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

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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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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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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Keywords

  • Contralateral breast cancer
  • Risk prediction
  • Validation
  • Clinical decision-making