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Clinical Research and Public HealthIn-Press PreviewClinical ResearchOncology Open Access | 10.1172/JCI177813

A predictive endocrine resistance index accurately stratifies luminal breast cancer treatment responders and non-responders

Guokun Zhang,1 Vindi Jurinovic,1 Stephan Bartels,2 Matthias Christgen,2 Henriette Christgen,2 Leonie Donata Kandt,2 Lidiya Mishieva,3 Hua Ni,4 Mieke Raap,2 Janin Klein,5 Anna-Lena Katzke,5 Winfried Hofmann,5 Doris Steinemann,5 Ronald E. Kates,6 Oleg Gluz,6 Monika Graeser,6 Sherko Kuemmel,6 Ulrike Nitz,6 Christoph Plass,7 Ulrich Lehmann,2 Christine zu Eulenburg,6 Ulrich Mansmann,1 Clarissa Gerhauser,7 Nadia Harbeck,4 and Hans H. Kreipe2

1Institute for Medical Information Processing, Biometry, and Epidemiology, M, Ludwig Maximilians University (LMU), Munich, Germany

2Institute of Pathology, Hannover Medical School, Hannover, Germany

3Institute of Sociology (IfS), Faculty of Social Sciences, University of Bremen, Bremen, Germany

4Breast Center, Department OB&GYN and CCC Munich, LMU University Hospital, Munich, Germany

5Department of Human Genetics, Hannover Medical School, Hannover, Germany

6West German Study Group (WSG), Moenchengladbach, Germany

7Division of Cancer Epigenomics, German Cancer Research Center (DKFZ), Heidelberg, Germany

Find articles by Zhang, G. in: PubMed | Google Scholar

1Institute for Medical Information Processing, Biometry, and Epidemiology, M, Ludwig Maximilians University (LMU), Munich, Germany

2Institute of Pathology, Hannover Medical School, Hannover, Germany

3Institute of Sociology (IfS), Faculty of Social Sciences, University of Bremen, Bremen, Germany

4Breast Center, Department OB&GYN and CCC Munich, LMU University Hospital, Munich, Germany

5Department of Human Genetics, Hannover Medical School, Hannover, Germany

6West German Study Group (WSG), Moenchengladbach, Germany

7Division of Cancer Epigenomics, German Cancer Research Center (DKFZ), Heidelberg, Germany

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1Institute for Medical Information Processing, Biometry, and Epidemiology, M, Ludwig Maximilians University (LMU), Munich, Germany

2Institute of Pathology, Hannover Medical School, Hannover, Germany

3Institute of Sociology (IfS), Faculty of Social Sciences, University of Bremen, Bremen, Germany

4Breast Center, Department OB&GYN and CCC Munich, LMU University Hospital, Munich, Germany

5Department of Human Genetics, Hannover Medical School, Hannover, Germany

6West German Study Group (WSG), Moenchengladbach, Germany

7Division of Cancer Epigenomics, German Cancer Research Center (DKFZ), Heidelberg, Germany

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1Institute for Medical Information Processing, Biometry, and Epidemiology, M, Ludwig Maximilians University (LMU), Munich, Germany

2Institute of Pathology, Hannover Medical School, Hannover, Germany

3Institute of Sociology (IfS), Faculty of Social Sciences, University of Bremen, Bremen, Germany

4Breast Center, Department OB&GYN and CCC Munich, LMU University Hospital, Munich, Germany

5Department of Human Genetics, Hannover Medical School, Hannover, Germany

6West German Study Group (WSG), Moenchengladbach, Germany

7Division of Cancer Epigenomics, German Cancer Research Center (DKFZ), Heidelberg, Germany

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1Institute for Medical Information Processing, Biometry, and Epidemiology, M, Ludwig Maximilians University (LMU), Munich, Germany

2Institute of Pathology, Hannover Medical School, Hannover, Germany

3Institute of Sociology (IfS), Faculty of Social Sciences, University of Bremen, Bremen, Germany

4Breast Center, Department OB&GYN and CCC Munich, LMU University Hospital, Munich, Germany

5Department of Human Genetics, Hannover Medical School, Hannover, Germany

6West German Study Group (WSG), Moenchengladbach, Germany

7Division of Cancer Epigenomics, German Cancer Research Center (DKFZ), Heidelberg, Germany

Find articles by Christgen, H. in: PubMed | Google Scholar

1Institute for Medical Information Processing, Biometry, and Epidemiology, M, Ludwig Maximilians University (LMU), Munich, Germany

2Institute of Pathology, Hannover Medical School, Hannover, Germany

3Institute of Sociology (IfS), Faculty of Social Sciences, University of Bremen, Bremen, Germany

4Breast Center, Department OB&GYN and CCC Munich, LMU University Hospital, Munich, Germany

5Department of Human Genetics, Hannover Medical School, Hannover, Germany

6West German Study Group (WSG), Moenchengladbach, Germany

7Division of Cancer Epigenomics, German Cancer Research Center (DKFZ), Heidelberg, Germany

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1Institute for Medical Information Processing, Biometry, and Epidemiology, M, Ludwig Maximilians University (LMU), Munich, Germany

2Institute of Pathology, Hannover Medical School, Hannover, Germany

3Institute of Sociology (IfS), Faculty of Social Sciences, University of Bremen, Bremen, Germany

4Breast Center, Department OB&GYN and CCC Munich, LMU University Hospital, Munich, Germany

5Department of Human Genetics, Hannover Medical School, Hannover, Germany

6West German Study Group (WSG), Moenchengladbach, Germany

7Division of Cancer Epigenomics, German Cancer Research Center (DKFZ), Heidelberg, Germany

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1Institute for Medical Information Processing, Biometry, and Epidemiology, M, Ludwig Maximilians University (LMU), Munich, Germany

2Institute of Pathology, Hannover Medical School, Hannover, Germany

3Institute of Sociology (IfS), Faculty of Social Sciences, University of Bremen, Bremen, Germany

4Breast Center, Department OB&GYN and CCC Munich, LMU University Hospital, Munich, Germany

5Department of Human Genetics, Hannover Medical School, Hannover, Germany

6West German Study Group (WSG), Moenchengladbach, Germany

7Division of Cancer Epigenomics, German Cancer Research Center (DKFZ), Heidelberg, Germany

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1Institute for Medical Information Processing, Biometry, and Epidemiology, M, Ludwig Maximilians University (LMU), Munich, Germany

2Institute of Pathology, Hannover Medical School, Hannover, Germany

3Institute of Sociology (IfS), Faculty of Social Sciences, University of Bremen, Bremen, Germany

4Breast Center, Department OB&GYN and CCC Munich, LMU University Hospital, Munich, Germany

5Department of Human Genetics, Hannover Medical School, Hannover, Germany

6West German Study Group (WSG), Moenchengladbach, Germany

7Division of Cancer Epigenomics, German Cancer Research Center (DKFZ), Heidelberg, Germany

Find articles by Raap, M. in: PubMed | Google Scholar

1Institute for Medical Information Processing, Biometry, and Epidemiology, M, Ludwig Maximilians University (LMU), Munich, Germany

2Institute of Pathology, Hannover Medical School, Hannover, Germany

3Institute of Sociology (IfS), Faculty of Social Sciences, University of Bremen, Bremen, Germany

4Breast Center, Department OB&GYN and CCC Munich, LMU University Hospital, Munich, Germany

5Department of Human Genetics, Hannover Medical School, Hannover, Germany

6West German Study Group (WSG), Moenchengladbach, Germany

7Division of Cancer Epigenomics, German Cancer Research Center (DKFZ), Heidelberg, Germany

Find articles by Klein, J. in: PubMed | Google Scholar

1Institute for Medical Information Processing, Biometry, and Epidemiology, M, Ludwig Maximilians University (LMU), Munich, Germany

2Institute of Pathology, Hannover Medical School, Hannover, Germany

3Institute of Sociology (IfS), Faculty of Social Sciences, University of Bremen, Bremen, Germany

4Breast Center, Department OB&GYN and CCC Munich, LMU University Hospital, Munich, Germany

5Department of Human Genetics, Hannover Medical School, Hannover, Germany

6West German Study Group (WSG), Moenchengladbach, Germany

7Division of Cancer Epigenomics, German Cancer Research Center (DKFZ), Heidelberg, Germany

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1Institute for Medical Information Processing, Biometry, and Epidemiology, M, Ludwig Maximilians University (LMU), Munich, Germany

2Institute of Pathology, Hannover Medical School, Hannover, Germany

3Institute of Sociology (IfS), Faculty of Social Sciences, University of Bremen, Bremen, Germany

4Breast Center, Department OB&GYN and CCC Munich, LMU University Hospital, Munich, Germany

5Department of Human Genetics, Hannover Medical School, Hannover, Germany

6West German Study Group (WSG), Moenchengladbach, Germany

7Division of Cancer Epigenomics, German Cancer Research Center (DKFZ), Heidelberg, Germany

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1Institute for Medical Information Processing, Biometry, and Epidemiology, M, Ludwig Maximilians University (LMU), Munich, Germany

2Institute of Pathology, Hannover Medical School, Hannover, Germany

3Institute of Sociology (IfS), Faculty of Social Sciences, University of Bremen, Bremen, Germany

4Breast Center, Department OB&GYN and CCC Munich, LMU University Hospital, Munich, Germany

5Department of Human Genetics, Hannover Medical School, Hannover, Germany

6West German Study Group (WSG), Moenchengladbach, Germany

7Division of Cancer Epigenomics, German Cancer Research Center (DKFZ), Heidelberg, Germany

Find articles by Steinemann, D. in: PubMed | Google Scholar

1Institute for Medical Information Processing, Biometry, and Epidemiology, M, Ludwig Maximilians University (LMU), Munich, Germany

2Institute of Pathology, Hannover Medical School, Hannover, Germany

3Institute of Sociology (IfS), Faculty of Social Sciences, University of Bremen, Bremen, Germany

4Breast Center, Department OB&GYN and CCC Munich, LMU University Hospital, Munich, Germany

5Department of Human Genetics, Hannover Medical School, Hannover, Germany

6West German Study Group (WSG), Moenchengladbach, Germany

7Division of Cancer Epigenomics, German Cancer Research Center (DKFZ), Heidelberg, Germany

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1Institute for Medical Information Processing, Biometry, and Epidemiology, M, Ludwig Maximilians University (LMU), Munich, Germany

2Institute of Pathology, Hannover Medical School, Hannover, Germany

3Institute of Sociology (IfS), Faculty of Social Sciences, University of Bremen, Bremen, Germany

4Breast Center, Department OB&GYN and CCC Munich, LMU University Hospital, Munich, Germany

5Department of Human Genetics, Hannover Medical School, Hannover, Germany

6West German Study Group (WSG), Moenchengladbach, Germany

7Division of Cancer Epigenomics, German Cancer Research Center (DKFZ), Heidelberg, Germany

Find articles by Gluz, O. in: PubMed | Google Scholar

1Institute for Medical Information Processing, Biometry, and Epidemiology, M, Ludwig Maximilians University (LMU), Munich, Germany

2Institute of Pathology, Hannover Medical School, Hannover, Germany

3Institute of Sociology (IfS), Faculty of Social Sciences, University of Bremen, Bremen, Germany

4Breast Center, Department OB&GYN and CCC Munich, LMU University Hospital, Munich, Germany

5Department of Human Genetics, Hannover Medical School, Hannover, Germany

6West German Study Group (WSG), Moenchengladbach, Germany

7Division of Cancer Epigenomics, German Cancer Research Center (DKFZ), Heidelberg, Germany

Find articles by Graeser, M. in: PubMed | Google Scholar

1Institute for Medical Information Processing, Biometry, and Epidemiology, M, Ludwig Maximilians University (LMU), Munich, Germany

2Institute of Pathology, Hannover Medical School, Hannover, Germany

3Institute of Sociology (IfS), Faculty of Social Sciences, University of Bremen, Bremen, Germany

4Breast Center, Department OB&GYN and CCC Munich, LMU University Hospital, Munich, Germany

5Department of Human Genetics, Hannover Medical School, Hannover, Germany

6West German Study Group (WSG), Moenchengladbach, Germany

7Division of Cancer Epigenomics, German Cancer Research Center (DKFZ), Heidelberg, Germany

Find articles by Kuemmel, S. in: PubMed | Google Scholar

1Institute for Medical Information Processing, Biometry, and Epidemiology, M, Ludwig Maximilians University (LMU), Munich, Germany

2Institute of Pathology, Hannover Medical School, Hannover, Germany

3Institute of Sociology (IfS), Faculty of Social Sciences, University of Bremen, Bremen, Germany

4Breast Center, Department OB&GYN and CCC Munich, LMU University Hospital, Munich, Germany

5Department of Human Genetics, Hannover Medical School, Hannover, Germany

6West German Study Group (WSG), Moenchengladbach, Germany

7Division of Cancer Epigenomics, German Cancer Research Center (DKFZ), Heidelberg, Germany

Find articles by Nitz, U. in: PubMed | Google Scholar

1Institute for Medical Information Processing, Biometry, and Epidemiology, M, Ludwig Maximilians University (LMU), Munich, Germany

2Institute of Pathology, Hannover Medical School, Hannover, Germany

3Institute of Sociology (IfS), Faculty of Social Sciences, University of Bremen, Bremen, Germany

4Breast Center, Department OB&GYN and CCC Munich, LMU University Hospital, Munich, Germany

5Department of Human Genetics, Hannover Medical School, Hannover, Germany

6West German Study Group (WSG), Moenchengladbach, Germany

7Division of Cancer Epigenomics, German Cancer Research Center (DKFZ), Heidelberg, Germany

Find articles by Plass, C. in: PubMed | Google Scholar

1Institute for Medical Information Processing, Biometry, and Epidemiology, M, Ludwig Maximilians University (LMU), Munich, Germany

2Institute of Pathology, Hannover Medical School, Hannover, Germany

3Institute of Sociology (IfS), Faculty of Social Sciences, University of Bremen, Bremen, Germany

4Breast Center, Department OB&GYN and CCC Munich, LMU University Hospital, Munich, Germany

5Department of Human Genetics, Hannover Medical School, Hannover, Germany

6West German Study Group (WSG), Moenchengladbach, Germany

7Division of Cancer Epigenomics, German Cancer Research Center (DKFZ), Heidelberg, Germany

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1Institute for Medical Information Processing, Biometry, and Epidemiology, M, Ludwig Maximilians University (LMU), Munich, Germany

2Institute of Pathology, Hannover Medical School, Hannover, Germany

3Institute of Sociology (IfS), Faculty of Social Sciences, University of Bremen, Bremen, Germany

4Breast Center, Department OB&GYN and CCC Munich, LMU University Hospital, Munich, Germany

5Department of Human Genetics, Hannover Medical School, Hannover, Germany

6West German Study Group (WSG), Moenchengladbach, Germany

7Division of Cancer Epigenomics, German Cancer Research Center (DKFZ), Heidelberg, Germany

Find articles by zu Eulenburg, C. in: PubMed | Google Scholar

1Institute for Medical Information Processing, Biometry, and Epidemiology, M, Ludwig Maximilians University (LMU), Munich, Germany

2Institute of Pathology, Hannover Medical School, Hannover, Germany

3Institute of Sociology (IfS), Faculty of Social Sciences, University of Bremen, Bremen, Germany

4Breast Center, Department OB&GYN and CCC Munich, LMU University Hospital, Munich, Germany

5Department of Human Genetics, Hannover Medical School, Hannover, Germany

6West German Study Group (WSG), Moenchengladbach, Germany

7Division of Cancer Epigenomics, German Cancer Research Center (DKFZ), Heidelberg, Germany

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1Institute for Medical Information Processing, Biometry, and Epidemiology, M, Ludwig Maximilians University (LMU), Munich, Germany

2Institute of Pathology, Hannover Medical School, Hannover, Germany

3Institute of Sociology (IfS), Faculty of Social Sciences, University of Bremen, Bremen, Germany

4Breast Center, Department OB&GYN and CCC Munich, LMU University Hospital, Munich, Germany

5Department of Human Genetics, Hannover Medical School, Hannover, Germany

6West German Study Group (WSG), Moenchengladbach, Germany

7Division of Cancer Epigenomics, German Cancer Research Center (DKFZ), Heidelberg, Germany

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1Institute for Medical Information Processing, Biometry, and Epidemiology, M, Ludwig Maximilians University (LMU), Munich, Germany

2Institute of Pathology, Hannover Medical School, Hannover, Germany

3Institute of Sociology (IfS), Faculty of Social Sciences, University of Bremen, Bremen, Germany

4Breast Center, Department OB&GYN and CCC Munich, LMU University Hospital, Munich, Germany

5Department of Human Genetics, Hannover Medical School, Hannover, Germany

6West German Study Group (WSG), Moenchengladbach, Germany

7Division of Cancer Epigenomics, German Cancer Research Center (DKFZ), Heidelberg, Germany

Find articles by Harbeck, N. in: PubMed | Google Scholar

1Institute for Medical Information Processing, Biometry, and Epidemiology, M, Ludwig Maximilians University (LMU), Munich, Germany

2Institute of Pathology, Hannover Medical School, Hannover, Germany

3Institute of Sociology (IfS), Faculty of Social Sciences, University of Bremen, Bremen, Germany

4Breast Center, Department OB&GYN and CCC Munich, LMU University Hospital, Munich, Germany

5Department of Human Genetics, Hannover Medical School, Hannover, Germany

6West German Study Group (WSG), Moenchengladbach, Germany

7Division of Cancer Epigenomics, German Cancer Research Center (DKFZ), Heidelberg, Germany

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Published July 24, 2025 - More info

J Clin Invest. https://doi.org/10.1172/JCI177813.
Copyright © 2025, Zhang et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published July 24, 2025 - Version history
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Abstract

BACKGROUND. 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.

METHODS. 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.

RESULTS.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.

CONCLUSION. Our results highlight the potential of PERCI to guide personalized endocrine therapy and improve patient outcomes.

TRIAL REGISTRATION. WSG-ADAPT, ClinicalTrials.gov NCT01779206, Registered 2013-01-25, retrospectively registered.

Graphical Abstract
graphical abstract
Supplemental material

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View R2_Supplemental Table 1 ADAPT cohorts and PERCI.xlsx

View R2_Supplemental Table 6 NGS Panel sequencing.xlsx

View R2_Supplemental Table 7 Differential methylation.xlsx

View R2_Supplemental Table 8 NanoString gene expression data.xlsx

View R2_Supplemental Table 13 TCGA BRCA sub-cohort and PERCI 450k.xlsx

View Supplemental figures with legends

Version history
  • Version 1 (July 24, 2025): In-Press Preview
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