TY - JOUR

T1 - PredictCBC-2.0

T2 - a contralateral breast cancer risk prediction model developed and validated in ~ 200,000 patients

AU - Giardiello, Daniele

AU - Hooning, Maartje J.

AU - Hauptmann, Michael

AU - Keeman, Renske

AU - Heemskerk-Gerritsen, B. A.M.

AU - Becher, Heiko

AU - Blomqvist, Carl

AU - Bojesen, Stig E.

AU - Bolla, Manjeet K.

AU - Camp, Nicola J.

AU - Czene, Kamila

AU - Devilee, Peter

AU - Eccles, Diana M.

AU - Fasching, Peter A.

AU - Figueroa, Jonine D.

AU - Flyger, Henrik

AU - García-Closas, Montserrat

AU - Haiman, Christopher A.

AU - Hamann, Ute

AU - Hopper, John L.

AU - Jakubowska, Anna

AU - Leeuwen, Floor E.

AU - Lindblom, Annika

AU - Lubiński, Jan

AU - Margolin, Sara

AU - Martinez, Maria Elena

AU - Nevanlinna, Heli

AU - Nevelsteen, Ines

AU - Pelders, Saskia

AU - Pharoah, Paul D.P.

AU - Siesling, Sabine

AU - Southey, Melissa C.

AU - van der Hout, Annemieke H.

AU - van Hest, Liselotte P.

AU - Chang-Claude, Jenny

AU - Hall, Per

AU - Easton, Douglas F.

AU - Steyerberg, Ewout W.

AU - Schmidt, Marjanka K.

N1 - Funding Information: This work is supported by the Alpe d’HuZes/Dutch Cancer Society (KWF Kankerbestrijding) project 6253. BCAC is funded by Cancer Research UK [C1287/A16563, C1287/A10118], the European Union's Horizon 2020 Research and Innovation Programme (Grant Numbers 634935 and 633784 for BRIDGES and B-CAST, respectively), and by the European Community´s Seventh Framework Programme under grant agreement number 223175 (Grant Number HEALTH-F2-2009-223175) (COGS). The EU Horizon 2020 Research and Innovation Programme funding source had no role in study design, data collection, data analysis, data interpretation, or writing of the report. Additional funding for BCAC is provided via the Confluence project which is funded with intramural funds from the National Cancer Institute Intramural Research Program, National Institutes of Health. The Australian Breast Cancer Family Study (ABCFS) was supported by grant UM1 CA164920 from the National Cancer Institute (USA). The ABCFS was also supported by the National Health and Medical Research Council of Australia, the New South Wales Cancer Council, the Victorian Health Promotion Foundation (Australia), and the Victorian Breast Cancer Research Consortium. J.L.H. is a National Health and Medical Research Council (NHMRC) Senior Principal Research Fellow. M.C.S. is a NHMRC Senior Research Fellow. The ABCS study was supported by the Dutch Cancer Society [Grants NKI 2007-3839; 2009 4363]. The work of the BBCC was partly funded by ELAN-Fond of the University Hospital of Erlangen. BOSOM was supported by the Dutch Cancer Society Grant Numbers DCS-NKI 2001-2423, DCS-NKI 2007-3839, and DCSNKI 2009-4363; the Cancer Genomics Initiative; and notary office Spier & Hazenberg for the coding procedure. The BREast Oncology GAlician Network (BREOGAN) is funded by Acción Estratégica de Salud del Instituto de Salud Carlos III FIS PI12/02125/Cofinanciado and FEDER PI17/00918/Cofinanciado FEDER; Acción Estratégica de Salud del Instituto de Salud Carlos III FIS Intrasalud (PI13/01136); Programa Grupos Emergentes, Cancer Genetics Unit, Instituto de Investigacion Biomedica Galicia Sur. Xerencia de Xestion Integrada de Vigo-SERGAS, Instituto de Salud Carlos III, Spain; Grant 10CSA012E, Consellería de Industria Programa Sectorial de Investigación Aplicada, PEME I + D e I + D Suma del Plan Gallego de Investigación, Desarrollo e Innovación Tecnológica de la Consellería de Industria de la Xunta de Galicia, Spain; Grant EC11-192. Fomento de la Investigación Clínica Independiente, Ministerio de Sanidad, Servicios Sociales e Igualdad, Spain; and Grant FEDER-Innterconecta. Ministerio de Economia y Competitividad, Xunta de Galicia, Spain. The EMC was supported by grants from Alpe d’HuZes/Dutch Cancer Society NKI2013-6253 and from Pink Ribbon 2012.WO39.C143. The HEBCS was financially supported by the Helsinki University Hospital Research Fund, the Finnish Cancer Society, and the Sigrid Juselius Foundation. The HEBON study is supported by the Dutch Cancer Society grants NKI1998-1854, NKI2004-3088, NKI2007-3756, NKI 12535, the Netherlands Organisation of Scientific Research grant NWO 91109024, the Pink Ribbon Grants 110005 and 2014-187.WO76, the BBMRI Grant NWO 184.021.007/CP46, and the Transcan Grant JTC 2012 Cancer 12-054. Financial support for KARBAC was provided through the regional agreement on medical training and clinical research (ALF) between Stockholm County Council and Karolinska Institutet, the Swedish Cancer Society, The Gustav V Jubilee foundation and Bert von Kantzows foundation. The KARMA study was supported by Märit and Hans Rausings Initiative Against Breast Cancer. LMBC is supported by the ‘Stichting tegen Kanker.’ The MARIE study was supported by the Deutsche Krebshilfe e.V. [70-2892-BR I, 106332, 108253, 108419, 110826, 110828], the Hamburg Cancer Society, the German Cancer Research Center (DKFZ) and the Federal Ministry of Education and Research (BMBF) Germany [01KH0402]. MEC was supported by NIH grants CA63464, CA54281, CA098758, CA132839 and CA164973. The ORIGO study was supported by the Dutch Cancer Society (RUL 1997-1505) and the Biobanking and Biomolecular Resources Research Infrastructure (BBMRI-NL CP16). The Netherlands Cancer Registry is hosted by the Netherlands Comprehensive Cancer Organisation (IKNL) and financed by the Dutch Ministry of Health, Welfare and Sports. The PBCS was funded by Intramural Research Funds of the National Cancer Institute, Department of Health and Human Services, USA. The POSH study is funded by Cancer Research UK (grants C1275/A11699, C1275/C22524, C1275/A19187, C1275/A15956 and Breast Cancer Campaign 2010PR62, 2013PR044). SKKDKFZS is supported by the DKFZ. The SZBCS was supported by Grant PBZ_KBN_122/P05/2004 and the program of the Minister of Science and Higher Education under the name "Regional Initiative of Excellence" in 2019–2022 project number 002/RID/2018/19 amount of financing 12 000 000 PLN. UBCS was supported by funding from National Cancer Institute (NCI) grant R01 CA163353 (to N.J. Camp) and the Women’s Cancer Center at the Huntsman Cancer Institute (HCI). Data collection for UBCS was supported by the Utah Population Database, Intermountain Healthcare and the Utah Cancer Registry which is funded by the NCI's SEER Program (HHSN261201800016I), the US Centers for Disease Control and Prevention's National Program of Cancer Registries (NU58DP006320), with additional support from the University of Utah and Huntsman Cancer Foundation. Funding Information: We thank all individuals who took part in these studies and all researchers, clinicians, technicians, and administrative staff who have enabled this work to be carried out. ABCFS thanks Maggie Angelakos, Judi Maskiell, and Gillian Dite. ABCS thanks the Blood bank Sanquin, The Netherlands. ABCTB Investigators: Christine Clarke, Deborah Marsh, Rodney Scott, Robert Baxter, Desmond Yip, Jane Carpenter, Alison Davis, Nirmala Pathmanathan, Peter Simpson, J. Dinny Graham, Mythily Sachchithananthan. ABCS and BOSOM thank all the collaborating hospitals and pathology departments and many individuals that made this study possible; specifically, we wish to acknowledge: Annegien Broeks, Sten Cornelissen, Frans Hogervorst, Laura van ‘t Veer, Emiel Rutgers. EMC thanks J.C. Blom-Leenheer, P.J. Bos, C.M.G. Crepin, and M. van Vliet for data management. CGPS thanks staff and participants of the Copenhagen General Population Study. For the excellent technical assistance: Dorthe Uldall Andersen, Maria Birna Arnadottir, Anne Bank, Dorthe Kjeldgård Hansen. The Danish Cancer Biobank is acknowledged for providing infrastructure for the collection of blood samples for the cases. HEBCS thanks Johanna Kiiski, Taru A. Muranen, Kristiina Aittomäki, Kirsimari Aaltonen, Karl von Smitten, and Irja Erkkilä. The Hereditary Breast and Ovarian Cancer Research Group Netherlands (HEBON) consists of the following Collaborating Centers: Netherlands Cancer Institute (coordinating center), Amsterdam, NL: M.A. Rookus, F.B.L. Hogervorst, M.A. Adank, D.J. Stommel-Jenner, R. de Groot; Erasmus Medical Center, Rotterdam, NL: J.M. Collée, A.M.W. van den Ouweland, M.J. Hooning, I.A. Boere; Leiden University Medical Center, NL: C.J. van Asperen, P. Devilee, R.B. van der Luijt, T.C.T.E.F. van Cronenburg; Radboud University Nijmegen Medical Center, NL: M.R. Wevers, A.R. Mensenkamp; University Medical Center Utrecht, NL: M.G.E.M. Ausems, M.J. Koudijs; Amsterdam UMC, Univ of Amsterdam, NL: I. van de Beek; Amsterdam UMC, Vrije Universiteit Amsterdam, NL: J.J.P. Gille; Maastricht University Medical Center, NL: E.B. Gómez García, M.J. Blok, M. de Boer; University of Groningen, NL: L.P.V. Berger, M.J.E. Mourits, G.H. de Bock; The Netherlands Comprehensive Cancer Organisation (IKNL): J. Verloop; The nationwide network and registry of histo- and cytopathology in The Netherlands (PALGA): E.C. van den Broek. HEBON thanks the study participants and the registration teams of IKNL and PALGA for part of the data collection. KARMA thanks the Swedish Medical Research Counsel. LMBC thanks Gilian Peuteman, Thomas Van Brussel, EvyVanderheyden and Kathleen Corthouts. MARIE thanks Petra Seibold, Nadia Obi, Sabine Behrens, Ursula Eilber and Muhabbet Celik ORIGO thanks E. Krol-Warmerdam, and J. Blom for patient accrual, administering questionnaires, and managing clinical information. The authors thank the registration team of the Netherlands Comprehensive Cancer Organisation (IKNL) for the collection of data for the Netherlands Cancer Registry as well as IKNL staff for scientific advice. PBCS thanks Louise Brinton, Mark Sherman, Neonila Szeszenia-Dabrowska, Beata Peplonska, Witold Zatonski, Pei Chao, and Michael Stagner. The ethical approval for the POSH study is MREC /00/6/69, UKCRN ID: 1137. We thank the SEARCH and EPIC teams. SKKDKFZS thanks all study participants, clinicians, family doctors, researchers, and technicians for their contributions and commitment to this study. SZBCS thanks Ewa Putresza. UBCS thanks all study participants, the ascertainment, laboratory and research informatics teams at Huntsman Cancer Institute and Intermountain Healthcare, and Justin Williams, Brandt Jones, Myke Madsen, Melissa Cessna, Stacey Knight, and Kerry Rowe for their important contributions to this study. Special thanks are due to Stefano Bottelli for his R programming support.We highly appreciate the help of Tom Hueting to translate PREDICTCBC-2.0 into an online tool. Publisher Copyright: © 2022, The Author(s).

PY - 2022

Y1 - 2022

N2 - Background: Prediction of contralateral breast cancer (CBC) risk is challenging due to moderate performances of the known risk factors. We aimed to improve our previous risk prediction model (PredictCBC) by updated follow-up and including additional risk factors. Methods: We included data from 207,510 invasive breast cancer patients participating in 23 studies. In total, 8225 CBC events occurred over a median follow-up of 10.2 years. In addition to the previously included risk factors, PredictCBC-2.0 included CHEK2 c.1100delC, a 313 variant polygenic risk score (PRS-313), body mass index (BMI), and parity. Fine and Gray regression was used to fit the model. Calibration and a time-dependent area under the curve (AUC) at 5 and 10 years were assessed to determine the performance of the models. Decision curve analysis was performed to evaluate the net benefit of PredictCBC-2.0 and previous PredictCBC models. Results: The discrimination of PredictCBC-2.0 at 10 years was higher than PredictCBC with an AUC of 0.65 (95% prediction intervals (PI) 0.56–0.74) versus 0.63 (95%PI 0.54–0.71). PredictCBC-2.0 was well calibrated with an observed/expected ratio at 10 years of 0.92 (95%PI 0.34–2.54). Decision curve analysis for contralateral preventive mastectomy (CPM) showed the potential clinical utility of PredictCBC-2.0 between thresholds of 4 and 12% 10-year CBC risk for BRCA1/2 mutation carriers and non-carriers. Conclusions: Additional genetic information beyond BRCA1/2 germline mutations improved CBC risk prediction and might help tailor clinical decision-making toward CPM or alternative preventive strategies. Identifying patients who benefit from CPM, especially in the general breast cancer population, remains challenging.

AB - Background: Prediction of contralateral breast cancer (CBC) risk is challenging due to moderate performances of the known risk factors. We aimed to improve our previous risk prediction model (PredictCBC) by updated follow-up and including additional risk factors. Methods: We included data from 207,510 invasive breast cancer patients participating in 23 studies. In total, 8225 CBC events occurred over a median follow-up of 10.2 years. In addition to the previously included risk factors, PredictCBC-2.0 included CHEK2 c.1100delC, a 313 variant polygenic risk score (PRS-313), body mass index (BMI), and parity. Fine and Gray regression was used to fit the model. Calibration and a time-dependent area under the curve (AUC) at 5 and 10 years were assessed to determine the performance of the models. Decision curve analysis was performed to evaluate the net benefit of PredictCBC-2.0 and previous PredictCBC models. Results: The discrimination of PredictCBC-2.0 at 10 years was higher than PredictCBC with an AUC of 0.65 (95% prediction intervals (PI) 0.56–0.74) versus 0.63 (95%PI 0.54–0.71). PredictCBC-2.0 was well calibrated with an observed/expected ratio at 10 years of 0.92 (95%PI 0.34–2.54). Decision curve analysis for contralateral preventive mastectomy (CPM) showed the potential clinical utility of PredictCBC-2.0 between thresholds of 4 and 12% 10-year CBC risk for BRCA1/2 mutation carriers and non-carriers. Conclusions: Additional genetic information beyond BRCA1/2 germline mutations improved CBC risk prediction and might help tailor clinical decision-making toward CPM or alternative preventive strategies. Identifying patients who benefit from CPM, especially in the general breast cancer population, remains challenging.

KW - BCAC

KW - BRCA1/2 germline mutation

KW - Breast Cancer Association Consortium

KW - Breast cancer genetic predisposition

KW - Clinical decision-making

KW - Contralateral breast cancer

KW - Contralateral preventive mastectomy

KW - Polygenic risk score

KW - Prediction performance

KW - Risk prediction

U2 - 10.1186/s13058-022-01567-3

DO - 10.1186/s13058-022-01567-3

M3 - Journal article

C2 - 36271417

AN - SCOPUS:85140206823

VL - 24

JO - Breast Cancer Research

JF - Breast Cancer Research

SN - 1465-5411

IS - 1

M1 - 69

ER -