Purpose The Predictors of Breast Cancer Recurrence (ProBe CaRe) study was established to evaluate modification of tamoxifen (TAM) effectiveness in premenopausal women through reduced activity of TAM-metabolising enzymes. It comprehensively evaluates the effects of pharmacogenetic variants, use of concomitant medications and biomarkers involved in oestrogen metabolism on breast cancer recurrence risk.
Participants The ProBe CaRe study was established using resources from the Danish Breast Cancer Group (DBCG), including 5959 premenopausal women diagnosed with stage I–III primary breast cancer between 2002 and 2010 in Denmark. Eligible participants were divided into two groups based on oestrogen receptor alpha (ERα) expression and receipt of TAM therapy, 4600 are classified as ERα+/TAM+ and 1359 are classified as ERα−/TAM−. The ProBe CaRe study is a population-based cohort study nested in a nearly complete source population, clinical, tumour and demographic data were abstracted from DBCG registry data. Linkage to Danish registries allows for abstraction of information regarding comorbid conditions, comedication use and mortality. Formalin-fixed paraffin-embedded tissue samples have been prepared for DNA extraction and immunohistochemical assay.
Findings to date To mitigate incorrect classification of patients into specific categories, we conducted a validation substudy. We compared data acquired from registry and from medical record review to calculate positive predictive values (PPVs) and negative predictive values. We observed PPVs near 100% for tumour size, lymph node involvement, receptor status, surgery type, receipt of radiotherapy, receipt of chemotherapy and TAM treatment. We found that the PPVs were 96% (95% CI 83% to 100%) for change in endocrine therapy and 61% (95% CI 42% to 77%) for menopausal transition.
Future plans The ProBeCaRe cohort study is well positioned to comprehensively examine pharmacogenetic variants. We will use a Bayesian pathway analysis to evaluate the complete TAM metabolic path to allow for gene–gene interactions, incorporating information of other important patient characteristics.
- cohort study
- breast tumours
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Contributors Contributors: LJC prepared the original draft of the manuscript. AK conducted data analyses and put together the tables. TLL, DPC-F, HTS, SH-D and TPA were responsible for study development and planning. DPC-F and HTS were responsible for application for data access in Denmark. SH-D led the collection and preparation of the tumour samples for genotyping and immunohistochemistry assays. PD provided methodological input surrounding the pharmacogenetic aspects of the study. PMC, BE and RAS provided methodological insight into study design, operationalisation of the study aims and clinical insights. All authors provided critical review of the manuscript and approved the final version.
Funding The ProBe CaRe cohort study was established with funding from the National Cancer Institute at the US National Institutes of Health (R01 CA166825; PI: Lash).
Competing interests None declared.
Patient consent Not required.
Ethics approval All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards. The research is approved by the regional ethical board in Denmark and by the institutional review boards in the USA. The study does not contain any animal experiments performed by any of the authors.
Provenance and peer review Not commissioned; externally peer reviewed.
Data sharing statement Once the initial data analyses are complete, we will be open to collaborations with outside investigators as permitted by the IRBs of participating sites. In particular, we will encourage collaborations with researchers whose expertise is under-represented on our research team. To become a collaborator, a researcher will be required to submit an application, which will undergo both a scientific and IRB review. In view of the complexity of the database and requirements of Danish Law, interested investigators will be asked to form collaborative arrangement with the ProBe CaRe investigators rather than sharing data directly.
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