A predictive endocrine resistance index accurately stratifies luminal breast cancer treatment responders and nonresponders
BACKGROUNDEndocrine therapy (ET) with tamoxifen (TAM) or aromatase inhibitors (AI) is highly effective against hormone receptor-positive (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.METHODSWe selected more than 800 patients in 3 subcohorts (Discovery, n = 364, matched pairs; Validation 1, n = 270, Validation 2, n = 176) of the West German Study Group (WSG) ADAPT trial who underwent short-term preoperative 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 posttreatment tumor samples.RESULTSTP53 mutations were strongly associated with primary resistance to both TAM and AI. 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 nonresponders in both treatment groups in all 3 subcohorts and predicted progression-free survival in an external validation cohort and in the combined subcohorts.CONCLUSIONOur results highlight the potential of PERCI to guide personalized endocrine therapy and improve patient outcomes.TRIAL REGISTRATIONWSG-ADAPT, ClinicalTrials.gov NCT01779206, retrospectively registered 01-25-2013.FUNDINGGerman Cancer Aid (Grant Number 70112954), German Federal Ministry of Education and Research (Grant Number 01ZZ1804C, DIFUTURE).
Authors
- Clarissa Gerhäuser (ORCID: https://orcid.org/0000-0002-5792-3901)
- Ulrike Nitz (ORCID: https://orcid.org/0000-0003-0143-0507)
- Oleg Gluz (ORCID: https://orcid.org/0000-0001-6019-7544)
- Stephan Bartels (ORCID: https://orcid.org/0000-0002-8903-2345)
- Matthias Christgen (ORCID: https://orcid.org/0000-0002-0891-7839)
- Christoph Plass (ORCID: https://orcid.org/0000-0003-2554-3952)
- Ronald Kates (ORCID: https://orcid.org/0000-0003-3550-1051)
- Mieke Raap (ORCID: https://orcid.org/0000-0001-8338-6209)
- Nadia Harbeck (ORCID: https://orcid.org/0000-0002-9744-7372)
- Guokun Zhang (ORCID: https://orcid.org/0009-0004-7646-5661)
- Janin Klein
- Monika Graeser (ORCID: https://orcid.org/0000-0003-1916-717X)
- Christine zu Eulenburg (ORCID: https://orcid.org/0000-0001-9365-5548)
- Hans Heinrich Kreipe (ORCID: https://orcid.org/0000-0003-0708-1790)
- Henriette Christgen
- Ulrich Mansmann (ORCID: https://orcid.org/0000-0002-9955-8906)
- Hua Ni (ORCID: https://orcid.org/0000-0002-7895-8396)
- Vindi Jurinović
- Winfried Hofmann (ORCID: https://orcid.org/0000-0001-6658-3366)
- Doris Steinemann (ORCID: https://orcid.org/0000-0001-8797-0816)
- Leonie Donata Kandt
- Anna-Lena Katzke (ORCID: https://orcid.org/0009-0007-8773-9201)
- Ulrich Lehmann (ORCID: https://orcid.org/0000-0003-2350-6584)
- Sherko Kümmel
- Lidiya Mishieva
Institutions
- Universität Hamburg (DE)
- Hochschule Bremen (DE)
- University of Applied Sciences Utrecht (NL)
- German Cancer Research Center (DE)
- University of Bremen (DE)
- Utrecht University (NL)
- Heidelberg University (DE)
- Medizinische Hochschule Hannover (DE)
- MSH Medical School Hamburg – University of Applied Sciences and Medical University (DE)
- Zimmer Biomet (Germany) (DE)
- University Medical Center Hamburg-Eppendorf (DE)
- Institute for Information Management Bremen (DE)
- Breast Center (CH)
- Women‘s Healthcare Group (DE)
- Kliniken Essen-Mitte (DE)
- Charité - Universitätsmedizin Berlin (DE)
- Ludwig-Maximilians-Universität München (DE)
- Epigenomics (Germany) (DE)
Publication Details
- Journal
- Journal of Clinical Investigation
- Published
- 2025-07-24
- DOI
- https://doi.org/10.1172/jci177813
- Citations
- 2
- Primary Topic
- Estrogen and related hormone effects
- Type
- article
- Field-Weighted Citation Impact
- 3.63
Funders
- Deutsches Krebsforschungszentrum
- Bundesministerium für Bildung und Forschung
- Deutsche Krebshilfe
- National Human Genome Research Institute
- National Cancer Institute