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Combining method of detection and 70-gene signature for enhanced prognostication of breast cancer

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Abstract

Purpose

Studies have shown that screen detection by national screening programs is independently associated with better prognosis of breast cancer. The aim of this study is to evaluate the association between tumor biology according to the 70-gene signature (70-GS) and survival of patients with screen-detected and interval breast cancers.

Methods

All Dutch breast cancer patients enrolled in the MINDACT trial (EORTC-10041/BIG3-04) accrued 2007–2011, who participated in the national screening program (biennial screening, ages 50–75) were included (n = 1102). Distant Metastasis-Free Interval (DMFI) was evaluated according to the 70-GS for patients with screen-detected (n = 754) and interval cancers (n = 348).

Results

Patients with screen-detected cancers had 8-year DMFI rates of 98.2% for 70-GS ultralow-, 94.6% for low-, and 93.8% for high-risk tumors (p = 0.4). For interval cancers, there was a significantly lower 8-year DMFI rate for patients with 70-GS high-risk tumors (85.2%) compared to low- (92.2%) and ultralow-risk tumors (97.4%, p = 0.0023). Among patients with 70-GS high-risk tumors, a significant difference in 8-year DMFI rate was observed between interval (85.2%, n = 166) versus screen-detected cancers (93.8%, n = 238; p = 0.002) with a HR of 2.3 (95%CI 1.2–4.4, p = 0.010) adjusted for clinical-pathological characteristics and adjuvant systemic treatment.

Conclusion

Among patients with 70-GS high-risk tumors, a significant difference in DMFI was observed between screen-detected and interval cancers, suggesting that method of detection is an additional prognostic factor in this subgroup and should be taken into account when deciding on adjuvant treatment strategies.

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Data availability

The MINDACT dataset with patient characteristics and clinical outcomes was made available by the EORTC (https://www.eortc.org/data-sharing/). Following a successful data request procedure, the EORTC can share all or a selection of the clinical-pathological and/or full-transcriptome data for translational research.

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Acknowledgements

We acknowledge the contribution of the European Organisation for Research and Treatment of Cancer (EORTC) and the Breast International Group (BIG). We thank the Dutch Screening Facilities for providing the screening data used in this study. We thank Annuska Glas from Agendia for providing valuable information on the 70-gene signature results. We are indebted to all the Dutch women who participated in the MINDACT trial. Josephine Lopes Cardozo’s work as Fellow at EORTC Headquarters was supported by a grant from the EORTC Breast Cancer Group and from the Netherlands Cancer Institute. The funding sources had no role in the study design, data collection, data analysis, data interpretation, in writing the report, or in the decision to submit for publication. The MINDACT study was supported by grants from the European Commission Sixth Framework Program (FP6-LSHC-CT-2004-503426, to the TRANSBIG Network of Excellence), the Breast Cancer Research Foundation, Novartis, F. Hoffmann–La Roche, Sanofi-Aventis, Eli Lilly, Veridex, the European Breast Cancer Council–Breast Cancer Working Group (BCWG grant for the MINDACT biobank), the Jacqueline Seroussi Memorial Foundation for Cancer Research (JSMF; 2006 JSMF Award), Prix Mois du Cancer du Sein (2004 award), Susan G. Komen for the Cure (SG05-0922-02), Fondation Belge contre le Cancer (SCIE 2005-27), Dutch Cancer Society (KWF), the Netherlands Genomics Initiative–Cancer Genomics Center (2008-2012), Association le Cancer du Sein, Parlons-en!, the Brussels Breast Cancer Walk-Run and the American Women’s Club of Brussels, NIF Trust, German Cancer Aid, the Grant Simpson Trust and Cancer Research UK, Ligue Nationale contre le Cancer, and the EORTC Cancer Research Fund. Whole-genome analysis was provided by Agendia without cost. We are grateful to all patients and families who participated in the MINDACT study. We are grateful to the European Commission Sixth Framework Programme (FP6-LSHC-CT-2004-503426), the European Community Seventh Framework Programme (HEALTH-F2-2009-223175 to the Collaborative Oncological Gene-environment Study), the Breast International Group (BIG) AISBL, F. Hoffmann-La Roche, Novartis, Sanofi-Aventis, for supporting this independent EORTC Study. Special thanks to all national coordinating centers and BIG Groups participating in MINDACT (BOOG, EORTC-BCG, GOIRC, NCRI-BCSG, SOLTI, UNICANCER-UCBG, WSG).

Funding

This research was supported by a grant from the EORTC Breast Cancer Group and from the Netherlands Cancer Institute. The MINDACT trial was supported by grants from the European Commission Sixth Framework Program (FP6-LSHC-CT-2004–503426, to the TRANSBIG Network of Excellence), the Breast Cancer Research Foundation, Novartis, F. Hoffmann–La Roche, Sanofi-Aventis, Eli Lilly, Veridex, the European Breast Cancer Council–Breast Cancer Working Group (BCWG grant for the MINDACT biobank), the Jacqueline Seroussi Memorial Foundation for Cancer Research (JSMF; 2006 JSMF Award), Prix Mois du Cancer du Sein (2004 award), Susan G. Komen for the Cure (SG05-0922-02), Fondation Belge contre le Cancer (SCIE 2005-27), Dutch Cancer Society (KWF), the Netherlands Genomics Initiative–Cancer Genomics Center (2008–2012), Association le Cancer du Sein, Parlons-en!, the Brussels Breast Cancer Walk-Run and the American Women’s Club of Brussels, NIF Trust, German Cancer Aid, the Grant Simpson Trust and Cancer Research UK, Ligue Nationale contre le Cancer, and the EORTC Cancer Research Fund. Whole-genome analysis was provided by Agendia without cost.

Author information

Authors and Affiliations

  1. Department of Surgical Oncology, Netherlands Cancer Institute, Amsterdam, The Netherlands

    J. M. N. Lopes Cardozo & E. J. T. Rutgers

  2. European Organisation for Research and Treatment of Cancer (EORTC) Headquarters, Brussels, Belgium

    J. M. N. Lopes Cardozo & C. Poncet

  3. Department of Molecular Pathology and Division of Psychosocial Research and Epidemiology, Netherlands Cancer Institute, Amsterdam, The Netherlands

    M. K. Schmidt

  4. Department of Laboratory Medicine, UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, USA

    L. J. van ’t Veer

  5. Breast Unit, Champalimaud Clinical Center/Champalimaud Foundation, Lisbon, Portugal

    F. Cardoso

  6. Department of Surgery, Tergooi Hospital, Hilversum, The Netherlands

    C. A. Drukker

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  1. J. M. N. Lopes Cardozo
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  2. M. K. Schmidt
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  4. F. Cardoso
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Contributions

CD, MKS, LvtV, ER, and FC were responsible for the study design and development of the protocol. JLC and CD coordinated the study and CD collected the data on method of detection. FC and CP provided the MINDACT baseline characteristics and outcome data. JLC, CD, and MKS performed the data analysis. All authors took part in data interpretation. The first draft of the manuscript was written by JLC and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to C. A. Drukker.

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Conflict of interest

L.J. van ‘t Veer reports being shareholder in and part-time employed by Agendia NV, the commercial company that markets the 70-gene signature as MammaPrint. F. Cardoso has received personal fees from Amgen, Astellas/Medivation, AstraZeneca, Celgene, Daiichi-Sankyo, Eisai, GE Oncology, Genentech, GlaxoSmithKline, Macrogenics, Medscape, Merck-Sharp, Merus BV, Mylan, Mundipharma, Novartis, Pfizer, Pierre-Fabre, prIME Oncology, Roche, Samsung Bioepis, Sanofi, Seagen, and Teva outside the submitted work.

Ethical approval

This study was performed in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. The MINDACT study was approved by the ethics commitees of all participating sites. This project was approved by the MINDACT Executive Committee and MINDACT Steering Committee, after review by experts from the MINDACT Independent Review Committee, the MINDACT Statistician, and the MINDACT Ethical-Legal committee. This project was reviewed by the ethics committee who concluded it was a non-CT directive study that did not require further ethical approval, and could be performed under the scope of the MINDACT protocol and informed consent.

Consent to participate

All patients included in the MINDACT trial provided written informed consent. This consent allowed linkage to the Dutch national screening database.

Consent for publication

All authors reviewed draft and final versions of the manuscript before submission and approved the final version. The first and last authors had full access to all of the data and had final responsibility for the decision to submit for publication.

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Lopes Cardozo, J.M.N., Schmidt, M.K., van ’t Veer, L.J. et al. Combining method of detection and 70-gene signature for enhanced prognostication of breast cancer. Breast Cancer Res Treat 189, 399–410 (2021). https://doi.org/10.1007/s10549-021-06315-3

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