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Kurian AW, Bernhisel R, Larson K, et al. Prevalence of Pathogenic Variants in Cancer Susceptibility Genes Among Women With Postmenopausal Breast Cancer. JAMA. 2020;323(10):995–997. doi:10.1001/jama.2020.0229
Germline genetic testing for pathogenic variants (PVs) in cancer susceptibility genes after breast cancer diagnosis may inform cancer treatment, prevention, and testing of relatives. Whether testing should be performed depends partly on PV prevalence, which may be low in the general population but higher in women with risk factors (eg, young diagnosis age, family history). For the best-characterized breast cancer susceptibility genes, BRCA1, BRCA2, or both (BRCA1/2), a minimum PV prevalence of 2.5% to 10% has been recommended for testing.1 However, guidelines vary in testing all breast cancer patients2 vs only those with features suggestive of hereditary risk.3 Most guidelines do not address testing among postmenopausal women without hereditary risk factors, the most common subgroup of breast cancer patients, as PV prevalence data are lacking. This study’s purpose was to determine PV prevalence among women diagnosed with breast cancer after menopause vs the background prevalence among cancer-free postmenopausal women.
The Women’s Health Initiative (WHI) is a prospective study of morbidity and mortality that enrolled 161 808 postmenopausal women aged 50 to 79 years at 40 US sites from 1993 through 1998. Research was approved by each institution’s review board, and all participants provided written informed consent.4 We performed a nested case-control study of women without personal history of breast cancer at WHI enrollment who were diagnosed with invasive breast cancer (case participants) or remained cancer free (control participants) as of September 20, 2017. Case and control participants were unmatched and randomly selected from all WHI participants having banked DNA samples.
Next-generation sequencing and large rearrangement analysis was performed by Myriad Genetics using a panel of 28 genes; among these, BRCA1/2, ATM, BARD1, CDH1, CHEK2, NBN, PALB2, STK11, and TP53 were considered breast cancer associated.1,5 Variants were classified as pathogenic or likely pathogenic, of uncertain significance, or benign or likely benign.6
Gene-specific prevalence was reported as a percentage for case and control participants with 95% CIs and P values calculated using the exact binomial method for CIs and χ2 tests for P values. The percentages of PV carriers meeting National Comprehensive Cancer Network 2019 testing guidelines (most relevant to oncology practice and relying primarily on diagnosis age and family history) were analyzed.1 Association with age was examined. Tests for PV prevalence trend by age among BRCA1/2 and other breast cancer–associated genes were performed using χ2 tests (R version 3.5.3) (2-sided P < .05 was considered statistically significant).
Among 4517 women, the median age at breast cancer diagnosis was 73 years for case participants (n = 2195) and 81 years at last follow-up for control participants (n = 2322). In the case group, 66.3% were white vs 84.9% in the control group. PVs were detected in 241 women (148 case participants [6.74%; 95% CI, 5.73%-7.87%] and 93 control participants [4.01%; 95% CI, 3.24%-4.88%]; P < .001). A PV was detected in any breast cancer–associated gene in 3.55% (95% CI, 2.82%-4.42%) of case participants and 1.29% (95% CI, 0.87%-1.84%) of control participants (P < .001). Of women with BRCA1/2 PVs, 30.8% of case participants and 20% of control participants met testing guidelines; of women with PVs in other breast cancer–associated genes, 34% of case participants and 16% of control participants met testing guidelines (Table 1).
For BRCA1/2, PV prevalence was 2.21% (95% CI, 0.82%-4.76%) among case participants diagnosed when younger than 65 years and 1.09% (95% CI, 0.67%-1.68%) among case participants diagnosed at 65 years or older. There was no trend by age for PV prevalence in BRCA1/2 (P = .34) or other breast cancer–associated genes (P = .54) (Table 2).
In this study, 3.55% of unselected, postmenopausal patients with breast cancer carried PVs in breast cancer–associated genes, a 3-fold higher prevalence than among cancer-free control participants and without decrease by age. Women diagnosed when younger than 65 years had similar probability of BRCA1/2 PVs as Ashkenazi Jewish individuals (≈2.5%), for whom testing is supported. Limitations: women chose to participate in WHI so the study may not represent all US women, a small number of PVs, and wide CIs in some subgroups.
These data on the prevalence of PVs in breast cancer susceptibility genes among postmenopausal women should inform testing guidelines. Among postmenopausal patients with breast cancer, PV prevalence may be high enough to warrant testing even in the absence of early diagnosis age or family history.
Accepted for Publication: January 8, 2020.
Corresponding Author: Allison W. Kurian, MD, MSc, Stanford University School of Medicine, 150 Governor’s Ln, HRP Redwood Bldg, Room T254A, Stanford, CA 94305-5405 (firstname.lastname@example.org).
Author Contributions: Dr Kurian had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Concept and design: Kurian, Stefanick.
Acquisition, analysis, or interpretation of data: All authors.
Drafting of the manuscript: Kurian, Bernhisel, Larson.
Critical revision of the manuscript for important intellectual content: Kurian, Caswell-Jin, Shadyab, Ochs-Balcom, Stefanick.
Statistical analysis: Bernhisel, Larson.
Obtained funding: Stefanick.
Conflict of Interest Disclosures: Dr Kurian reported research funding to her institution from Myriad Genetics. Mr Bernhisel and Ms Larson reported employment and stock from Myriad Genetics. Dr Shadyab reported personal fees (consultancy services) for Rancho Biosciences. No other disclosures were reported.
Funding/Support: Funding was provided by Myriad Genetics, by the Suzanne Pride Bryan Fund for Breast Cancer Research, the Jan Weimer Faculty Chair in Breast Oncology, and the BRCA Foundation. The WHI program is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, and the US Department of Health and Human Services (HHSN268201600018C, HHSN268201600001C, HHSN268201600002C, HHSN268201600003C, and HHSN268201600004C).
Role of the Funder/Sponsor: The funder was involved in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication by way of individuals employed by the funding institution who are included as authors or in the acknowledgments.
Meeting Presentation: Preliminary results were presented in partial form at the American Society of Clinical Oncology Annual Meeting, Chicago, Illinois, June 2019.
Additional Contributions: We thank Krystal Brown, PhD, Maria Elias, PhD, Anne-Renee Hartman, MD, (currently employed by GRAIL Inc), Elisha Hughes, PhD, Jonathan Lancaster, MD, PhD, Eric Rosenthal, PhD, ScM, and Nanda Singh, PhD, Myriad Genetics; Kathy Pan, MD, Los Angeles Biomedical Institute at Harbor-UCLA; Lihong Qi, PhD, University of California, Davis; Kerryn Reding, PhD, Fred Hutchinson Cancer Research Center and University of Washington; and Jean Tang, MD, PhD, Stanford University; for their assistance in assay performance and analysis, preparation, and critical review of the manuscript. Brown, Elias, Hartman, Hughes, Rosenthal, and Lancaster were employed by Myriad Genetics at the time of their participation in this study and received salaries and stock options as compensation. No other individuals received compensation for their roles in the study.
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