Global Gene Expression Analysis Of Tamoxifen-Resistant Breast Cancer Cell Lines Identified A Gene Signature Predictive Of Clinical Outcome Of Breast Cancer Patients Treated With Endocrine Therapy

Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA Objective: Altered gene expression associated with endocrine resistance in breast cancer cell lines may have potential prognostic/predictive values in patients with ER+ breast cancer receiving endocrine therapy. In this study, we investigated mRNA expression profiles associated with the tamoxifen-resistant phenotype using a panel of isogenic MCF-7-based breast cancer cell lines to elucidate the endocrine resistance mechanism and assess whether the pattern of gene expression predicted clinical outcome in breast cancer patients treated with endocrine therapy. Method: Gene array was performed on a panel of clinically-relevant tamoxifen-resistant breast cancer cell lines (TamR) and their tamoxifen-sensitive parental cell line. Genes that showed significant alteration in expression (FDR 0.01) in TamRs vs parental cell lines were evaluated for their potential to stratify tamoxifen-treated breast cancer patients based on outcome using published gene expression data sets. Results: Using a testing set consisting of microarray data from 163 ER+ primary breast cancer patients treated with tamoxifen we identified 20 genes among those that showed significant altered expression in TamR that could stratify patients according to clinical outcome. . The potential of this 20-gene signature to stratify patients was further confirmed in 2 independent data sets consisting of ER+ tamoxifen-treated breast cancer patients with a sensitivity and specificity 53% and 79% respectively in the first cohort (N=153), and sensitivity and specificity of 37% and 91% respectively in the second cohort (N=201). Evaluation of relapse-free survival of tamoxifen-treated patients classified by the signature as having bad or good outcomes showed significant differences in time-to-relapse, with median disease-free survival times of 5.1 vs 8.9 years in the first cohort (N=153, p=0.03) and 4.2 vs 7.7 years in the second (N=201, p=0.006). Conclusions: The expression pattern of the 20-gene signature identified in this study appears to have a strong potential as a biomarker of clinical outcome of endocrine-treated breast cancer patients. Citation Format: Daniel Elias Roro, Henriette Vever, Anne Lykkesfeldt, Henrik Ditzel. Global gene expression analysis of tamoxifen-resistant breast cancer cell lines identified a gene signature predictive of clinical outcome of breast cancer patients treated with endocrine therapy. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1887. doi:10.1158/1538-7445.AM2014-1887