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

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.

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.)

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