PITX2 DNA-methylation predicts response to anthracycline-based adjuvant chemotherapy in triple-negative breast cancer patients

Absmaier,Magdalena; Napieralski,Rudolf; Schuster,Tibor; Aubele,Michaela; Walch,Axel; Magdolen,Viktor; Dorn,Julia; Gross,Eva; Harbeck,Nadia; Noske,Aurelia; Kiechle,Marion; Schmitt,Manfred

doi:10.3892/ijo.2018.4241

PITX2 DNA-methylation predicts response to anthracycline-based adjuvant chemotherapy in triple-negative breast cancer patients

Authors:
- Magdalena Absmaier
- Rudolf Napieralski
- Tibor Schuster
- Michaela Aubele
- Axel Walch
- Viktor Magdolen
- Julia Dorn
- Eva Gross
- Nadia Harbeck
- Aurelia Noske
- Marion Kiechle
- Manfred Schmitt
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Affiliations: Department of Obstetrics and Gynecology, Technische Universität München, Munich, Germany, Institute of Medical Statistics and Epidemiology, Technische Universität München, Munich, Germany, Institute of Pathology, Helmholtz Zentrum Muenchen, Neuherberg, Germany, Breast Center, Klinikum der Ludwig Maximilians Universität München, Munich, Germany, Department of Pathology and Pathological Anatomy, Technische Universität München, Munich, Germany
Published online on: January 8, 2018 https://doi.org/10.3892/ijo.2018.4241
Pages: 755-767
Copyright: © Absmaier et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Triple-negative breast cancer (TNBC) constitutes a heterogeneous breast cancer subgroup with poor prognosis; survival rates are likely to be lower with TNBC compared to other breast cancer subgroups. For this disease, systemic adjuvant chemotherapy regimens often yield suboptimal clinical results. To improve treatment regimens in TNBC, identification of molecular biomarkers may help to select patients for individualized adjuvant therapy. Evidence has accumulated that determination of the methylation status of the PITX2 gene provides a predictive value in various breast cancer subgroups, either treated with endocrine-based therapy or anthracycline-containing chemotherapy. To further explore the validity of this novel predictive candidate biomarker, in the present exploratory retrospective study, determination of the PITX2 DNA-methylation status was assessed for non-metastatic TNBC patients treated with adjuvant anthracycline-based chemotherapy by molecular analysis of breast cancer tissues. The PITX2 DNA-methylation status was determined in fresh-frozen tumor tissue specimens (n=56) by methylation-specific qRT-PCR (qMSP) and the data related to disease-free and overall survival, applying an optimized DNA-methylation score of 6.35%. For non-metastatic TNBC patients treated with adjuvant systemic anthracycline-based chemotherapy, a low PITX2 DNA-methylation status (<6.35) defines TNBC patients with poor disease-free and overall survival. Univariate and multivariate analyses demonstrate the statistically independent predictive value of PITX2 DNA-methylation. For non-metastatic TNBC patients, selective determination of the PITX2 DNA-methylation status may serve as a cancer biomarker for predicting response to anthracycline-based adjuvant chemotherapy. The assay based on methylation of the PIXT2 gene can be applied to frozen and routinely available formalin-fixed, paraffin-embedded (FFPE) breast cancer tumor tissues that will not only define those TNBC patients who may benefit from anthracycline-based chemotherapy but also those who should be spared the necessity of such potentially toxic treatment. Such patients should be allocated to alternative treatment options.

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