Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2020 May 1;38(13):1409-1418.
doi: 10.1200/JCO.19.02190. Epub 2020 Mar 3.

Evaluation of Germline Genetic Testing Criteria in a Hospital-Based Series of Women With Breast Cancer

Siddhartha Yadav  1 , Chunling Hu  2 , Steven N Hart  3 , Nicholas Boddicker  3 , Eric C Polley  3 , Jie Na  3 , Rohan Gnanaolivu  3 , Kun Y Lee  2 , Tricia Lindstrom  3 , Sebastian Armasu  3 , Patrick Fitz-Gibbon  3 , Karthik Ghosh  4 , Daniela L Stan  4 , Sandhya Pruthi  4 , Lonzetta Neal  4 , Nicole Sandhu  4 , Deborah J Rhodes  4 , Christine Klassen  4 , Prema P Peethambaram  1 , Tufia C Haddad  1 , Janet E Olson  3 , Tanya L Hoskin  3 , Matthew P Goetz  1 , Susan M Domchek  5 , Judy C Boughey  6 , Kathryn J Ruddy  1 , Fergus J Couch  2
Affiliations

Evaluation of Germline Genetic Testing Criteria in a Hospital-Based Series of Women With Breast Cancer

Siddhartha Yadav et al. J Clin Oncol. .

Abstract

Purpose: To determine the sensitivity and specificity of genetic testing criteria for the detection of germline pathogenic variants in women with breast cancer.

Materials and methods: Women with breast cancer enrolled in a breast cancer registry at a tertiary cancer center between 2000 and 2016 were evaluated for germline pathogenic variants in 9 breast cancer predisposition genes (ATM, BRCA1, BRCA2, CDH1, CHEK2, NF1, PALB2, PTEN, and TP53). The performance of the National Comprehensive Cancer Network (NCCN) hereditary cancer testing criteria was evaluated relative to testing of all women as recommended by the American Society of Breast Surgeons.

Results: Of 3,907 women, 1,872 (47.9%) meeting NCCN criteria were more likely to carry a pathogenic variant in 9 predisposition genes compared with women not meeting criteria (9.0% v 3.5%; P < .001). Of those not meeting criteria (n = 2,035), 14 (0.7%) had pathogenic variants in BRCA1 or BRCA2. The sensitivity of NCCN criteria was 70% for 9 predisposition genes and 87% for BRCA1 and BRCA2, with a specificity of 53%. Expansion of the NCCN criteria to include all women diagnosed with breast cancer at ≤ 65 years of age achieved > 90% sensitivity for the 9 predisposition genes and > 98% sensitivity for BRCA1 and BRCA2.

Conclusion: A substantial proportion of women with breast cancer carrying germline pathogenic variants in predisposition genes do not qualify for testing by NCCN criteria. Expansion of NCCN criteria to include all women diagnosed at ≤ 65 years of age improves the sensitivity of the selection criteria without requiring testing of all women with breast cancer.

PubMed Disclaimer

Figures

FIG 1.
FIG 1.
Evaluation of sensitivity of National Comprehensive Cancer Network (NCCN) criteria for pathogenic variant carriers in 3,907 women with breast cancer. (A) Percent of total pathogenic variant carriers missed by NCCN criteria in 9 breast cancer predisposition genes, 6 high-risk predisposition genes, and BRCA1 or BRCA2 (9 genes: ATM, BRCA1, BRCA2, CDH1, CHEK2, NF1, PALB2, PTEN, and TP53; 6 genes: BRCA1, BRCA2, CDH1, PALB2, PTEN, and TP53). (B) Comparison of germline pathogenic variant frequencies between women meeting and not meeting NCCN guidelines.
FIG A1.
FIG A1.
Sample selection. MCBCS, Mayo Clinic Breast Cancer Study; NCCN, National Comprehensive Cancer Network.
FIG A2.
FIG A2.
Frequency of germline pathogenic variants by family history of breast cancer according to the number of first- or second-degree relatives with breast cancer.
FIG A3.
FIG A3.
Frequencies of variants of uncertain significance by gene.
See this image and copyright information in PMC

References

    1. NCCN Clinical Practice Guidelines in Oncology . Genetic/familial high-risk assessment: Breast, ovarian, and pancreatic Version 1. National Comprehensive Cancer Network: ; https://www.nccn.org/professionals/physician_gls/pdf/genetics_bop.pdf - PubMed
    1. Beitsch PD, Whitworth PW, Hughes K, et al. Underdiagnosis of hereditary breast cancer: Are genetic testing guidelines a tool or an obstacle? J Clin Oncol. 2019;37:453–460. - PMC - PubMed
    1. Yang S, Axilbund JE, O’Leary E, et al. Underdiagnosis of hereditary breast and ovarian cancer in Medicare patients: Genetic testing criteria miss the mark. Ann Surg Oncol. 2018;25:2925–2931. - PubMed
    1. Manahan ER, Kuerer HM, Sebastian M, et al. Consensus guidelines on genetic’ testing for hereditary breast cancer from the American Society of Breast Surgeons. Ann Surg Oncol. 2019;26:3025–3031. - PMC - PubMed
    1. doi: 10.1038/s41436-019-0712-x. Pal T, Agnese D, Daly M, et al: Points to consider: Is there evidence to support BRCA1/2 and other inherited breast cancer genetic testing for all breast cancer patients? A statement of the American College of Medical Genetics and Genomics (ACMG). Genet Med . [Epub ahead of print on December 13, 2019] - DOI - PubMed

Publication types