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      Call for Papers: Digital Platforms and Artificial Intelligence in Dementia

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      Prevalence of Pathogenic Germline Variants in Women with Non-Familial Unilateral Triple-Negative Breast Cancer

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          Abstract

          Introduction

          International guidelines recommend genetic testing for women with familial breast cancer at an expected prevalence of pathogenic germline variants (PVs) of at least 10%. In a study sample of the German Consortium for Hereditary Breast and Ovarian Cancer (GC-HBOC), we have previously shown that women with TNBC diagnosed before the age of 50 years but without a family history of breast or ovarian cancer (sTNBC) meet this criterion. The present study investigates the PV prevalence in BRCA1, BRCA2, and nine additional cancer predisposition genes in an extended sTNBC study sample including a cohort of women with a later age at sTNBC diagnosis.

          Patients and Methods

          In 1,600 women with sTNBC (median age at diagnosis: 41 years, range 19–78 years), we investigated the association between age at diagnosis and PV occurrence in cancer predisposition genes using logistic regression.

          Results

          260 sTNBC patients (16.2%) were found to have a PV in cancer predisposition genes ( BRCA1: n = 170 [10.6%]; BRCA2: n = 46 [2.9%], other: n = 44 [2.8%]). The PV prevalence in women diagnosed between 50 and 59 years ( n = 194) was 11.3% (22/194). Logistic regression showed a significant increase in PV prevalence with decreasing age at diagnosis (OR 1.41 per 10 years younger age at diagnosis; 95% confidence interval: 1.21–1.65; p < 0.001). The PV prevalence predicted by the model was above 10% for diagnoses before the age of 56.8 years.

          Conclusion

          Based on the data presented, we recommend genetic testing by gene panel analysis for sTNBC patients diagnosed before the age of 60 years. Due to the still uncertain estimate for women with sTNBC diagnosed above the age of 60 years, further studies are needed.

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          Most cited references24

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          Triple-negative breast cancer.

          Triple-negative breast cancer, so called because it lacks expression of the estrogen receptor, progesterone receptor, and HER2, is often, but not always, a basal-like breast cancer. This review focuses on its origin, molecular and clinical characteristics, and treatment.
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            Sequence variant classification and reporting: recommendations for improving the interpretation of cancer susceptibility genetic test results.

            Genetic testing of cancer susceptibility genes is now widely applied in clinical practice to predict risk of developing cancer. In general, sequence-based testing of germline DNA is used to determine whether an individual carries a change that is clearly likely to disrupt normal gene function. Genetic testing may detect changes that are clearly pathogenic, clearly neutral, or variants of unclear clinical significance. Such variants present a considerable challenge to the diagnostic laboratory and the receiving clinician in terms of interpretation and clear presentation of the implications of the result to the patient. There does not appear to be a consistent approach to interpreting and reporting the clinical significance of variants either among genes or among laboratories. The potential for confusion among clinicians and patients is considerable and misinterpretation may lead to inappropriate clinical consequences. In this article we review the current state of sequence-based genetic testing, describe other standardized reporting systems used in oncology, and propose a standardized classification system for application to sequence-based results for cancer predisposition genes. We suggest a system of five classes of variants based on the degree of likelihood of pathogenicity. Each class is associated with specific recommendations for clinical management of at-risk relatives that will depend on the syndrome. We propose that panels of experts on each cancer predisposition syndrome facilitate the classification scheme and designate appropriate surveillance and cancer management guidelines. The international adoption of a standardized reporting system should improve the clinical utility of sequence-based genetic tests to predict cancer risk. (c) 2008 Wiley-Liss, Inc.
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              Approximate is Better than “Exact” for Interval Estimation of Binomial Proportions

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                Author and article information

                Journal
                Breast Care (Basel)
                Breast Care (Basel)
                BRC
                Breast Care
                S. Karger AG (Allschwilerstrasse 10, P.O. Box · Postfach · Case postale, CH–4009, Basel, Switzerland · Schweiz · Suisse, Phone: +41 61 306 11 11, Fax: +41 61 306 12 34, karger@karger.com )
                1661-3791
                1661-3805
                May 2023
                6 January 2023
                6 January 2023
                : 18
                : 2
                : 106-112
                Affiliations
                [1] aCenter for Hereditary Breast and Ovarian Cancer and Center for Integrated Oncology (CIO), Medical Faculty, University Hospital Cologne, Cologne, Germany
                [2] bInstitute for Medical Informatics, Statistics and Epidemiology, Leipzig University, Leipzig, Germany
                [3] cDepartment of Gynecology and Center for Hereditary Breast and Ovarian Cancer, Klinikum Rechts der Isar, Technical University Munich (TUM), Munich, Germany
                [4] dDepartment of Obstetrics and Gynecology, University Hospital, Ludwig-Maximilians-University, Munich, Germany
                [5] eDepartment of Gynecology and Obstetrics, University of Heidelberg, Heidelberg, Germany
                [6] fDepartment Gynecology and Obstetrics, University Hospital Schleswig Holstein (UKSH) Campus Kiel, Kiel, Germany
                [7] gDepartment of Gynecology and Obstetrics, University Hospital Düsseldorf, Düsseldorf, Germany
                [8] hInstitute for Gynecology and Obstetrics and Center for Hereditary Breast and Ovarian Can-cer, Medical Faculty, University Hospital Würzburg, Würzburg, Germany
                [9] iDepartment of Human Genetics, Hannover Medical School, Hannover, Germany
                [10] jInstitute of Human Genetics, University of Münster, Münster, Germany
                [11] kDepartment of Gynecology and Obstetrics, Technische Universität Dresden, Dresden, Germany
                [12] lNational Center for Tumor Diseases (NCT/UCC), Dresden, Germany: German Cancer Research Center (DKFZ), Heidelberg, Germany
                [13] mFaculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
                [14] nHelmholtz-Centre Dresden - Rossendorf (HZDR), Dresden, Germany
                [15] oDepartment of Gynecology and Breast Centre, Centre for Hereditary Breast and Ovarian Cancer Charité, Charité University Hospital, Berlin, Germany
                [16] pDepartment of Gynecology and Obstetrics, University Hospital Ulm, Ulm, Germany
                [17] qInstitute of Medical Genetics and Applied Genomics, University Hospital Tübingen, Tübingen, Germany
                [18] rDepartment of Gynecology, University Hospital Hamburg-Eppendorf, Hamburg, Germany
                [19] sDepartment of Gynecology and Obstetrics, University Medicine Göttingen, Göttingen, Germany
                [20] tInstitute of Human Genetics, University of Regensburg, Regensburg, Germany
                [21] uInstitute of Clinical Human Genetics, University Hospital Regensburg, Regensburg, Germany
                [22] vCenter for Hereditary Breast and Ovarian Cancer, University Hospital Frankfurt, Frankfurt, Germany
                [23] wDepartment of Gynecology, University of Leipzig Medical Center, Leipzig, Germany
                Author notes

                Kerstin Rhiem and Silke Zachariae contributed equally as first authors. Christoph Engel and Rita Schmutzler contributed equally as senior authors.

                Article
                brc-0018-0106
                10.1159/000528972
                10228253
                37261134
                db33ffe4-8473-4098-94c8-2157987fe5b9
                Copyright © 2023 by The Author(s). Published by S. Karger AG, Basel

                This article is licensed under the Creative Commons Attribution-NonCommercial 4.0 International License (CC BY-NC). Usage and distribution for commercial purposes requires written permission.

                History
                : 19 August 2022
                : 2 January 2023
                : 2023
                Page count
                Figures: 2, Tables: 3, References: 26, Pages: 7
                Funding
                The GC-HBOC was supported by the German Cancer Aid (Grant no. 110837 and Grant no. 70114178, coordinator: Rita K. Schmutzler, Cologne) and is currently supported by the Federal Ministry of Education and Research (BMBF), Germany (Grant no. 01GY1901). The funding sources had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; or in the decision to submit the manuscript for publication.
                Categories
                Research Article

                brca1,brca2, triple negative,breast cancer,hereditary breast and ovarian cancer

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