INTRODUCTION: Currently used tools for breast cancer prognostication and prediction may not adequately reflect a young patient's prognosis or likely treatment benefit because they were not adequately validated in young patients. Since breast cancers diagnosed at a young age are considered prognostically unfavourable, many treatment guidelines recommend adjuvant systemic treatment for all young patients. Patients cured by locoregional treatment alone are, therefore, overtreated. Lack of prognosticators for young breast cancer patients represents an unmet medical need and has led to the initiation of the PAtients with bReAst cancer DIaGnosed preMenopausally (PARADIGM) initiative. Our aim is to reduce overtreatment of women diagnosed with breast cancer aged ≤40 years. METHODS AND ANALYSIS: All young, adjuvant systemic treatment naive breast cancer patients, who had no prior malignancy and were diagnosed between 1989 and 2000, were identified using the population based Netherlands Cancer Registry (n=3525). Archival tumour tissues were retrieved through linkage with the Dutch nationwide pathology registry. Tissue slides will be digitalised and placed on an online image database platform for clinicopathological revision by an international team of breast pathologists. Immunohistochemical subtype will be assessed using tissue microarrays. Tumour RNA will be isolated and subjected to next-generation sequencing. Differences in gene expression found between patients with a favourable and those with a less favourable prognosis will be used to establish a prognostic classifier, using the triple negative patients as proof of principle. ETHICS AND DISSEMINATION: Observational data from the Netherlands Cancer Registry and left over archival patient material are used. Therefore, the Dutch law on Research Involving Human Subjects Act (WMO) is not applicable. The PARADIGM study received a 'non-WMO' declaration from the Medical Ethics Committee of the Netherlands Cancer Institute - Antoni van Leeuwenhoek hospital, waiving individual patient consent. All data and material used are stored in a coded way. Study results will be presented at international (breast cancer) conferences and published in peer-reviewed, open-access journals.

Candiolo Cancer Institute FPO IRCCS Candiolo Piemonte Italy Department of Medical Sciences University of Torino Torino Italy

Core Facility Molecular Pathology and Biobanking Division of Molecular Pathology NetherlandsCancer Institute Amsterdam Noord Holland Netherlands

Department of Computational Cancer Biology Netherlands Cancer Institute Antoni van Leeuwenhoek Hospital Amsterdam Noord Holland Netherlands

Department of Epidemiology and Biostatistics Netherlands Cancer Institute Antoni van Leeuwenhoek Hospital Amsterdam Noord Holland Netherlands

Department of Epidemiology Maastricht University Maastricht Limburg Netherlands Department of Research Netherlands Comprehensive Cancer Organization Utrecht Utrecht UK

Department of Medical Oncology Netherlands Cancer Institute Antoni van Leeuwenhoek Hospital Amsterdam Noord Holland Netherlands

Department of Pathology Canisius Wilhelmina Ziekenhuis Nijmegen Gelderland Netherlands

Department of Pathology Complejo Hospitalario de Navarra Pamplona Spain

Department of Pathology ErasmusMC Cancer Institute Rotterdam Zuid Holland Netherlands

Department of Pathology Gelre Ziekenhuizen Apeldoorn Gelderland Netherlands

Department of Pathology IsalaKlinieken Zwolle Zwolle Overijssel Netherlands

Department of Pathology Leids Universitair Medisch Centrum Leiden Zuid Holland Netherlands

Department of Pathology Netherlands Cancer Institute Antoni van Leeuwenhoek Hospital Amsterdam Noord Holland Netherlands

Department of Pathology Rion University Hospital University of Patras Medical School Patras Greece

Department of Pathology University Medical Center Utrecht Utrecht Netherlands

Department of Research Netherlands Comprehensive Cancer Organization Utrecht Utrecht UK Department of Health Technology and Services Research MIRA Institute for Biomedical Technology and Technical Medicine Enschede Overijssel Netherlands

Department of Tumor Pathology Maria Sklodowska Curie Memorial Cancer Center and Institute of Oncology Gliwice Poland

Departmentof Obstetrics and Gynaecology at the Catholic Universityof Leuven Leuven Belgium

Division of Internal Medicine and Dermatology University Medical Center Utrecht Utrecht Netherlands

Division of Molecular Pathology Netherlands Cancer Institute Amsterdam Noord Holland Netherlands

Division of Molecular Pathology Netherlands Cancer Institute Amsterdam Noord Holland Netherlands Department of Pathology University Medical Center Utrecht Utrecht Netherlands

Division of Molecular Pathology Netherlands Cancer Institute Amsterdam Noord Holland Netherlands Department of Pathology University Medical Center Utrecht Utrecht Netherlands Department of Medical Oncology Netherlands Cancer Institute Antoni van Leeuwenhoek Hospital Amsterdam Noord Holland Netherlands

Division of Molecular Pathology Netherlands Cancer Institute Amsterdam Noord Holland Netherlands Division of Psychosocial Research and Epidemiology Netherlands Cancer Institute Antoni van Leeuwenhoek Hospital Amsterdam Noord Holland Netherlands

Faculty of Medicine and University Hospital Charles University Prague Hradec Kralove Czech Republic

Genomics Core Facility Netherlands Cancer Institute Antoni van Leeuwenhoek Hospital Amsterdam Noord Holland Netherlands

Institute of Surgical Pathology University Hospital Zurich Zurich Switzerland

Medical Image Analysis Group Technische Universiteit Eindhoven Eindhoven Noord Brabant Netherlands

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$a Long-term prognosis of young breast cancer patients (≤40 years) who did not receive adjuvant systemic treatment: protocol for the PARADIGM initiative cohort study / $c GM. Dackus, ND. Ter Hoeve, M. Opdam, W. Vreuls, Z. Varga, E. Koop, SM. Willems, CH. Van Deurzen, EJ. Groen, A. Cordoba, J. Bart, AL. Mooyaart, JG. van den Tweel, V. Zolota, J. Wesseling, A. Sapino, E. Chmielik, A. Ryska, F. Amant, A. Broeks, R. Kerkhoven, N. Stathonikos, M. Veta, A. Voogd, K. Jozwiak, M. Hauptmann, M. Hoogstraat, MK. Schmidt, G. Sonke, E. van der Wall, S. Siesling, PJ. van Diest, SC. Linn,

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$a INTRODUCTION: Currently used tools for breast cancer prognostication and prediction may not adequately reflect a young patient's prognosis or likely treatment benefit because they were not adequately validated in young patients. Since breast cancers diagnosed at a young age are considered prognostically unfavourable, many treatment guidelines recommend adjuvant systemic treatment for all young patients. Patients cured by locoregional treatment alone are, therefore, overtreated. Lack of prognosticators for young breast cancer patients represents an unmet medical need and has led to the initiation of the PAtients with bReAst cancer DIaGnosed preMenopausally (PARADIGM) initiative. Our aim is to reduce overtreatment of women diagnosed with breast cancer aged ≤40 years. METHODS AND ANALYSIS: All young, adjuvant systemic treatment naive breast cancer patients, who had no prior malignancy and were diagnosed between 1989 and 2000, were identified using the population based Netherlands Cancer Registry (n=3525). Archival tumour tissues were retrieved through linkage with the Dutch nationwide pathology registry. Tissue slides will be digitalised and placed on an online image database platform for clinicopathological revision by an international team of breast pathologists. Immunohistochemical subtype will be assessed using tissue microarrays. Tumour RNA will be isolated and subjected to next-generation sequencing. Differences in gene expression found between patients with a favourable and those with a less favourable prognosis will be used to establish a prognostic classifier, using the triple negative patients as proof of principle. ETHICS AND DISSEMINATION: Observational data from the Netherlands Cancer Registry and left over archival patient material are used. Therefore, the Dutch law on Research Involving Human Subjects Act (WMO) is not applicable. The PARADIGM study received a 'non-WMO' declaration from the Medical Ethics Committee of the Netherlands Cancer Institute - Antoni van Leeuwenhoek hospital, waiving individual patient consent. All data and material used are stored in a coded way. Study results will be presented at international (breast cancer) conferences and published in peer-reviewed, open-access journals.

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