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Study: What is the risk for contralateral breast cancer in women with an inherited BRCA1, BRCA2 or TP53 mutation?

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Contents

At a glance                  Questions for your doctor
What does this mean for me? In-depth            
Clinical trials Limitations
Guidelines Resources


STUDY AT A GLANCE

This study is about:

The risk of breast cancer in the opposite breast among breast cancer patients who have an inherited mutation in , or .

Why is this study important?

Women who are diagnosed with breast cancer must make decisions about surgery to treat their current cancer, and to manage their risk for a future cancer diagnosis. Understanding their risk for a second breast cancer diagnosis can help these women make decisions.  

Study findings: 

A total of 397 women diagnosed with breast cancer under age 36 participated in this study.

  • 60% of women who were diagnosed before age 36 had an inherited mutation in a , or gene:
    • 53% had a mutation.
    • 7% had a mutation.
  • 25% of women with an inherited mutation had during the study:
    • Among women with a mutation, 23% had a .
    • Among women with a mutation, 25% had a .
    • Among women with a mutation, 30% had a .
  • The average time to a new diagnosis was 7 years, 7 months; this was similar for women with any of these three mutations.
  • 5% of women with no identified mutation had a contralateral breast cancer:
    • This included women with a known family history of breast and ovarian cancer (7%) who had contralateral breast cancer; this is similar to the group with no family history (8%). Among women with unknown family history 2% had a .

The annual rate of was almost 10 times higher in women who had an inherited mutation (3.4 percent) than among women who had no mutation (0.4%):

  • BRCA1/BRCA2
    • The annual rate of was 3.6% for women with an inherited mutation and 2.6% for women with an inherited mutation. 
    • The total risk of having breast cancer in the opposite breast 10 years after diagnosis was 32% for women with a mutation and 21% for women with a mutation.
  • P53
    • The annual rate of was 7% for women with a mutation in , twice the annual risk of women with a mutation and almost 18 times the risk of women who did not have a or mutation. 
    • 45% women with mutations in this study developed within 10 years of their original
    • 82% of women with mutations developed within 20 years of their original diagnosis.

Women with mutations were less likely to have risk-reducing mastectomy, despite having a high risk of having a (18 times more likely than women without a mutation and twice as likely as women with a mutation).

  • 6% of women with mutations had contralateral mastectomy compared to 16% women with mutations.

What does this mean for me?

If you have been diagnosed with breast cancer at a young age, experts recommend genetic counseling and testing for an inherited mutation. Genetic counseling before and after genetic testing is important to ensure that you understand the risks and benefits of genetic testing and your risk of additional cancers in the breast or elsewhere.

If you have been diagnosed with breast cancer and have an inherited mutation in a gene linked to breast cancer, you may want to discuss treatment options with your healthcare provider. The rate of is high among people with a mutation in , or . This is something that you may want to consider in your decision-making about surgical options, including , mastectomy for treatment or risk-reducing  mastectomy. Ask your physician how treatment options and follow-up is impacted by having an inherited mutation. Different treatments, surveillance or clinical trials may be available.

People with inherited mutations have an increased risk of radiation-induced tumors. If you have a mutation, talk with your healthcare provider about whether you should avoid radiation therapy.

The authors state:

"Women with mutations in these genes should be informed of their high risk of developing a to help guide their future risk management, including the option of bilateral/ contralateral mastectomy."

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Reference

Hyder Z, Harkness EF, Woodward ER, et al. “Risk of in Women with and without Pathogenic Variants in , , and Genes in Women with Very Early-Onset (<36 Years) Breast Cancer.” Cancers (Basel). 2020 Feb 7;12(2):378.

 

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:

Women diagnosed with breast cancer before age 40

This article is also relevant for:

Breast cancer survivors

ER/PR +

Her2+ breast cancer

People with a genetic mutation linked to cancer risk

Triple negative breast cancer

Women under 45

Newly diagnosed

People with a family history of cancer

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IN-DEPTH REVIEW OF RESEARCH

Study background:

The risk of breast cancer is greater among woman with an inherited mutation and depends on which gene is mutated. Mutations in and are associated with an increased risk of breast, ovarian and other cancers. The lifetime risk of breast cancer in women with or mutations is estimated to range from 55 to 85 percent. Inherited mutations in the gene lead to a disease called (LFS) that is associated with increased risk of several types of cancer at young ages. The number of people with mutations is much lower (about 1 in 5,000 to 20,000 people) than those with or 2 mutations (about 1 in 500 people). However, the lifetime risk of cancer for those with mutations is high—up to 85 percent—akin to mutations. Diagnosis of breast cancer at an early age is known to indicate high risk of an inherited mutation.

The presence of an inherited mutation also increases the risk of a second breast cancer in the opposite (contralateral) breast. A review of multiple studies reported that the 10-year cumulative risks of were 27 percent and 19 percent, respectively, among women with   and mutations. Data on among women with mutation is lacking, although the National Cancer Institute’s LFS Study observed that half of individuals developed a second primary cancer, with breast cancer being the most common second cancer diagnosis.

is generally thought to be a second primary cancer. These contralateral breast cancers may be have metastasized from the first primary cancer, although metastases typically have other patterns. Women who have an inherited mutation in a gene that predisposes them to breast cancer are predicted to have higher rates of second cancers in the breast or other susceptible organs. This study examined the frequency of inherited mutations and with a focus on women under age 36 with , and mutations.

Researchers of this study wanted to know:

What the risk of breast cancer is in the other breast of women diagnosed with breast cancer at a young age (under 36) who had a harmful mutation in , or .

Populations looked at in this study:

A total of 397 women diagnosed with breast cancer under age 36 participated in this study. Participants were identified from three groups in Britain: a North West England population study that enrolled participants from 1980 to 1997, referrals from St. Mary's Hospital from 1990 to 2018 and the Family History Clinic at Wythenshawe Hospital in South Manchester.

Study design:

Researchers confirmed the breast cancer diagnosis and family history of each participant from hospital and other records. Participants were defined as having a family history if they had one or more close relative under age 65 with breast cancer or ovarian cancer at the time of the participant's diagnosis.

Researchers sequenced the of participants to identify mutations in the , or genes (including copy number variations). For the purpose of this study, researchers only considered pathogenic or likely pathogenic mutations. Researchers tested genes based on prior information of genes that are most likely to be present among women with very early breast cancer; researchers did not test for other known breast cancer genes. (For example, women with mutations in genes such as or  typically have breast cancers at ages over 36).

Researchers tracked health information about each participant from the time of their initial diagnosis up to 20 years later, including history of , last healthcare assessment and whether they were living or dead or had undergone risk-reducing mastectomy.

Participants diagnosed with within three months of their original breast cancer diagnoses were defined as having synchronous breast cancer (two or more primary tumors in different breasts during the same time period).

Annual rates for contralateral cancer were calculated as a proportion of the total years of follow-up until the occurred or until the participant either had risk-reducing mastectomy, left the trial or died.

Study findings:  

60% of women diagnosed before age 36 had an inherited mutation in , or (see table).

  • BRCA1/BRCA2: 53% of women under age 36 who were diagnosed with breast cancer had a mutation in either or . This matches prior reports of mutations in young women.
  • TP53: 7% of women (approximately 1 in 14) in this study had gene mutations compared to 1 in 5,000-20,000 of unselected people in the general population. As expected, the number of women with breast cancer diagnosed before age 36 included many more women with mutations than in the general population. This reflects the high risk of breast cancer in young women who have a mutation.
Mutation
status
        Women        
Number  Percent  Number Percent
All participants 658       111 17%
Mutation found 397 60% 98 25%
218 33% 54 25%
 132 20% 30 23%
47 7% 14 30%
No mutation 261 40% 13 5%
Family history 53 8% 6 7%
No family history 74 11% 4 8%
Unknown family history 134 20% 3 2%
  • 25% of women with an inherited mutation had during the study. The average time to diagnosis was 7 years, 7 months (ranging from 0 to 29.5 years after their first diagnosis).
  • The time to diagnosis of was similar for women in all three mutation groups:
    • BRCA1/BRCA2
      • 23% of women with a mutation had a .
      • 25% of women with a mutation had a .
      • Among 6 women (4 with 1 and 2 with mutations), contralateral cancer was detected within 3 months of their original diagnosis and was therefore considered to be a synchronous cancer. These rates match prior reports of mutations in young women. One woman who had a mutation in both and was omitted from the analysis.
    • TP53
      • 30% of women with a mutation also had a . Two women had synchronous contralateral cancers.
      • This high rate of is consistent with the observations that increases the risk of breast diagnosis at a young age.
  • 5% of women with no identified mutation had a . This includes women (7%) with a known family history of breast and ovarian cancer who have , similar to the group (8%) with no family history. These women may have had no mutation in their family, may not have inherited their family's mutation but developed an early sporadic cancer, or they may have had a mutation in another gene that increased breast cancer risk (e.g., ), but at a lower rate or typically later onset. The average time to diagnosis was 9 years, 9 months (ranging from 1 year, 7 months to 18 years after their first diagnosis). Among women without a mutation, none of the contralateral breast cancers were synchronous.

  • The annual rate of was almost 10 times higher in women who had an inherited mutation (3.4 percent) than among women who had no mutation (0.4%). In other words, on an annual basis, a woman with an inherited mutation was more likely to have diagnosed than a woman without an inherited mutation (see table below). The cumulative risks of breast cancer for women with a , or mutation at 5, 10 and 15 years are shown below.

  • BRCA1/BRCA2: 53% of women under age 36 who were diagnosed with breast cancer had a mutation in either or . This matches prior reports of mutations in young women.
  • TP53: 7% of women (approximately 1 in 14) in this study had gene mutations compared to 1 in 5,000-20,000 of unselected people in the general population. As expected, the number of women with breast cancer diagnosed before age 36 included many more women with mutations than in the general population. This reflects the high risk of breast cancer in young women who have a mutation.
Mutation
status
       Risk of
Annual rate*  5 years after 1st
diagnosis** 
10 years after 1st
diagnosis**
20 years after 1st 
diagnosis**
Mutation found 3.4%      
3.6% 10% 32% 57%
 2.6% 7% 21% 45%
7.0% 19% 53% 83%
No mutation 0.4%      
Family history 0.7% n.d. n.d. n.d.
No family history 0.6% n.d. n.d. n.d.
Unknown family history 0.2% n.d. n.d. n.d.

*Excludes synchronous breast cancers that occurred within 3 months of original diagnosis
** Adjusted for women who had risk-reducing mastectomy, left the study or died.
n.d. = not reported numerically

  • BRCA1/BRCA2: The annual rate of was 3.6% for women with a mutation and 2.6% for women with a mutation. The cumulative risks of having breast cancer in the other breast 10 years after diagnosis were 32% and 21% for women with a mutation in and , respectively, in this study. This is similar to prior studies that observed 27% and 19% rates for and , respectively. The study authors suggest that the slightly higher rates observed may reflect increased surveillance given the knowledge about mutation status.
  • TP53:  The annual rate of was 7% for women with a mutation in the gene, twice the annual risk of women with a mutation and almost 18 times the risk of women without a mutation. Among study participants with mutations, 45 developed a within 10 years, while 82% developed within 20 years of their original diagnosis. This matches the 85% rate of any cancer by age 60 observed among people with mutations. These observations strongly suggest that women with mutations may want to consider or hormone-modulating drugs such as tamoxifen, and at minimum, have a robust surveillance plan.

 

  • Women with mutations (6%) were less likely to have risk-reducing mastectomy than their counterparts with mutations (16 to 17%), despite having a risk of that was 18 times more likely than women without a mutation and twice as likely as women with a mutation.

At time of original diagnosis, women with or mutations should discuss their risk of with their healthcare providers for fully informed decision making.

Strengths and limitations:

Strengths of this study include:

  • A considerable group of participants with breast cancer under age 36, including a large number of participants with and mutations.
  • Long-term follow-up of the participants.

Limitations of this study include:

  • A limited number of participants. While larger than many studies, the number of participants with mutations limits the possible subgroup analyses.
  • Lack of pathology details on medical records limited analysis for grade or receptor status, particularly in patients who were diagnosed before 1990.
  • Limited information about cancer treatment. The authors note that endocrine therapy may impact the rate of observed, likely reducing it. Similarly, radiation therapy may increase rate of second cancers in people with mutations.
  • Lack of information about menopausal status or risk-reducing , which may impact rates of breast cancer.
  • This study took place in one region of Britain, therefore it is not clear how generally the results can be applied to other populations in terms of the rates of mutations among young women with breast cancer. Furthermore, participants in this study were selected from a mixture of a population study and more selected high-risk families in Britain. Other populations may have a different rate of mutations in these particular genes.

Conclusions:

In this study of a selected, high-risk sample of the British population, the majority of women diagnosed with breast cancer under age 36 have an inherited mutation. The rate of is high for women with mutation in the , or genes; this risk increases each year from the time of first diagnosis.

Expert Guidelines
Expert Guidelines

The National Comprehensive Cancer Network has guidelines on who should undergo genetic counseling and testing. If you have been diagnosed with breast cancer, you should speak with a genetics expert about genetic testing if any of the following apply to you:     

  • You have a blood relative who has tested positive for an inherited mutation 
  • You have any of the following:  
    • Breast cancer at age 50 or younger  
    • Male breast cancer at any age
    • Ovarian cancer at any age  
    • at any age 
    • Two separate breast cancer diagnoses
    • Eastern European Jewish ancestry and breast cancer at any age 
    • breast cancer 
    • Testing of your tumor shows a mutation in a gene that is associated with
    • breast cancer and high risk for recurrence
    • Lobular breast cancer and a family history of diffuse gastric cancer

OR 

  • You have one or more close family members who have had:  
    • Young-onset or rare cancers 
    • Breast cancer at age 50 or younger
    • Male breast cancer, ovarian cancer, pancreatic cancer, or   cancer at any age
    • Two separate cancer diagnoses 
    • cancer at age 55 or younger or prostate cancer 

The American Society of Breast Cancer Surgeons (ASBrS) released guidelines in 2019 that recommend all women diagnosed with breast cancer have access to genetic testing for inherited mutations in breast cancer genes. 

If you are uncertain whether you meet the guidelines above and you are interested in or considering genetic testing, you should speak with a cancer genetics expert

 

Updated: 11/22/2021

Expert Guidelines
Expert Guidelines

The National Comprehensive Cancer Network (NCCN) provides breast cancer risk management guidelines for people with and mutations. We recommend that you speak with a genetics expert who can look at your personal and family history of cancer and can help you to determine the best risk management plan. 

Screening for women:

  • Learn to be aware of changes in breasts beginning at age 18.
  • Clinical breast exam every 6-12 months beginning at age 25.
  • Annual breast  with contrast (or  if  is unavailable) beginning at age 25 and continuing until age 75.
  • Annual  at age 30 until age 75 (consider 3D  if available).
  • Screening after age 75 should be considered on an individual basis.

Risk reduction for women:

  • Women should have a discussion with their doctors about of the advantages and disadvantages of risk-reducing mastectomy.
    • Research has shown that risk-reducing mastectomy can lower the risk for breast cancer in high risk women by about 90%. Despite this, mastectomy has not been shown to help high risk women live longer.
    • Even after mastectomies, some breast tissue-and therefore some breast cancer risk remains. 
  • Women should have a conversation with their doctor about the possible benefits of tamoxifen or other estrogen-blocking drugs to reduce breast cancer risk in women with  mutations. Research on the benefit of these drugs to reduce breast cancer risk in women with  mutations has been mixed.

Risk management in men:

  • Breast self-exam training and education beginning at age 35.
  • Clinical breast exam every 12 months beginning at age 35.
  • In men with enlarged breasts, (gynecomastia) consider annual  in men with gynecomastia beginning at age 50 or 10 years younger then the earliest case of male breast cancer in the family (whichever comes first). 

Updated: 12/14/2021

Expert Guidelines
Expert Guidelines

The National Comprehensive Cancer Network (NCCN) provides risk management guidelines for men and women with  mutations. These are listed below. 

Screening and prevention for adults with a  mutation

  • Complete physical and neurologic exams every 6-12 months
  • Annual whole body 
  • Annual brain 
  • Endoscopy and colonoscopy every 2–5 years beginning by age 25, or 5 years earlier than the youngest age of diagnosis in the family
  • Annual dermatologic examination beginning by age 18

People with  mutation carriers are advised to minimize radiation exposure due to the potential association with increased risk of a cancer diagnosis.

Breast cancer screening and prevention for women

  • Breast self-awareness beginning at age 18
  • Clinical breast examination by a health care provider twice a year starting by age 20
  • Annual breast  with contrast beginning at age 20 ( or  if  not available, but  is preferred) or at the age of earliest breast cancer diagnosis if there is a history of breast cancer before age 20 in family
  • Annual breast  and  beginning at age 30
  • Consider 3D 
  • Consider risk reducing mastectomy

Updated: 12/09/2021

Questions To Ask Your Doctor
Questions To Ask Your Doctor

  • Given my personal and family history and mutation status, what is my risk of ?
  • What are the pros and cons of risk-reducing mastectomy in my contralateral breast?
  • If I have a mutation and choose not to have risk-reducing mastectomy of my contralateral breast, what type of surveillance do you recommend and how often?
  • Do you recommend that I have genetic testing?
  • How do I get genetic testing?

Open Clinical Trials
Open Clinical Trials

The following are breast cancer screening or prevention studies enrolling people at high risk for breast cancer.   

Additional risk-management clinical trials for people at high risk for breast cancer may be found here.

Updated: 06/29/2022

Peer Support
Peer Support

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

Updated: 11/29/2022

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