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 and reference


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 prospective 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 (ATM, BRCA1, BRCA2, CDH1, CHEK2, NF1, PALB2, PTEN and TP53). 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, lumpectomy and radiation, or prophylactic bilateral 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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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

Be part of XRAY:

Questions to Ask
  • 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?
Clinical Trials
  • NCT04009148: Cascade Testing in Families With Newly Diagnosed Hereditary Breast and Ovarian Cancer Syndrome. This study offers referral to a genetic counselor and genetic testing for family members of people known to have a mutation in BRCA1 or BRCA2 or mutations in BRIP1, MSH2, MLH1, MSH6, PMS2, EPCAM, RAD51C and RAD51D.
  • NCT04245176: Genetic Testing for All Breast Cancer Patients (GET FACTS). This study aims to determine the impact of a novel genetic counseling method on surgical decisions in individuals with newly diagnosed breast cancer. Open to patients with a new breast cancer diagnosis (invasive or in-situ) who are considering genetic testing and who have not had panel testing for inherited mutations (those with negative test results for BRCA1/2 may still be eligible).
  • NCT02595957: Genomic Services Research Program. This study is recruiting people who received unexpected genetic test results about their cancer risk after having genetic testing done for some other reason. This may include people who have results related to the BRCA1, BRCA2, MLH1, MSH2, MSH6, PMS2, PTEN, STK11, TP53 genes. 
  • Connect My Variant. This study aims to help participants talk to relatives (both immediate and distant) about their family history and genetic test results, to connect them with others who have the same variant and to describe and discuss their family trees together. Eligible people have a known mutation in a gene that increases the risk for disease where there are clear prevention guidelines.
  • NCT04476654: Improving Uptake of Genetic Cancer Risk Assessment in African American Women- Video. This study will look at the usefulness of a culturally-tailored video to improve uptake of genetic counseling in Black women with increased risk of hereditary cancer.
  • NCT03470402: Decision Support for BRCA Testing in Ethnically Diverse Women. This study will look at whether patient education tools help expand genetic testing for hereditary breast and ovarian cancer syndrome to more high-risk women. Eligible people are women ages 21 to 75 who meet criteria for genetic testing based on family history, who receive care at the Columbia University (CUMC) /New York Presbyterian (NYP) Ambulatory Care Network and can communicate in English or Spanish.
  • NCT00579488: Clinical Significance of Germline BRCA Mutations. This study measures the cancer risks of known mutations in the BRCA1 and BRCA2 genes. The study will also look for other cancer genes. Participants may have genetic testing during the study. Eligible people include individuals and families referred for genetic counseling consultation at Memorial Hospital in NY/NJ or those with family members who have breast cancer. 

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 prospective 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 ATM, BRCA1, BRCA2, CDH1, CHEK2, NF1, PALB2, PTEN and TP53 genes.
  • 6 genes associated with the highest risk of breast cancer.
    • These include the BRCA1, BRCA2, CDH1, PALB2, PTEN and TP53 genes.
  • BRCA1 and BRCA2 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 (ATM, BRCA1, BRCA2, CDH1, CHEK2, NF1, PALB2, PTEN and TP53).
  • 134 (3.4%) women had a mutation in one of the 6 highest-risk breast cancer genes (BRCA1, BRCA2, CDH1, PALB2, PTEN and TP53).
  • 107 (2.7%) women had a mutation in BRCA1 or BRCA2.

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 BRCA1 or BRCA2:

  • 93 (2.3%) of 3907 participants had a mutation in BRCA1 or BRCA2 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 BRCA1 or BRCA2 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 BRCA1 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 BRCA1 or BRCA2 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 BRCA1 mutation
  • 16% of women with BRCA2 mutation
  • About half of women with either a PALB2, CHEK2 or TP53 mutation
  • One-third of women with an ATM mutation
  • Two-thirds of women with a CDH1 mutation (CDH1 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 CDH1 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%)

ATM

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

BRCA1

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

BRCA2

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

CDH1

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

CHEK2

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

NF1

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

PALB2

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

PTEN

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

TP53

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.

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Posted 8/27/20

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