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Prediction of contralateral breast cancer: external validation of risk calculators in 20 international cohorts

  • Epidemiology
  • Published:
Breast Cancer Research and Treatment Aims and scope Submit manuscript

Abstract

Background

Three tools are currently available to predict the risk of contralateral breast cancer (CBC). We aimed to compare the performance of the Manchester formula, CBCrisk, and PredictCBC in patients with invasive breast cancer (BC).

Methods

We analyzed data of 132,756 patients (4682 CBC) from 20 international studies with a median follow-up of 8.8 years. Prediction performance included discrimination, quantified as a time-dependent Area-Under-the-Curve (AUC) at 5 and 10 years after diagnosis of primary BC, and calibration, quantified as the expected-observed (E/O) ratio at 5 and 10 years and the calibration slope.

Results

The AUC at 10 years was: 0.58 (95% confidence intervals [CI] 0.57–0.59) for CBCrisk; 0.60 (95% CI 0.59–0.61) for the Manchester formula; 0.63 (95% CI 0.59–0.66) and 0.59 (95% CI 0.56–0.62) for PredictCBC-1A (for settings where BRCA1/2 mutation status is available) and PredictCBC-1B (for the general population), respectively. The E/O at 10 years: 0.82 (95% CI 0.51–1.32) for CBCrisk; 1.53 (95% CI 0.63–3.73) for the Manchester formula; 1.28 (95% CI 0.63–2.58) for PredictCBC-1A and 1.35 (95% CI 0.65–2.77) for PredictCBC-1B. The calibration slope was 1.26 (95% CI 1.01–1.50) for CBCrisk; 0.90 (95% CI 0.79–1.02) for PredictCBC-1A; 0.81 (95% CI 0.63–0.99) for PredictCBC-1B, and 0.39 (95% CI 0.34–0.43) for the Manchester formula.

Conclusions

Current CBC risk prediction tools provide only moderate discrimination and the Manchester formula was poorly calibrated. Better predictors and re-calibration are needed to improve CBC prediction and to identify low- and high-CBC risk patients for clinical decision-making.

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Acknowledgements

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 thank Maggie Angelakos, Judi Maskiell, Gillian Dite. ABCS and BOSOM thanks all the collaborating hospitals and pathology departments and many individual that made this study possible, specifically, we wish to acknowledge: Annegien Broeks, Sten Cornelissen, Frans Hogervorst, Laura van ‘t Veer, Floor van Leeuwen, 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. HEBCS thanks Taru A. Muranen, Kristiina Aittomäki, Karl von Smitten, Irja Erkkilä. KARMA thanks the Swedish Medical Research Counsel. LMBC thanks Gilian Peuteman, Thomas Van Brussel, EvyVanderheyden and Kathleen Corthouts. MARIE thanks Petra Seibold, Dieter Flesch-Janys, Judith Heinz, Nadia Obi, Alina Vrieling, Sabine Behrens, Ursula Eilber, Muhabbet Celik, Til Olchers and Stefan Nickels. 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, Michael Stagner. The ethical approval for the POSH study is MREC /00/6/69, UKCRN ID: 1137. We thank the SEARCH team.

Funding

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 Nos. 634935 and 633784 for BRIDGES and B-CAST respectively), and by the European Community´s Seventh Framework Programme under grant agreement number 223175 (Grant No. 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. 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 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. 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 support 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 PBCS was funded by Intramural Research Funds of the National Cancer Institute, Department of Health and Human Services, USA. Genotyping for PLCO was supported by the Intramural Research Program of the National Institutes of Health, NCI, Division of Cancer Epidemiology and Genetics. The POSH study is funded by Cancer Research UK (Grants C1275/A11699, C1275/C22524, C1275/A19187, C1275/A15956 and Breast Cancer Campaign 2010PR62, 2013PR044. PROCAS is funded from NIHR grant PGfAR 0707-10031. SEARCH is funded by Cancer Research UK [C490/A10124, C490/A16561] and supported by the UK National Institute for Health Research Biomedical Research Centre at the University of Cambridge. The University of Cambridge has received salary support for PDPP from the NHS in the East of England through the Clinical Academic Reserve. SKKDKFZS is supported by the DKFZ. The SZBCS (Szczecin Breast Cancer Study) was supported by Grant PBZ_KBN_122/P05/2004 and The National Centre for Research and Development (NCBR) within the framework of the international ERA-NET TRANSAN JTC 2012 application no. Cancer 12-054 (Contract No. ERA-NET-TRANSCAN / 07/2014).

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Authors and Affiliations

  1. Division of Molecular Pathology, The Netherlands Cancer Institute - Antoni Van Leeuwenhoek Hospital, Amsterdam, The Netherlands

    Daniele Giardiello, Renske Keeman, Iris Kramer, Alexandra J. van den Broek, Laura J. Van’t Veer & Marjanka K. Schmidt

  2. Department of Biomedical Data Sciences, Leiden University Medical Center, Leiden, The Netherlands

    Daniele Giardiello & Ewout W. Steyerberg

  3. Brandenburg Medical School, Institute of Biostatistics and Registry Research, Neuruppin, Germany

    Michael Hauptmann

  4. Department of Epidemiology and Biostatistics, The Netherlands Cancer Institute - Antoni Van Leeuwenhoek Hospital, Amsterdam, The Netherlands

    Michael Hauptmann

  5. Department of Public Health, Erasmus MC Cancer Institute, Rotterdam, The Netherlands

    Ewout W. Steyerberg

  6. Family Cancer Clinic, The Netherlands Cancer Institute - Antoni Van Leeuwenhoek Hospital, Amsterdam, The Netherlands

    Muriel A. Adank

  7. Department of Medical Oncology, Family Cancer Clinic, Erasmus MC Cancer Institute, Rotterdam, The Netherlands

    Delal Akdeniz, Jannet C. Blom, Saskia Pelders & Maartje J. Hooning

  8. Department of Oncology, Helsinki University Hospital, University of Helsinki, Helsinki, Finland

    Carl Blomqvist

  9. Department of Oncology, Örebro University Hospital, Örebro, Sweden

    Carl Blomqvist

  10. Copenhagen General Population Study, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark

    Stig E. Bojesen

  11. Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark

    Stig E. Bojesen

  12. Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark

    Stig E. Bojesen

  13. Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK

    Manjeet K. Bolla, Douglas F. Easton, Paul D. P. Pharoah & Qin Wang

  14. Laboratory for Pathology, East-Netherlands, Hengelo, The Netherlands

    Mariël Brinkhuis

  15. Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany

    Jenny Chang-Claude & Audrey Jung

  16. University Medical Center Hamburg-Eppendorf, Cancer Epidemiology, University Cancer Center Hamburg (UCCH), Hamburg, Germany

    Jenny Chang-Claude

  17. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden

    Kamila Czene & Per Hall

  18. Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands

    Peter Devilee & Vincent T. H. B. M. Smit

  19. Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands

    Peter Devilee

  20. Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK

    Alison M. Dunning, Douglas F. Easton, Paul D. P. Pharoah & Mitul Shah

  21. Cancer Sciences Academic Unit, Faculty of Medicine, University of Southampton, Southampton, UK

    Diana M. Eccles

  22. David Geffen School of Medicine, Department of Medicine Division of Hematology and Oncology, University of California At Los Angeles, Los Angeles, CA, USA

    Peter A. Fasching

  23. University Hospital Erlangen, Department of Gynecology and Obstetrics, Comprehensive Cancer Center ER-EMN, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Germany

    Peter A. Fasching & Lothar Haeberle

  24. The University of Edinburgh Medical School, Usher Institute of Population Health Sciences and Informatics, Edinburgh, UK

    Jonine Figueroa

  25. Cancer Research UK Edinburgh Centre, Edinburgh, UK

    Jonine Figueroa

  26. Department of Health and Human Services, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA

    Jonine Figueroa & Montserrat García-Closas

  27. Department of Breast Surgery, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark

    Henrik Flyger

  28. Division of Genetics and Epidemiology, Institute of Cancer Research, London, UK

    Montserrat García-Closas

  29. Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA

    Christopher A. Haiman

  30. Department of Oncology, Södersjukhuset, Stockholm, Sweden

    Per Hall

  31. Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany

    Ute Hamann & Mehdi Manoochehri

  32. Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, VIC, Australia

    John L. Hopper

  33. Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands

    Agnes Jager

  34. Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland

    Anna Jakubowska & Jan Lubiński

  35. Independent Laboratory of Molecular Biology and Genetic Diagnostics, Pomeranian Medical University, Szczecin, Poland

    Anna Jakubowska

  36. Department of Surgical Oncology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands

    Linetta B. Koppert

  37. VIB Center for Cancer Biology, Leuven, Belgium

    Diether Lambrechts

  38. Laboratory for Translational Genetics, Department of Human Genetics, University of Leuven, Leuven, Belgium

    Diether Lambrechts

  39. Epidemiology Program, University of Hawaii Cancer Center, Honolulu, HI, USA

    Loic Le Marchand

  40. Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden

    Annika Lindblom

  41. Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden

    Annika Lindblom

  42. Unit of Clinical Epidemiology and Trial Organization, Fondazione IRCCS Istituto Nazionale Dei Tumori, Milan, Italy

    Luigi Mariani

  43. Department of Obstetrics and Gynecology, Helsinki University Hospital, University of Helsinki, Helsinki, Finland

    Heli Nevanlinna

  44. Department of Surgical Oncology, The Netherlands Cancer Institute - Antoni Van Leeuwenhoek Hospital, Amsterdam, The Netherlands

    Hester S. A. Oldenburg

  45. Department of Research, Netherlands Comprehensive Cancer Organisation, Utrecht, The Netherlands

    Sabine Siesling

  46. Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, VIC, Australia

    Melissa C. Southey

  47. Department of Clinical Pathology, The University of Melbourne, Melbourne, VIC, Australia

    Melissa C. Southey

  48. Faculty of Medicine, University of Southampton, Southampton, UK

    William J. Tapper

  49. Department of Surgery, Leiden University Medical Center, Leiden, The Netherlands

    Rob A. E. M. Tollenaar

  50. Department of Pathology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands

    Carolien H. M. van Deurzen

  51. Division of Psychosocial Research and Epidemiology, The Netherlands Cancer Institute - Antoni Van Leeuwenhoek Hospital, Amsterdam, The Netherlands

    Flora E. van Leeuwen & Marjanka K. Schmidt

  52. Leuven Cancer Institute, Leuven Multidisciplinary Breast Center, Department of Oncology, University Hospitals Leuven, Leuven, Belgium

    Chantal van Ongeval

  53. Department of Clinical Science and Education, Karolinska Institutet, Södersjukhuset, Stockholm, Sweden

    Camilla Wendt

  54. Laboratory for Pathology, Dordrecht, The Netherlands

    Pieter J. Westenend

  55. Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands

    Marjanka K. Schmidt

Authors
  1. Daniele Giardiello
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  2. Michael Hauptmann
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  3. Ewout W. Steyerberg
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  57. Marjanka K. Schmidt
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Corresponding author

Correspondence to Marjanka K. Schmidt.

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Conflict of interest

Author DG, MH, EW, MAA, DA, JCB, CB, SEB, MKB, JCC, KC, PD, AMD, DFE, JF, HF, MGC, LH, CAH, PH, UH, JLH, AJ, AJ2, AJ3, RK, LBK, IK, DL, LLN, AL, JL, MM, LM, HN, HSAO, SP, PDPP, MS, SS, VTHBMS, MCS, WJT, RAEMT, AJvdB, CHMvD, FEvL, CvO, LvV, QW, CW, PJW, MJH declares that he has no conflict of interest. Author DMM declares that she receives a lecture fee from Pierre Fabre and personal fees for consultancy from Astra Zeneca. Author PAF reports grants from Novartis, grants from Biontech, personal fees from Novartis, personal fees from Roche, personal fees from Pfizer, personal fees from Celgene, personal fees from Daiichi-Sankyo, personal fees from TEVA, personal fees from Astra Zeneca, personal fees from Merck Sharp & Dohme, personal fees from Myelo Therapeutics, personal fees from Macrogenics, personal fees from Eisai, personal fees from Puma, grants from Cepheid.

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All procedures performed in studies involving human participants were in accordance with the ethical standards of international, national, and institutional research committees and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

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Informed consent was obtained from all individual participants included in the study.

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Giardiello, D., Hauptmann, M., Steyerberg, E.W. et al. Prediction of contralateral breast cancer: external validation of risk calculators in 20 international cohorts. Breast Cancer Res Treat 181, 423–434 (2020). https://doi.org/10.1007/s10549-020-05611-8

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