Molecular determinants of primary endocrine resistance in luminal breast cancer

Endocrine therapy to block the estrogen receptor pathway in breast cancer is highly effective, but its usefulness is limited by common intrinsic and acquired resistance. In up to 20% of patients diagnosed with operable estrogen receptor-positive (luminal) tumors, these will recur during or after adjuvant endocrine therapy. The mechanisms of resistance are poorly understood.

In the WSG-ADAPT trial, more than 3200 luminal breast cancer patients have received short-term endocrine therapy prior to surgery. This internationally unique trial setting allowed pre- and post-therapeutic tumor cell proliferation to be centrally assessd and thus endocrine resistance detected in an in vivo setting. Endocrine responsiveness was evidenced by a proliferation decrease which was lacking in resistant tumors. The tumor tissue available from this trial opens up the unique opportunity to study molecular aberrations associated with endocrine resistance.

Accordingly, the current proposal plans to perform comprehensive genetic profiling of tissue samples including DNA sequencing, copy number variations, gene expression and aberrant methylation. Central data analysis and mathematical modeling will search for links to the resistant phenotype and common pathways recurrently affected by diverse aberrations.

Despite the perspective that resistance mechanisms are probably heterogeneous, their elucidation will most likely uncover novel and useful biomarkers. These may be applied for risk stratification in future therapy trials or, at the very best, they may even lead to the discovery of new druggable targets.

Coordination

Prof. Hans H. Kreipe, Institute of Pathology, Hannover Medical School, Central Pathology for Women’s Healthcare Study Group (WSG), Carl-Neuberg-Str. 1, 30625 Hannover, Germany

Prof. Nadia Harbeck, Breast Unit of University of Munich and Women’s Healthcare Study Group (WSG), Marchioninistr. 15, 81377 Munich, Germany

Subprojects

SP 1: Mutational profile of endocrine-sensitive and resistant luminal breast cancer, Matthias Christgen MD, PhD; Hans Kreipe, MD, Institute of Pathology, Hannover Medical School, Hannover

SP 2: Epigenomic landscape of endocrine-sensitive and resistant luminal breast cancer, Clarissa Gerhäuser, Dr. rer. nat.; Christoph Plass, Dr. rer. nat., Deutsches Krebsforschungszentrum (DKFZ), Abteilung Epigenomik und Krebsrisikofaktoren, Heidelberg

SP 3: Copy number variations associated with response and resistance to endocrine therapy, Doris Steinemann, Dr. rer. nat.; Brigitte Schlegelberger, MD, Institute of Human Genetics, Hannover Medical School, Hannover

SP 4: Characterization of RNA profiles in luminal breast cancers with different responses to endocrine therapy, Nadia Harbeck, MD, Brustzentrum, Klinik und Poliklinik für Frauenheilkunde, Klinikum der Ludwig-Maximilians-Universität, München

SP 5: Integrated molecular and genomic analysis, Ulrich Mansmann, Dr. rer. nat., Institute for Medical Information Processing, Biometry, and Epidemiology, Ludwig-Maximilians-University, Munich

SP 6: Central Tissue and Clinical Data Bank, Hans Kreipe, MD, Nadia Harbeck, MD

• funded bei Deutsche Krebshilfe