Clinical implications of incorporating genetic and non-genetic risk factors in CanRisk-based breast cancer risk prediction
Anja Tüchler,
Antoine De Pauw,
Corinna Ernst,
Amélie Anota,
Inge M.M. Lakeman,
Julia Dick,
Nienke van der Stoep,
Christi J. van Asperen,
Monika Maringa,
Natalie Herold,
Britta Blümcke,
Robert Remy,
Anke Westerhoff,
Denise J. Stommel-Jenner,
Eléonore Frouin,
Lisa Richters,
Lisa Golmard,
Nadine Kütting,
Chrystelle Colas,
Barbara Wappenschmidt,
Kerstin Rhiem,
Peter Devilee,
Dominique Stoppa-Lyonnet,
Rita K. Schmutzler,
Eric Hahnen
Affiliations
Anja Tüchler
Center for Familial Breast and Ovarian and Cancer, Center for Integrated Oncology (CIO), Medical Faculty, University Hospital of Cologne, Cologne, Germany
Antoine De Pauw
Institut Curie, Department of Genetics, Paris, France; Université PSL, Paris, France
Corinna Ernst
Center for Familial Breast and Ovarian and Cancer, Center for Integrated Oncology (CIO), Medical Faculty, University Hospital of Cologne, Cologne, Germany
Amélie Anota
Department of Clinical Research and Innovation, Centre Léon Bérard, Lyon, France; Human and Social Sciences Department, Centre Léon Bérard, Lyon, France; French National Platform Quality of Life and Cancer, Centre Léon Bérard, Lyon, France
Inge M.M. Lakeman
Department of Clinical Genetics, Leiden University Medical Center, Leiden, the Netherlands; Department of Human Genetics, Leiden University Medical Center, Leiden, the Netherlands
Julia Dick
Center for Familial Breast and Ovarian and Cancer, Center for Integrated Oncology (CIO), Medical Faculty, University Hospital of Cologne, Cologne, Germany
Nienke van der Stoep
Department of Clinical Genetics, Leiden University Medical Center, Leiden, the Netherlands
Christi J. van Asperen
Department of Clinical Genetics, Leiden University Medical Center, Leiden, the Netherlands
Monika Maringa
Center for Familial Breast and Ovarian and Cancer, Center for Integrated Oncology (CIO), Medical Faculty, University Hospital of Cologne, Cologne, Germany
Natalie Herold
Center for Familial Breast and Ovarian and Cancer, Center for Integrated Oncology (CIO), Medical Faculty, University Hospital of Cologne, Cologne, Germany
Britta Blümcke
Center for Familial Breast and Ovarian and Cancer, Center for Integrated Oncology (CIO), Medical Faculty, University Hospital of Cologne, Cologne, Germany
Robert Remy
Center for Familial Breast and Ovarian and Cancer, Center for Integrated Oncology (CIO), Medical Faculty, University Hospital of Cologne, Cologne, Germany
Anke Westerhoff
Center for Familial Breast and Ovarian and Cancer, Center for Integrated Oncology (CIO), Medical Faculty, University Hospital of Cologne, Cologne, Germany
Denise J. Stommel-Jenner
Department of Epidemiology, Netherlands Cancer Institute, Amsterdam, the Netherlands
Eléonore Frouin
Université PSL, Paris, France; Clinical Bioinformatics Unit, Institut Curie, Paris, France
Lisa Richters
Center for Familial Breast and Ovarian and Cancer, Center for Integrated Oncology (CIO), Medical Faculty, University Hospital of Cologne, Cologne, Germany
Lisa Golmard
Institut Curie, Department of Genetics, Paris, France; Université PSL, Paris, France
Nadine Kütting
Center for Familial Breast and Ovarian and Cancer, Center for Integrated Oncology (CIO), Medical Faculty, University Hospital of Cologne, Cologne, Germany
Chrystelle Colas
Institut Curie, Department of Genetics, Paris, France; Université PSL, Paris, France; Institut Curie, Inserm U830, Paris, France
Barbara Wappenschmidt
Center for Familial Breast and Ovarian and Cancer, Center for Integrated Oncology (CIO), Medical Faculty, University Hospital of Cologne, Cologne, Germany
Kerstin Rhiem
Center for Familial Breast and Ovarian and Cancer, Center for Integrated Oncology (CIO), Medical Faculty, University Hospital of Cologne, Cologne, Germany
Peter Devilee
Department of Human Genetics, Leiden University Medical Center, Leiden, the Netherlands; Department of Pathology, Leiden University Medical Center, Leiden, the Netherlands
Dominique Stoppa-Lyonnet
Institut Curie, Department of Genetics, Paris, France; Institut Curie, Inserm U830, Paris, France; Université Paris Cité, Paris, France
Rita K. Schmutzler
Center for Familial Breast and Ovarian and Cancer, Center for Integrated Oncology (CIO), Medical Faculty, University Hospital of Cologne, Cologne, Germany
Eric Hahnen
Center for Familial Breast and Ovarian and Cancer, Center for Integrated Oncology (CIO), Medical Faculty, University Hospital of Cologne, Cologne, Germany; Corresponding author. University Hospital Cologne, Kerpener Straße 62, 50937, Cologne, Germany.
Background: Breast cancer (BC) risk prediction models consider cancer family history (FH) and germline pathogenic variants (PVs) in risk genes. It remains elusive to what extent complementation with polygenic risk score (PRS) and non-genetic risk factor (NGRFs) data affects individual intensified breast surveillance (IBS) recommendations according to European guidelines. Methods: For 425 cancer-free women with cancer FH (mean age 40·6 years, range 21–74), recruited in France, Germany and the Netherlands, germline PV status, NGRFs, and a 306 variant-based PRS (PRS306) were assessed to calculate estimated lifetime risks (eLTR) and estimated 10-year risks (e10YR) using CanRisk. The proportions of women changing country-specific European risk categories for IBS recommendations, i.e. ≥20 % and ≥30 % eLTR, or ≥5 % e10YR were determined. Findings: Of the women with non-informative PV status, including PRS306 and NGRFs changed clinical recommendations for 31·0 %, (57/184, 20 % eLTR), 15·8 % (29/184, 30 % eLTR) and 22·4 % (41/183, 5 % e10YR), respectively whereas of the women tested negative for a PV observed in their family, clinical recommendations changed for 16·7 % (25/150), 1·3 % (2/150) and 9·5 % (14/147). No change was observed for 82 women with PVs in high-risk genes (BRCA1/2, PALB2). Combined consideration of eLTRs and e10YRs identified BRCA1/2 PV carriers benefitting from IBS <30 years, and women tested non-informative/negative for whom IBS may be postponed. Interpretation: For women who tested non-informative/negative, PRS and NGRFs have a considerable impact on IBS recommendations. Combined consideration of eLTRs and e10YRs allows personalizing IBS starting age. Funding: Horizon 2020, German Cancer Aid, Federal Ministry of Education and Research, Köln Fortune.
