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Biologic markers determine both the risk and the timing of recurrence in breast cancer

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Abstract

Breast cancer has a long natural history. Established and emerging biologic markers address overall risk but not necessarily timing of recurrence. 346 adjuvant naïve breast cancer cases from Guy’s Hospital with 23 years minimum follow-up and archival blocks were recut and reassessed for hormone-receptors (HR), HER2-receptor and grade. Disease-specific survival (DSS) was analyzed by recursive partitioning. To validate insights from this analysis, gene-signatures (proliferative and HR-negative) were evaluated for their ability to predict early versus late metastatic risk in 683 node-negative, adjuvant naïve breast cancers annotated with expression microarray data. Risk partitioning showed that adjuvant naïve node-negative outcome risk was primarily partitioned by tumor receptor status and grade but not tumor size. HR-positive and HER2-negative (HRpos) risk was partitioned by tumor grade; low grade cases have very low early risk but a 20% fall-off in DSS 10 or more years after diagnosis. Higher grade HRpos cases have risk over >20 years. Triple-negative (Tneg) and HER2-positive (HER2pos) cases DSS events occurred primarily within the first 5 years. Among node-positive cases, only low grade conferred late risk, suggesting that proliferative gene signatures that identify proliferation would be important for predicting early but not late recurrence. Using pooled data from four publicly available data sets for node-negative tumors annotated with gene expression and outcome data, we evaluated four prognostic gene signatures: two proliferation-based and two immune function-based. Tumor proliferative capacity predicted early but not late metastatic risk for HRpos cases. The immune function or HRneg specific signatures predicted only early metastatic risk in Tneg and HER2pos cases. Breast cancer prognostic signatures need to inform both risk and timing of metastatic events and may best be applied within subsets. Current signatures predict for outcome risk within 5 years of diagnosis. Predictors of late risk for HR positive disease are needed.

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Acknowledgments

This work was supported by the Early Detection Research Network (EDRN) initiative of the National Cancer Institute (5 UO1 CA111234); and from the Department of Health via the National Institute for Health Research (NIHR) Comprehensive Biomedical Research Centre award to Guy’s & St Thomas’ NHS Foundation Trust in partnership with King’s College London and King’s College Hospital NHS Foundation Trust.

Conflicts of interest

None of the authors declared any conflict of interest.

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Authors and Affiliations

  1. Department of Surgery and Radiology, University of California, San Francisco, CA, USA

    Laura J. Esserman, Pamela J. Tsing, Philip W. Chu, Vickram J. Tandon & Stig Kreps

  2. Department of Biostatistics, University of California, San Francisco, CA, USA

    Dan H. Moore

  3. Department of Pathology and Laboratory Medicine, University of California, San Francisco , CA, USA

    Frederick L. Baehner

  4. Buck Institute for Aging, Novato, CA, USA

    Christina Yau & Christopher C. Benz

  5. Department of Radiology and Outcomes, Massachusetts General Hospital, Boston, MA, USA

    Elissa Ozanne

  6. Department of Demography, University of California, Berkeley, CA, USA

    Robert E. Chung

  7. Department of Medicine, University of California, San Francisco, CA, USA

    John W. Park

  8. Breakthrough Breast Cancer Research Unit, Guy’s Hospital, King’s Health Partners AHSC, London, UK

    Andrew N. J. Tutt

  9. Breast Tissue & Data Bank, Research Oncology, King’s College London, Guy’s Hospital, London, UK

    Cheryl E. Gillett

  10. Carol Franc Buck Breast Care Center, University of California San Francisco, 1600 Divisadero St, Box 1710, San Francisco, CA, 94115, USA

    Laura J. Esserman

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  1. Laura J. Esserman
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  2. Dan H. Moore
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Correspondence to Laura J. Esserman.

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Esserman, L.J., Moore, D.H., Tsing, P.J. et al. Biologic markers determine both the risk and the timing of recurrence in breast cancer. Breast Cancer Res Treat 129, 607–616 (2011). https://doi.org/10.1007/s10549-011-1564-5

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  • DOI: https://doi.org/10.1007/s10549-011-1564-5

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