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@ARTICLE{Zhang:303115,
      author       = {G. Zhang and V. Jurinovic and S. Bartels and M. Christgen
                      and H. Christgen and L. D. Kandt and L. Mishieva and H. Ni
                      and M. Raap and J. Klein and A.-L. Katzke and W. Hofmann and
                      D. Steinemann and R. E. Kates and O. Gluz and M. Graeser and
                      S. Kuemmel and U. Nitz and C. Plass$^*$ and U. Lehmann and
                      C. Zu Eulenburg and U. Mansmann and C. Gerhauser$^*$ and N.
                      Harbeck and H. H. Kreipe},
      title        = {{A} predictive endocrine resistance index accurately
                      stratifies luminal breast cancer treatment responders and
                      non-responders.},
      journal      = {The journal of clinical investigation},
      volume       = {nn},
      issn         = {0021-9738},
      address      = {Ann Arbor, Mich.},
      publisher    = {ASCJ},
      reportid     = {DKFZ-2025-01534},
      pages        = {nn},
      year         = {2025},
      note         = {epub},
      abstract     = {Endocrine therapy (ET) with tamoxifen (TAM) or aromatase
                      inhibitors (AI) is highly effective against hormone receptor
                      (HR) positive early breast cancer (BC), but resistance
                      remains a major challenge. The primary objectives of our
                      study were to understand the underlying mechanisms of
                      primary resistance and to identify potential biomarkers.We
                      selected >800 patients in three sub-cohorts (Discovery,
                      N=364, matched pairs), Validation 1, N=270, Validation 2, N=
                      176) of the West German Study Group (WSG) Adjuvant Dynamic
                      marker-Adjusted Personalized Therapy (ADAPT) trial who
                      underwent short-term pre-operative TAM or AI treatment.
                      Treatment response was assessed by immunohistochemical
                      labeling of proliferating cells with Ki67 before and after
                      ET. We performed comprehensive molecular profiling,
                      including targeted next-generation sequencing (NGS) and DNA
                      methylation analysis using EPIC arrays, on post-treatment
                      tumor samples.TP53 mutations were strongly associated with
                      primary resistance to both TAM and AI. In addition, we
                      identified distinct DNA methylation patterns in resistant
                      tumors, suggesting alterations in key signaling pathways and
                      tumor microenvironment composition. Based on these findings
                      and patient age, we developed the Predictive Endocrine
                      ResistanCe Index (PERCI). PERCI accurately stratified
                      responders and non-responders in both treatment groups in
                      all three sub-cohorts and predicted progression-free
                      survival in an external validation cohort and in the
                      combined sub-cohorts.Our results highlight the potential of
                      PERCI to guide personalized endocrine therapy and improve
                      patient outcomes.WSG-ADAPT, ClinicalTrials.gov NCT01779206,
                      Registered 2013-01-25, retrospectively registered.},
      keywords     = {Bioinformatics (Other) / Breast cancer (Other) / Clinical
                      Research (Other) / Clinical trials (Other) / Epigenetics
                      (Other) / Oncology (Other)},
      cin          = {B370},
      ddc          = {610},
      cid          = {I:(DE-He78)B370-20160331},
      pnm          = {312 - Funktionelle und strukturelle Genomforschung
                      (POF4-312)},
      pid          = {G:(DE-HGF)POF4-312},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:40705465},
      doi          = {10.1172/JCI177813},
      url          = {https://inrepo02.dkfz.de/record/303115},
}