors still recommend screening, starting at age 30-35.
  • Women should be aware of the symptoms of gynecologic cancer and report abnormalities to their doctors. 

Updated: 02/05/2022

Questions to Ask Questions to Ask Your Doctor

  • How can I reduce my risk of endometrial cancer?
  • What are the signs of endometrial cancer?
  • I have a personal history of breast or ovarian cancer. Am I at greater risk for endometrial cancer?
  • I have a diagnosis of endometrial cancer. Do I need to be tested for an inherited mutation?
  • I have an inherited mutation. Should I be screened for endometrial cancer?

Peer Support Peer Support

The following organizations offer peer support services for people with, or at high risk for endometrial cancer:

Updated: 11/27/2021

IN-DEPTH REVIEW OF RESEARCH

Study background

and mutations are known to put women at greater risk for breast, ovarian and pancreatic cancer. Scientists have speculated that these gene mutations may put women at greater risk for other cancers as well, including endometrial cancer.

Research linking mutations to endometrial cancer has been inconclusive. Some studies have suggested that mutations increase the risk for an aggressive but rare form of endometrial cancer. Other studies have suggested that mutations do not increase endometrial cancer risk but that women with mutations who previously took tamoxifen to prevent or treat breast cancer may have increased endometrial cancer risk. More studies are needed to determine the level of endometrial cancer risk in people with a or mutation.

 

Researchers of this study wanted to know

The researchers wanted to know if people with inherited or mutations are at greater risk for endometrial cancer.

 

Populations looked at in this study

The study looked at 5,980 women with inherited mutations:

  • 3,788 had a mutation
  • 2,151 had a mutation
  • 41 had both a and mutation

The study compared women with mutations to 8,451 women from BRCA-positive families who had tested negative for their family's gene mutation, as well as the general population of Dutch women.

Participants were identified from the Dutch cohort (HEBON) of the Hereditary Breast and Ovarian cancer study. Women without a gene mutation were required to have a family member with a known mutation. All participants were at least age 25 (the age at which women are considered at risk for endometrial cancer) when they enrolled in the study. Women diagnosed with endometrial cancer before the start of the study or before the age of 25 were excluded.

 

Study design

The frequency of endometrial cancer in women with a mutation was compared to two populations:

  • The general population of Dutch women (derived from data from the Netherland Cancer Registry).
  • Study participants without mutations who were from families with gene mutations.

Women with a mutation were followed from January 1, 1989, or the date they turned 25, to January 1, 2016. Women without mutations were followed from January 1, 1989, to January 1, 2012. Follow-ups were concluded due to death or an endometrial cancer diagnosis.

Tissue samples from women with an endometrial cancer diagnosis were evaluated by a pathologist to determine the subtype of cancer. Researchers then performed a statistical analysis to compare the rates of endometrial cancer in study groups and the rates of each subtype of endometrial cancer.

 

Study findings

Study findings showed that the estimated lifetime risk (by age 75) for developing endometrial cancer in women with an inherited mutation was low. A total of 3.4 percent women with mutations were likely to develop endometrial cancer in their lifetime compared to women with mutations, who had a 2 percent chance of developing endometrial cancer in their lifetime.

Comparison analyses showed that:

  • Compared with the women in the general Dutch population, women with a mutation were three times more likely to develop any form of endometrial cancer.
    • Endometrial cancer in women with a mutation was 12 times more likely to be a subtype called serous-like (an aggressive form of cancer with poor prognosis) compared to women in the general population.
  • Compared with women in the general population, women with a mutation were almost twice as likely to develop endometrial cancer. However, this result was barely significant and does not differ much from the estimated risk for women in the general Dutch population (1.0%-1.4%).
  • The overall risk for endometrial cancer was greatest in women with a mutation who were between the ages 25 to 40 compared with the general population of women.
  • The risk for a serous-like endometrial cancer was most prevalent in women from ages 60 to 80.
  • Compared with women without a mutation who came from families with a known mutation, women with a mutation were approximately three times more likely to develop endometrial cancer in their lifetime.
    • Endometrial cancer in women with mutation was 8 times more likely to be diagnosed as serous-like cancer and 11 times more likely to be diagnosed as p53-abnormal cancer (another aggressive cancer subtype), compared to women without a mutation.
  • Women with a mutation did not have a greater risk for any form of endometrial cancer compared to women without a mutation whose family had a known mutation.

 

Tamoxifen and endometrial cancer risk

Tamoxifen and aromatase inhibitors are a type of hormone therapy (HT) used to treat some breast cancers. However, using HT is believed to increase the risk of endometrial cancer. To test this belief, researchers looked at endometrial cancer among women with an inherited mutation who had any type of HT compared to those who did not have HT.

  • Women with an inherited or mutation had a similar risk of endometrial cancer whether or not they had hormone therapy.

 

Strengths and limitations

Strengths

  • The study followed participants over a long period (average follow-up was 22.5 years), allowing researchers to evaluate long-term trends.
  • This study compares people with mutations to family members without mutations. This is a stronger comparison than to the general population in which the portion of people with a mutation is unknown. The families of people with mutations are expected to share many genetic and environmental features (more than with the general population).
  • Researchers were able to account for the possible role of breast cancer treatment on endometrial cancer risk.

Limitations

  • While the study included over 5,000 participants, only 58 endometrial cancers were observed.
  • The study only looked at mutations in and . It did not include other cancer risk genes (e.g., , , , , ).
  • The researchers did not have access to participants’ risk factors for endometrial cancer or additional health information, making it impossible to account for these factors in the statistical analysis.
  • The study only included women in the Netherlands, limiting its generalizability to women of other nationalities or racial backgrounds.

 

Context

Endometrial cancer is the most common gynecologic malignancy worldwide. Although and mutations have been associated with increased risk for breast and ovarian cancer, previous studies were unable to determine whether these mutations also increase endometrial cancer risk. Like this study, some (but not all) studies have shown an increased risk for endometrial cancer, mainly in carriers, with the highest risk observed for serous-like endometrial cancer.

 

Conclusions

Similar to some studies, this study showed that an inherited mutation may be a risk factor for endometrial cancer. Although the lifetime risk for endometrial cancer in this study was low, women with a mutation had a two- or three-fold higher rate of endometrial cancer compared with women without a mutation. Women with a mutation had a 3.4 percent chance of developing endometrial cancer by age 75 compared to 2.0 percent (in the general Dutch population). Among women with a mutation, the risk of endometrial cancer was similar from that of women without a mutation. Endometrial cancer in people with a mutation is more likely to be an aggressive type that is linked to poorer outcomes.


Share your thoughts on this XRAY review by taking our brief survey.  

posted 11/30/21

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