TY  - JOUR
AU  - Zhang, Guokun
AU  - Jurinovic, Vindi
AU  - Bartels, Stephan
AU  - Christgen, Matthias
AU  - Christgen, Henriette
AU  - Kandt, Leonie Donata
AU  - Mishieva, Lidiya
AU  - Ni, Hua
AU  - Raap, Mieke
AU  - Klein, Janin
AU  - Katzke, Anna-Lena
AU  - Hofmann, Winfried
AU  - Steinemann, Doris
AU  - Kates, Ronald E
AU  - Gluz, Oleg
AU  - Graeser, Monika
AU  - Kuemmel, Sherko
AU  - Nitz, Ulrike
AU  - Plass, Christoph
AU  - Lehmann, Ulrich
AU  - Zu Eulenburg, Christine
AU  - Mansmann, Ulrich
AU  - Gerhauser, Clarissa
AU  - Harbeck, Nadia
AU  - Kreipe, Hans H
TI  - A predictive endocrine resistance index accurately stratifies luminal breast cancer treatment responders and non-responders.
JO  - The journal of clinical investigation
VL  - nn
SN  - 0021-9738
CY  - Ann Arbor, Mich.
PB  - ASCJ
M1  - DKFZ-2025-01534
SP  - nn
PY  - 2025
N1  - epub
AB  - 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.
KW  - Bioinformatics (Other)
KW  - Breast cancer (Other)
KW  - Clinical Research (Other)
KW  - Clinical trials (Other)
KW  - Epigenetics (Other)
KW  - Oncology (Other)
LB  - PUB:(DE-HGF)16
C6  - pmid:40705465
DO  - DOI:10.1172/JCI177813
UR  - https://inrepo02.dkfz.de/record/303115
ER  -