Abstract 223P
Background
Around 75% of breast cancer (BC) patients' tumors express the treatment-predictive biomarker estrogen receptor alpha (ER/ESR1) and are accordingly offered endocrine therapy. One-third of patients develop endocrine resistance, a majority with tumors that retain ER expression. For most patients, the resistance mechanism is still unknown but factors such as alterations in ER downstream signaling have been investigated. This study aims to examine the gene expression programs of endocrine-resistant tumors.
Methods
A cohort of verified endocrine-resistant BC patients diagnosed in 2005-2006 and 2008-2012 was retrospectively collected at the Karolinska University Hospital in Stockholm, Sweden. Cases (N=56) were defined as patients with an ER+ and human epidermal growth factor receptor 2 (HER2)-negative primary tumor who developed an ER+/HER2- relapse during endocrine therapy. Patients with an ER+/HER2- tumor without progression or relapse at 10 years of follow-up were defined as controls (N=56). RNA was extracted from formalin-fixed paraffin-embedded tissue and analyzed using Affymetrix Clariom D microarrays. Transcriptome Analysis Console (TAC) Software, Gene Set Enrichment (GSEA) application, and R were used for gene expression data analysis.
Results
The initial analysis generated differentially expressed genes, where in general more genes were upregulated in primary tumors of cases who eventually relapse versus controls and downregulated in relapse versus primary tumors of cases. Subsequent investigation of gene sets showed upregulations in epithelial-mesenchymal transition, androgen response, MYC targets, and reactive oxygen species in primary tumors of cases versus controls. We found upregulation in metabolism-associated gene sets and downregulation of estrogen response, epithelial-mesenchymal transition, androgen response, and ESR1 regulation in relapses of cases compared to their primary tumors.
Conclusions
This study of a unique cohort of endocrine-resistant tumors suggests that specific signaling pathways are associated with the development of endocrine resistance in BC. These gene expression signatures may guide further studies on the resistance mechanisms and develop future diagnostic tools for therapy response prediction.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
Karolinska Institutet.
Funding
Has not received any funding.
Disclosure
S. Robertson: Financial Interests, Full or part-time Employment: Stratipath AB. J. Hartman: Other, Personal, Advisory Board: Roche; Financial Interests, Institutional, Funding: Cepheid, Novartis, Roche; Financial Interests, Personal, Ownership Interest: Stratipath AB; Other, Personal, Speaker’s Bureau, Speakers honoraria: Roche, Novartis, Pfizer, Eli Lilly, MSD, Veracyte, ExactSciences. All other authors have declared no conflicts of interest.