Prevalence of Pathogenic Variants in Cancer Susceptibility Genes Among Women With Postmenopausal Breast Cancer

Kurian, Allison W.; Bernhisel, Ryan; Larson, Katie; Caswell-Jin, Jennifer L.; Shadyab, Aladdin H.; Ochs‐Balcom, Heather M.; Stefanick, Marcia L.

doi:10.1001/jama.2020.0229

Cited by 27 publications

(44 citation statements)

References 5 publications

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“…These overall findings were consistent with the results from a recent study involving 2,195 populationbased postmenopausal women with breast cancer (3.55% with PVs) and 2,322 population-based unaffected postmenopausal women (1.29% with PVs). 7 Importantly, women with breast cancer diagnosed over age 65 years with no other significant risk factors (eg, ERnegative disease, FH, or Ashkenazi Jewish) are not recommended by NCCN to receive genetic testing on the basis of a presumed low yield (, 2.5% probability of detecting a high-penetrance PV). In this study, we showed that 3.42% and 3.01% of population-based women with ER-negative breast cancer and TNBC, respectively, had PVs in the BRCA1, BRCA2, and PALB2 high-risk genes.…”

Section: Discussionmentioning

confidence: 99%

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Risk of Late-Onset Breast Cancer in Genetically Predisposed Women

Boddicker

Weitzel

et al. 2021

JCO

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PURPOSE The prevalence of germline pathogenic variants (PVs) in established breast cancer predisposition genes in women in the general population over age 65 years is not well-defined. However, testing guidelines suggest that women diagnosed with breast cancer over age 65 years might have < 2.5% likelihood of a PV in a high-penetrance gene. This study aimed to establish the frequency of PVs and remaining risks of breast cancer for each gene in women over age 65 years. METHODS A total of 26,707 women over age 65 years from population-based studies (51.5% with breast cancer and 48.5% unaffected) were tested for PVs in germline predisposition gene. Frequencies of PVs and associations between PVs in each gene and breast cancer were assessed, and remaining lifetime breast cancer risks were estimated for non-Hispanic White women with PVs. RESULTS The frequency of PVs in predisposition genes was 3.18% for women with breast cancer and 1.48% for unaffected women over age 65 years. PVs in BRCA1, BRCA2, and PALB2 were found in 3.42% of women diagnosed with estrogen receptor (ER)–negative, 1.0% with ER-positive, and 3.01% with triple-negative breast cancer. Frequencies of PVs were lower among women with no first-degree relatives with breast cancer. PVs in CHEK2, PALB2, BRCA2, and BRCA1 were associated with increased risks (odds ratio = 2.9-4.0) of breast cancer. Remaining lifetime risks of breast cancer were ≥ 15% for those with PVs in BRCA1, BRCA2, and PALB2. CONCLUSION This study suggests that all women diagnosed with triple-negative breast cancer or ER-negative breast cancer should receive genetic testing and that women over age 65 years with BRCA1 and BRCA2 PVs and perhaps with PALB2 and CHEK2 PVs should be considered for magnetic resonance imaging screening.

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Section: Discussionmentioning

confidence: 99%

“…10 WHI samples were independent from those reported previously. 7 All participants provided informed consent for research. The study was approved by the Mayo Clinic Institutional Review Board.…”

Section: Study Participantsmentioning

confidence: 99%

Risk of Late-Onset Breast Cancer in Genetically Predisposed Women

Boddicker

Weitzel

et al. 2021

JCO

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“…Evaluation of the CRS in a prospectively collected, unselected population-based sample is being pursued. 40 Future work to expand assessment tools such as Tyrer-Cuzick and the PRS for non-European ancestries will be required to apply these tools to other ancestry populations. Finally, information for Tyrer-Cuzick for the clinical testing populations was obtained from provider-completed test request forms.…”

Section: Discussionmentioning

confidence: 99%

Integrating Clinical and Polygenic Factors to Predict Breast Cancer Risk in Women Undergoing Genetic Testing

Hughes

Tshiaba

Wagner

et al. 2021

JCO Precision Oncology

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PURPOSE Screening and prevention decisions for women at increased risk of developing breast cancer depend on genetic and clinical factors to estimate risk and select appropriate interventions. Integration of polygenic risk into clinical breast cancer risk estimators can improve discrimination. However, correlated genetic effects must be incorporated carefully to avoid overestimation of risk. MATERIALS AND METHODS A novel Fixed-Stratified method was developed that accounts for confounding when adding a new factor to an established risk model. A combined risk score (CRS) of an 86–single-nucleotide polymorphism polygenic risk score and the Tyrer-Cuzick v7.02 clinical risk estimator was generated with attenuation for confounding by family history. Calibration and discriminatory accuracy of the CRS were evaluated in two independent validation cohorts of women of European ancestry (N = 1,615 and N = 518). Discrimination for remaining lifetime risk was examined by age-adjusted logistic regression. Risk stratification with a 20% risk threshold was compared between CRS and Tyrer-Cuzick in an independent clinical cohort (N = 32,576). RESULTS Simulation studies confirmed that the Fixed-Stratified method produced accurate risk estimation across patients with different family history. In both validation studies, CRS and Tyrer-Cuzick were significantly associated with breast cancer. In an analysis with both CRS and Tyrer-Cuzick as predictors of breast cancer, CRS added significant discrimination independent of that captured by Tyrer-Cuzick ( P < 10−11 in validation 1; P < 10−7 in validation 2). In an independent cohort, 18% of women shifted breast cancer risk categories from their Tyrer-Cuzick–based risk compared with risk estimates by CRS. CONCLUSION Integrating clinical and polygenic factors into a risk model offers more effective risk stratification and supports a personalized genomic approach to breast cancer screening and prevention.

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“…In fact, sub-stantial inherent biases exist in some of the published studies of breast cancer patients that report similar HBC identification yield from a risk-stratified versus broader testing approach. Yet, newer well-designed studies have suggest that the yield of testing all breast cancer patients for BRCA1/2 P/LP variants at or below age 65 would be ~2-3% [29,30]. Although broader testing approaches would increase the detection of positive patients (i.e., sensitivity), another parameter to consider is the proportion negative (i.e., without HBC) who do not meet criteria (i.e., specificity).…”

Section: Updated Guidelines To Address Low Genetic Testing Ratesmentioning

confidence: 99%