Study: Study identifies genes associated with risk of triple-negative breast cancer

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This study is about:

The identification of genes that increase risk of triple-negative breast cancer.

Why is this study important?

National guidelines currently recommend BRCA1 and BRCA2 testing for women diagnosed with triple-negative breast cancer (TNBC) at age 60 or younger or those who meet criteria based on a personal or family history of cancer. However, there are no guidelines for  genetic testing for other genes in TNBC patients. This study suggests that other non-BRCA genes also contribute to risk of TNBC.

Study findings: 

Panel testing in 10,901 triple-negative breast cancer patients revealed:

  • Inherited mutations were detected in approximately 14.5% of all participants.
    • Of these, approximately 9% of participants had mutations that were not in BRCA1 or BRCA2.
  • Inherited mutations in the BARD1, BRCA1, BRCA2, PALB2, and RAD51D genes were associated with a high risk of TNBC.
  • Inherited mutations in BRIP1, RAD51C, and TP53 were associated with moderate risk of TNBC.

What does this mean for me?

Genetic testing can help people with breast cancer learn if their cancer was caused by an inherited mutation. Panel testing, which tests for inherited mutations in many genes versus gene by gene testing, can identify those at increased risk for TNBC. Knowing that you are at increased risk for TNBC may impact your risk management strategies. Panel testing can also identify those TNBC patients who would benefit from targeted treatments such as patients with Lynch syndrome.

It is important to remember that this study only applied to TNBC risk and that some of the genes studied here could be associated with greater or different overall breast cancer risk or risk of other cancers such as ovarian or pancreatic cancer.

Results of this study suggest that all individuals with TNBC should undergo panel testing. If you have been diagnosed with TNBC, consider asking your health care providers if panel testing is right for you.

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This article is relevant for:

People diagnosed with triple-negative breast cancer

This article is also relevant for:

Breast cancer survivors

Metastatic cancer

People with a genetic mutation linked to cancer risk


Triple negative breast cancer

Women under 45

Women over 45

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Questions to Ask
  • Should I consider genetic testing?
  • Can you refer me to a genetics expert?
  • I had BRCA testing which was negative. Should I consider panel testing?
  • Are there different risk management strategies that would benefit me?
  • Are there targeted treatments that are appropriate for me?

Study background:

Triple-negative breast cancer (TNBC) is aggressive. These cancers lack estrogen, progesterone, and human epidermal growth factor (HER2) receptors, making them particularly difficult to treat given current treatment options. 
TNBC accounts for about 35% of breast cancer in African Americans and about 15% in whites.  At diagnosis, it is usually more advanced and is associated with an increased risk of recurrence and worse 5-year survival rates than other types of breast cancers.

Currently, NCCN guidelines recommend BRCA testing for TNBC patients diagnosed age 60 or younger. However, there are no recommendations for testing for other known breast cancer genes, because the risk of TNBC associated with other genes is unknown.

Researchers of this study wanted to better understand gene-specific risks for TNBC. Knowing who is at risk for TNBC should result in better clinical management for those at increased risk.

Researchers of this study wanted to know:

Of the genes known to increase breast cancer risk, which are associated with increased risk of TNBC?

Study design:

Researchers used panel testing to identify genes associated with increased risk of TNBC.

  • Between March 2012 and June 2016, 10,901 patients with TNBC were tested using panel testing.
    • A clinical cohort of 8,753 TNBC patients was tested for 21 genes by Ambry, a clinical testing laboratory.
    • A TNBC Consortium cohort of 2,148 was tested for 17 genes by a Triple-Negative Breast Cancer Consortium of researchers.

Study findings: 

Panel test results in the clinical cohort revealed:

  • 14.4% of participants had pathogenic mutations in the one of the 21 genes tested.
    • 8.4% of patients had pathogenic mutations in BRCA1 or BRCA2
    • 6% in non-BRCA genes.

Panel test results in the TNBC Consortium cohort revealed:

  • 14.5% of participants had pathogenic mutations in one of 17 genes tested.
    • 10.4% of participants had pathogenic mutations in BRCA1 or BRCA2.
    • 4 % in non-BRCA genes.
  • PALB2 (1.0%-1.6%) and BARD1 (0.5%-0.7%) were the most common mutated non-BRCA genes.

Compared to controls, BRCA1 mutations were associated with high risk of TNBC (this finding supports previous studies).  Similarly, BRCA2 was associated with high risk of TNBC in both cohorts.  In the clinical cohort, mutations in PALB2, BARD1, and RAD51D were also associated with high risk of TNBC.

In this study, BRCA1 and PALB2 mutations were associated with an 18% and 10% lifetime risk of TNBC, respectively, followed by mutations in the BARD1 (7%), BRCA2 (6%), and RAD51D (5%) genes.

Moderate-risk TNBC risk genes were BRIP1 and RAD51C, which were previously only associated with increased risk of ovarian cancer. Mutations in the Lynch syndrome gene, MSH6 were also associated with modest risk of TNBC, consistent with the twofold increase in overall breast cancer risk shown in a recent study (the topic of a recent XRAYS review).

Mutations in ATM, CHEK2, NBN, and RAD50 were not associated with increased risk of TNBC.


While this study identifies genes associated with an increased risk of TNBC, more research will need to be done to refine the actual risk associated with each gene. The control data used in this study came from publicly available DNA sequencing databases. Patients were not matched to controls (i.e. age, race, etc.).  However, these large sequencing databases likely provide reasonable population mutation frequencies and have been used successfully in other similar studies. 


Panel testing can identify women who are at increased risk of TNBC.  Mutations in BRCA1/2, BARD1, PAB2, and RAD51D are associated with high risk of TNBC.  Women with mutations in these genes may benefit from increased screening and cancer prevention strategies. Patients with TNBC may also benefit from panel testing when considering targeted therapies such as pembrolizumab (Keytruda) for Lynch syndrome.

Posted 8/23/18

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