Integrating Clinical and Polygenic Factors to Predict Breast Cancer Risk in Women Undergoing Genetic Testing
| Autor: | Shannon Gallagher, Jeffrey N. Weitzel, Eric Rosenthal, Placede Tshiaba, Danna F. Grear, Jerry S. Lanchbury, Judy Garber, Susanne Wagner, Benjamin B. Roa, Wade Hedegard, Kathryn Dalton, Mark E. Robson, Johnathan M. Lancaster, Alexander Gutin, Allison W. Kurian, Susan M. Domchek, Elisha Hughes, Thaddeus Judkins, Carol A. Adami, Stephanie Meek |
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| Rok vydání: | 2021 |
| Předmět: |
Adult
0301 basic medicine Oncology Multifactorial Inheritance Cancer Research medicine.medical_specialty Adolescent Psychological intervention MEDLINE Breast Neoplasms Risk Assessment Young Adult 03 medical and health sciences 0302 clinical medicine Breast cancer Internal medicine medicine Humans Genetic Testing Prospective Studies Aged Genetic testing Aged 80 and over medicine.diagnostic_test business.industry ORIGINAL REPORTS Middle Aged Prognosis medicine.disease 030104 developmental biology Increased risk 030220 oncology & carcinogenesis Female business Cancer Prevention |
| Zdroj: | JCO Precision Oncology |
| ISSN: | 2473-4284 |
| DOI: | 10.1200/po.20.00246 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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