From the Journals

Variants in five genes signal TNBC risk

 

Key clinical point: Pathogenic variants in five cancer predisposition genes are associated with significantly increased risk for triple negative breast cancer (TNBC).

Major finding: Pathogenic variants in BRCA1 were associated with a more than 16-fold risk for TNBC.

Study details: Retrospective review of multigene assay testing in 10,901 women with TNBC.

Disclosures: The study was supported in part by the National Institutes of Health and the Breast Cancer Research Foundation, and was sponsored by Ambry Genetics Inc. The authors reported having no conflicts of interest.

Source: Shimelis H et al. J Natl Cancer Inst. 2018 Aug 7. doi: 10.1093/jnci/djy106.


 

FROM JOURNAL OF THE NATIONAL CANCER INSTITUTE

Women with germline pathogenic variants in five genes are at high risk for developing triple-negative breast cancer, and have a greater than 20% lifetime risk for breast cancer in general, results of a large study suggest.

Multigene testing of nearly 11,000 women with triple-negative breast cancer (TNBC; lacking estrogen, progesterone, and human epidermal growth factor receptors) showed that germline pathogenic variants in BARD1, BRCA1, BRCA2, PALB2, and RAD51D were associated with risk for clinical TNBC ranging from nearly sixfold to more than 16-fold higher than that of women without the genetic variants, reported Fergus J. Couch, PhD, of the Mayo Clinic, Rochester, Minn., and his colleagues.

“The results suggest that all TNBC patients should undergo multigene panel testing, regardless of age at diagnosis or family history of cancer, for improved cancer risk assessment and because of the ongoing development of targeted therapeutic approaches for TNBC patients with mutations in predisposition genes,” they wrote. Their report is in the Journal of the National Cancer Institute.

Although National Comprehensive Cancer Network guidelines recommend testing for the cancer predisposition genes BRCA1 and BRCA2 in women with a TNBC diagnosis at age 60 or younger or those with a family history of breast and/or ovarian cancer, the picture is less clear regarding genetic predisposition to TNBC, the authors noted.

“[R]ecommendations for testing of other genes are not fully established because the risks of TNBC associated with mutations in cancer predisposition genes have not been established. Thus, a better understanding of gene-specific risks for TNBC is needed to identify the genes that should be tested in the setting of TNBC,” they wrote.

The investigators looked for associations between deleterious mutations in cancer predisposition genes and TNBC among 8,753 patients with TNBC testing with a 21-gene assay, and among 2,148 women tested for 17 genes in studies conducted by the Triple Negative Breast Cancer Consortium.

They found that among white women, germline pathogenic variants were associated with the following odds ratios (OR) for TNBC (all P values less than .0001):

  • BRCA2 = 5.42
  • BARD1 = 5.92
  • RAD51D = 6.97
  • PALB2 = 14.41
  • BRCA1 = 16.27

Although there were insufficient data on the risks for African American women, an exploratory analysis showed that risks for TNBC associated with specific pathogenic variants were similar to those for white women, the authors said.

The pathogenic variants were detected in 12% of all patients in the study.

“Continued study of gene-specific risks for breast cancer subtypes may lead to tailored medical management recommendations for PV [pathogenic variant] carriers. Consistent with this hypothesis, initial studies evaluating intensified screening in high-risk women have suggested that a decrease in mortality from TNBC can be achieved,” they wrote.

The study was supported in part by the National Institutes of Health and the Breast Cancer Research Foundation, and was sponsored by Ambry Genetics Inc. The authors reported having no conflicts of interest.

SOURCE: Shimelis H et al. J Natl Cancer Inst. 2018 Aug 7. doi: 10.1093/jnci/djy106.

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