Abstract
Trastuzumab and lapatinib are established treatments for patients with HER2 (human epidermal growth factor receptor 2)-positive breast cancer with different mechanisms of action. The focus of this study is to investigate, whether altered expression levels of potentially relevant microRNAs (miRs) in serum are associated with response to trastuzumab or lapatinib. Circulating miR-21, miR-210, and miR-373 were quantified with TaqMan MicroRNA assays in serum of 127 HER2-postive breast cancer patients before and after neoadjuvant therapy and in 19 healthy controls. Patients received chemotherapy combined with either trastuzumab or lapatinib within the prospectively randomized Geparquinto trial. The association between miR levels and pathological response (pCR) to therapy and type of therapy was examined. Serum levels of miR-21 (p = 5.04e-08, p = 1.43e-10), miR-210 (p = 0.00151, p = 1.6e-05), and miR-373 (p = 7.87e-06, p = 1.75e-07) were significantly higher in patients before and after chemotherapy than in healthy women. Concentrations of miR-21 (p = 5.73e-08), miR-210 (p = 0.000724), and miR-373 (p = 0.00209) increased further after chemotherapy. A significant association of higher serum levels of miR-373 with advanced clinical tumor stage could be detected (p < 0.002). An association of miR-21 levels before (p = 0.0091) and after (p = 0.037) chemotherapy with overall survival of the patients could be detected, independent of type of anti-HER2 therapy. No association of circulating miRs with pCR was found. Our findings demonstrate a specific influence of neoadjuvant therapy on the serum levels of miR-21, miR-210, and miR-373 in breast cancer patients together with a prognostic value of miR-21.
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Acknowledgments
This study was supported by the Deutsche Krebshilfe e.V (199232) and ERC (European Research Council) Advanced Investigator Grant (ERC-2010 AsG 20100317 DISSECT).
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Fig. S1
Diagram showing the number of participants in the GeparQuinto study with HER2 positive tumors analyzed (PPT 102 kb)
Fig. S2
Comparison of the three miRs between trastuzumab and lapatinib before and after therapy. All p-values were calculated using two-sided Wilcoxon tests (PPTX 79 kb)
Table S1
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Table S2
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Table S3
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Müller, V., Gade, S., Steinbach, B. et al. Changes in serum levels of miR-21, miR-210, and miR-373 in HER2-positive breast cancer patients undergoing neoadjuvant therapy: a translational research project within the Geparquinto trial. Breast Cancer Res Treat 147, 61–68 (2014). https://doi.org/10.1007/s10549-014-3079-3
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DOI: https://doi.org/10.1007/s10549-014-3079-3