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Study: Among women with breast cancer, who should have genetic testing for an inherited mutation?

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Contents

At a glance Clinical trials
How well do different guidelines work? Guidelines              
Strengths and limitations Questions for your doctor 
What does this mean for me? Resources


STUDY AT A GLANCE

This study is about:

Which women with breast cancer should have genetic testing for inherited mutations and which guidelines best identify them.


Why is this study important?

Knowing whether or not you have an inherited mutation can help you, your family and your healthcare team make treatment and prevention choices. Testing can also clarify risk for additional cancers and cancer risk for family members.


Study findings: 

The 3,907 participants in this study were women with breast cancer who were seen at Mayo Clinic from May 2000 to May 2016, and who agreed to participate in the registry for the Mayo Clinic Breast Cancer Study (MCBCS). All women diagnosed with a first invasive breast cancer or ductal carcinoma in situ were eligible for this registry.

Among the participants:

241 (6.2%) had a mutation in one of 9 known and actionable breast cancer genes (, , , , , , , and ). Recommendations for healthcare treatment or surveillance are different for women with mutations in these genes than for the general population.


How well do different guidelines identify women with inherited mutations?

The American Society of Breast Cancer Surgeons (ASBrS)

ASBrS recommends testing for all women with breast cancer. An XRAY review of the ASBrS recommendations can be found here. Using ASBrS guidelines:

  • According to these guidelines, in this study, all participants with mutations would be identified.

Pro: All women with mutations would be identified; none would be missed.

Con: 3,666 women who did not have an inherited mutation were tested, which may have caused unnecessary cost, stress and anxiety.

The National Comprehensive Cancer Network (NCCN)

NCCN has a complex set of guidelines for genetic testing recommendations (see guidelines below). Using current NCCN guidelines:

  • 169 (4.3%) of the 3,907 participants had a genetic mutation in one of 9 actionable breast cancer genes and would qualify for genetic testing under NCCN guidelines.
    • These 169 women represented 70% of 241 women with an inherited mutation.
  • 72 (1.8%) participants had a mutation in one of 9 actionable breast cancer genes but did not qualify for genetic testing under NCCN criteria.
    • These 72 women represented 30% of the 241 women with an inherited mutation.

Pro: Fewer women without inherited mutations were tested than under ASBrS guidelines and did not unnecessarily face the potential stress and anxiety of genetic testing.

Con: A large portion women with an inherited mutation (30%) were not identified, which prevented them from using this information to guide their treatment and surgical decisions.

The researchers evaluated the effect of expanding NCCN testing guidelines. They proposed expanding NCCN guidelines to include testing for all women diagnosed with breast cancer by age 65. This may be a better way to identify the most women with inherited mutations. It may also mean that fewer women without inherited mutations would be tested than with the ASBrS guidelines.

Expanded NCCN guidelines

Using the proposed expanded NCCN guidelines for testing all women by age 65 diagnosed with breast cancer:

  • 222 (5.7%) participants who had a mutation in one of 9 actionable breast cancer genes would qualify for genetic testing.
    • 92% of the 241 women with an inherited mutation would be identified by these guidelines.
  • 19 (0.4%) of the 3,907 participants had a mutation in one of the 9 known and actionable breast cancer genes but would not qualify for genetic testing under these guidelines.
    • 8% of the 241 women with an inherited mutation would not be identified by these guidelines.

Pro: The vast majority of women with an inherited mutation (92%) would be identified by expanding NCCN  guidelines.

Con: More women without mutations would be tested than under current NCCN guidelines and face the potential stress, cost and anxiety of genetic testing unnecessarily.

The researchers suggest that their proposed expansion of current NCCN guidelines to include testing for all women with diagnosed with breast cancer by age 65 would maximize identification of women with inherited mutations and minimize testing of women without inherited mutations.


Strengths and limitations:

  • The largest strength of this study is that all breast cancer patients were tested genetically. This allows direct comparison between current ASBrS, current NCCN and expanded NCCN guidelines, using the same data of the same participants.
  • A major weakness of this study is that the participants studied were predominantly White women from one geographic location, which may not be representative of the general population.


What does this mean for me?

Up to 5 to 10 percent of women with breast cancer have an inherited mutation that increases their risk of breast cancer. If you have breast cancer, you may want to consider talking with a healthcare provider about whether you should consider genetic testing.

NCCN recommendations are considered the gold standard for cancer care. However, cancer healthcare professionals express different views, including those of the American Society of Breast Surgeons. The researchers of this study propose expanding the NCCN guidelines to include testing of all breast cancer patients diagnosed by age 65. Speak with your healthcare provider about what guidelines they use and how that may impact their recommendations for you.

If you have an inherited mutation, you may want to consider which surgical choice best fits your situation: for example, mastectomy, and radiation, or prophylactic mastectomy. If you have an inherited mutation, your risk of cancer in other organs may be different than that of people without an inherited mutation. Also, you may want to talk to family members about your mutation status because it may affect their risk of cancer.

If you have an inherited mutation, some treatment options may be more effective than others for you (e.g., hormone treatment or PARP inhibitors for advanced breast cancer).

If you test negative for an inherited mutation, you can make decisions that reflect your personal risk of additional cancers or recurrence.

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References

Yadav S, Hu C, Hart SN, et al. Evaluation of Germline Genetic Testing in a Hospital-based Series of Women with Breast Cancer. March 3, 2020. Journal of Clinical Oncology 38(13):1409-1418.  

Manahan ER, Kuerer HM, Sebastian M, et al. "Consensus Guidelines on Genetic Testing for Hereditary Breast Cancer from the American Society of Breast Surgeons." July 29 2019. Annals of Surgical Oncology 26(10):3025–3031.
 

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 who do not know if they have an inherited mutation in a gene linked to breast cancer

This article is also relevant for:

Breast cancer survivors

ER/PR +

Her2+ breast cancer

Men with breast cancer

Metastatic cancer

Triple negative breast cancer

Women under 45

Women over 45

Newly diagnosed

People with a family history of cancer

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IN-DEPTH REVIEW OF RESEARCH

Study background:

The American Society of Breast Surgeons (ASBrS) recommends genetic testing for all women diagnosed with breast cancer. In contrast, the National Comprehensive Cancer Network (NCCN) has a complex set of criteria to determine whether a person should be tested for an inherited mutation (see guidelines above). Experts disagree which approach is better.

The ASBrS recommendation to test everyone with breast cancer is clear. Testing all breast cancer patients would ensure that no women with an inherited mutation would be overlooked. However, many women without an inherited mutation would also be tested, adding expense and anxiety that may not be warranted.

On the other hand, under the NCCN criteria, some women with an inherited mutation may not be tested. They would miss opportunities to have their treatment plan adjusted for their genetic status and to have increased surveillance for other cancers associated with their inherited mutation. However, women who do not have an inherited mutation would be less frequently tested, avoiding the cost, time and stress that they might otherwise experience with genetic testing.


Researchers wanted to know:

Which guidelines best identify women with breast cancer who would benefit from genetic testing.


Populations looked at in this study:

This study population consisted of women with breast cancer who were seen at Mayo Clinic from May 2000 to May 2016 and who agreed to participate in the registry for the Mayo Clinic Breast Cancer Study (MCBCS). All women diagnosed with a first invasive breast cancer or ductal carcinoma in situ were eligible for this registry.

The 3,907 women provided a family history and a blood sample for genetic testing. Among participants, 84 percent had invasive breast cancer and 16 percent had ductal carcinoma in situ. Their average age was 57 (ranging from age 21 to 94). Just under 47 percent had a family history of breast cancer; 40 percent had only one relative with breast cancer. A total of 3,719 participants were White women (95%), 29 (1%) were Black women and 159 (4%) did not indicate race.

Women were excluded if they ever had a prior cancer diagnosis, did not provide a family history or had incomplete genetic testing results for the genes of interest.


Study design:

Researchers tested blood samples from each participant for mutations in genes known to increase breast cancer risk.

Analyses of mutation rates were done among several groups of genes:

  • 9 known and actionable genes.
    • These genes are associated with increased breast cancer risk and have clear actionable guideline recommendations by the NCCN for treatment and/or surveillance. They include the , , , , , , , and genes.
  • 6 genes associated with the highest risk of breast cancer.
    • These include the , , , , and genes.
  • and only.
    • These two genes are found at relatively high frequency in the U.S. population and have the clearest actionable treatment recommendations.

Women who had a close relative with breast cancer were said to have a family history of cancer. For evaluation purposes, women were said to fit NCCN guidelines if they met any of the related criteria for genetic testing (see section on Guidelines).


Study findings:  

To compare how testing criteria affects the number of women with mutations who would be tested or not, the authors tested all participants for harmful mutations in any of the nine known actionable genes associated with breast cancer risk. They then applied ASBrS criteria, NCCN criteria or their proposed expanded NCCN criteria to determine which women would have qualified for genetic testing. This allowed the researchers to determine how each set of guidelines performed based on how frequently they identified or missed participants with an inherited mutation.  


How well do different guidelines identify women with inherited mutations?

The American Society of Breast Cancer Surgeons (ASBrS) recommends testing for all women with breast cancer.

Under the ASBrS guidelines, all 3,907 participants with mutations would be identified.

  • 241 (6.2%) women had a mutation in one of the 9 known and actionable breast cancer genes (, , , , , , , and ).
  • 134 (3.4%) women had a mutation in one of the 6 highest-risk breast cancer genes (, , , , and ).
  • 107 (2.7%) women had a mutation in or .

Pro: All 241 women with mutations were identified, none were missed.

Con: 3,666 women who did not have an inherited mutation were tested, which may have caused unnecessary stress, cost and anxiety.

The National Comprehensive Cancer Network (NCCN) has a complex set of guidelines for genetic testing recommendations (see guidelines above).

Among the 3,907 study participants:

  • 1,872 (48 %) met NCCN criteria and would have had genetic testing recommended.
  • 2,035 (52%) did not meet NCCN criteria and would not have had genetic testing recommended.

Mutations in the 9 actionable breast cancer genes:

  • 169 (4.3%) had a mutation in one of the 9 actionable breast cancer genes and would qualify for genetic testing under NCCN guidelines.
    • These 169 women included 70% of 241 women with an inherited mutation.
  • 72 (1.8%) had a mutation in one of the 9 actionable breast cancer genes but did not qualify for genetic testing under NCCN criteria.
    • These 72 women included 30% of the 241 women with an inherited mutation.

Mutations in the 6 highest-risk breast cancer genes:

  • 106 (2.7%) participants had a mutation in one of the 6 highest-risk breast cancer genes and would qualify for genetic testing under NCCN guidelines.
    • These 106 women included 79% of the 134 women with a mutation in these 6 genes.
  • 28 (0.7%) had a mutation in one of the 6 highest risk breast cancer genes and would qualify for genetic testing under NCCN guidelines.
    • These 28 women included 21% of 134 women with a mutation in these 6 genes.

Mutations in the or BRCA2:

  • 93 (2.3%) of 3907 participants had a mutation in or and would qualify for genetic testing under NCCN guidelines.
    • These 93 women included 87% of the 107 women with a mutation in these 6 genes.
  • 14 (0.4%) participants had a mutation in or genes and would qualify for genetic testing under NCCN guidelines.
    • These 14 women included 13% of 107 women with a mutation in these 6 genes.

Pro: Fewer women without inherited mutations would be tested using current NCCN guidelines than under ASBrS guidelines and would not face the potential stress and anxiety of genetic testing unnecessarily.

Con: A large portion of women with an inherited mutation (30%) would not be identified, which would prevent them from using test results to guide treatment and surgical decisions, and would prevent their relatives from gaining insight about their own risk for cancer.

The researchers evaluated the effect of expanding testing guidelines.

They proposed expanding NCCN guidelines to include testing all women diagnosed with breast cancer by age 65 as an effective way of identifying the most women with inherited mutations and testing the fewest women without inherited mutations.

Mutations in the 9 known and actionable breast cancer genes:

  • 222 (5.7%) of participants had a mutation in one of the 9 known and actionable breast cancer genes and would qualify for genetic testing under the researcher's proposed guidelines.
    • 22 (92%) of the 241 women with an inherited mutation would qualify for testing by these guidelines.
  • 19 (0.4%) participants had a mutation in one of the 9 known and actionable breast cancer genes, but would not qualify for genetic testing under this guideline.
    • 19 (8%) of the 241 women with an inherited mutation would not qualify for testing by these guidelines.

Mutations in the 6 highest-risk breast cancer genes:

  • 127 (95%) of 134 women would qualify for testing.
  • 7 (5%) of 134 women would not qualify for testing.

Mutations in the or BRCA2:

  • 105 ( 98%) of 107 women would qualify for testing.
  • 2 (2%) of 107 women would not qualify for testing.

Pro: The vast majority of women with an inherited mutation (92%) would be identified by expanded NCCN guidelines. Fewer women without mutations would be tested than under ASBrS guidelines, avoiding the potential stress, cost and anxiety of genetic testing unnecessarily.

Con: More women without mutations would be tested than under current NCCN guidelines and would face the potential stress and anxiety of genetic testing unnecessarily.

The researchers suggest that their proposed expanded guidelines of testing all women diagnosed with breast cancer by age 65 would balance maximal identification of women with inherited mutations with actionable healthcare options and minimal testing of women who do not have inherited mutations.

  ASBrS Guidelines NCCN Guidelines  NCCN Guidelines Expanded 
Number of women: Qualified for testing Qualified for testing Did not qualify for testing  Qualified for testing Did not qualify for testing
Total women 3,907
(100%)
1,872
(48%)
2,035
(52%)
3,081
(79%)
826
(21%)
with mutation in one of 9 actionable genes 241
(6.2%)
169
(4.3%)
72
(1.8%)
222
(5.7%)
19
(0.5%)
with mutation in one of 6 highest risk genes 134
(3.4%)
106
(2.7%)
28
(0.7%)
127
(3.2%)
7
(0.2%)
with mutation in or 107
(2.7%)
93
(2.4%)
14
(0.4%)
105
(2.7%)
2
(0.1%)

Among women with a mutation in a particular gene, the portion of women who are not identified by current NCCN guidelines among those with a mutation in that gene can be substantial:

  • 10% of women with mutation
  • 16% of women with mutation
  • About half of women with either a , or mutation
  • One-third of women with an mutation
  • Two-thirds of women with a mutation ( is linked to stomach cancer. NCCN guidelines for evaluating cancer in relatives of breast cancer patients does not include relatives with stomach cancer so some breast cancer patients with mutations may not qualify for genetic testing.)
  ASBrS Guidelines NCCN Guidelines 
  Qualified for testing Qualified for testing Did not qualify for testing 
Total women 3,907
(100%)
1,872
(48%)
2,035
(52%)

44
(1.1%)
29
(0.7%)
15
(0.7%)

51
(1.3%)
46
(1.1%)
5
(0.2%)

56
(1.4%)
47
(1.2%)
9
(0.4%)

6
(0.2%)
2
(0.1%)
4
(0.2%1

67
(1.7%)
39
(1%)
29
(1.4%)

1
(0%)
0
(0%)
1
(0%)

15
(0.3%)
7
(0.4%)
8
(0.4%)

1
(0%)
1
(0%)
0
(0%)

6
(0.2%)
3
(0.1%)
3
(0.1%)


Strengths and limitations:

  • The largest strength of this study is that all breast cancer patients were tested. This allows direct comparison of the guidelines using the same data on the same participants. Prior work that predicted how many women with inherited mutations might be missed or unnecessarily tested was based on theoretical projections.
  • A major weakness of this study is that the participants studied were predominantly White women from a single geographic location, and were possibly not representative of the general population. Despite this concern, the rates of mutation in the participants closely match the rates of particular genes in the population from previous studies.


Context:

Growing treatment options exist for people with breast cancer who have inherited mutations. People with a mutation in the highest risk genes have tailored approaches for surveillance and surgery as well as a number of promising drug therapies. Optimizing the identification of people with higher-risk mutations and not unnecessarily testing those without mutations resulted in the current NCCN guidelines. These were developed by a panel of experts who regularly review the current information and adjust guidelines accordingly. This study suggests that the current guidelines are weighted toward reducing the numbers of people tested at the expense of finding a substantial proportion of women with inherited mutations. Additionally, this study indicates that it might be useful to consider additionally revising the NCCN guidelines to expand testing of all women diagnosed with breast cancer by age 65. This suggestion is more conservative than the American Society of Breast Surgeons recommendation to test all women with breast cancer. However, it fits with changes to the NCCN criteria made in 2020 recommending against testing women age 65 and older who have no family history of cancer.


Conclusions:

NCCN guidelines on genetic testing recommendations for women with breast cancer identified 70 percent of women with inherited mutations in this study. However, these guidelines would have missed 30 percent of women with inherited mutations in this particular study group. An alternative guideline recommendation that expands current NCCN guidelines to include testing women diagnosed with breast cancer by age 65 may be useful to better inform women about their personal and family risk.

Share your thoughts on this XRAYS article by taking our brief survey

Posted 8/27/20

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

Questions to Ask Questions to Ask Your Doctor

  • What guidelines do you use for considering whether or not to recommend genetic testing?
  • Should I consider genetic testing?
  • What are the risks and benefits of genetic testing?
  • How do I contact a genetic counselor?
  • If I have an inherited mutation, how would that affect your recommendations for my healthcare?
  • Will my insurance company pay for genetic testing?

Open Clinical Trials Open Clinical Trials

Below are clinical trials that include genetic counseling and testing.

Other genetic counseling or testing studies may be found here.

 

Updated: 12/05/2021

Find Experts Find Experts

Health care providers who are specially trained in genetics can help you more clearly understand your risk for . The following resources can help you locate a genetics expert in your area.

  • The National Society of Genetic Counselor website offers a searchable directory for finding a genetic counselor by state and specialty. To find a genetic counselor who specializes in cancer genetics, choose "cancer" under the options "Area of Practice/Specialization." 
  • InformedDNA is a network of board-certified genetic counselors providing this service by telephone. They can also help you find a qualified expert in your area for face-to-face genetic counseling if that is your preference. 
  • JScreen is a national program based out of Emory University that provides low-cost at-home genetic counseling and testing with financial assistance available.
  • Grey Genetics provides access to genetic counselors who offer genetic counseling by telephone. 
  • The Genetic Support Foundation offers genetic counseling with board-certified genetic counselors. 
  • FORCE's toll-free helpline at: 866-288-RISK, ext. 704 will connect you with a volunteer board-certified genetic counselor who can answer general questions about genetic testing and cancer and help you find a genetics expert near you. 
  • FORCE Peer Navigator Program will match you with a volunteer who has undergone genetic counseling and can help you navigate resources to find a genetic counselor near you.
  • Ask your doctor for a referral to a genetics expert. 

Updated: 03/16/2022

Who covered this study?

Drugs.com

Genetic testing proposed for all women ≤65 with breast cancer This article rates 2.5 out of 5 stars

Medical Express

Researchers recommend all women with breast cancer diagnosis under age 66 This article rates 1.5 out of 5 stars

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