Abstract 1938: Increased miR-126 and miR-375 expression in primary ER-positive breast cancer predict longer relapse-free time following treatment with tamoxifen.
Authors: Hoppe Reiner , Achinger-Kawecka Joanna , Winter Stefan , Fritz Peter , Lo Wing-Yee , Schroth Werner , Brauch Hiltrud 
Published: August 2014

Abstract
Adjuvant tamoxifen treatment provides benefit for millions of women with estrogen receptor positive breast cancer; however, up to 50% of patients experience distant or local recurrence or even die. Tamoxifen resistance is contributed to by host and tumor associated factors and the latter has been particularly attributed to adaptive changes of the tumor involving the regulation of cellular pathways associated with growth, proliferation and apoptosis. Recently, microRNA expression signatures have been appreciated as useful tools to improve the classification of tumors into subtypes and the assessment of tumor heterogeneity. However it is not clear to what extend microRNA signatures derived from the primary tumor can predict treatment outcome. Here we test the hypothesis that distinct microRNAs expressed in the primary tumor can predict the onset of local and distant recurrence following adjuvant tamoxifen. We investigated 115 patients diagnosed with ER positive breast cancer at the Robert Bosch Hospital, Stuttgart, Germany, who had received adjuvant tamoxifen, and had a median follow up of 9.23 years (range: 0.21 - 19.96 years). We compared tumor microRNA expression profiles of 6 patients who developed recurrence under tamoxifen with expression profiles of 6 patients who stayed recurrence-free. Matching of patients was based on age at diagnosis, year of surgery and major histopathological parameters. Candidate microRNAs were identified by global microRNA expression profiling using GeneChip miRNA 2.0 arrays (Affymetrix). Different expression of microRNAs was validated using real-time PCR in 103 tumor samples. We identified miR-126 and miR-375 to be expressed at higher levels in tumors of patients with a lower risk of recurrence (p = 0.0003 and p = 0.0081, respectively). Receiver operator characteristics (ROC) were calculated to further validate their values for predicting breast cancer relapse. The area under the curve (AUC) for miR-126 was 0.6838 (p = 0.0006) and 0.6450 (p = 0.0071) for miR-375, respectively. Kaplan-Meier survival analyses showed that a higher expression of miR-126 and/or miRNA-375 in the patients primary tumor was associated with longer relapse-free time (p = 0.0024 and p = 0.0351, respectively). Our data suggest that miR-126 and miR-375 are promising candidates for further evaluation as tamoxifen outcome predictors in ER-positive breast cancer. R.H. and J.A.K. contributed equally to this work
Citation Format: Reiner Hoppe, Joanna Achinger-Kawecka, Stefan Winter, Peter Fritz, Wing-Yee Lo, Werner Schroth, Hiltrud Brauch. Increased miR-126 and miR-375 expression in primary ER-positive breast cancer predict longer relapse-free time following treatment with tamoxifen. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1938. doi:10.1158/1538-7445.AM2013-1938