DNA-methylation of the homeodomain transcription factor PITX2 reliably predicts risk of distant disease recurrence in tamoxifen-treated, node-negative breast cancer patients - Technical and clinical validation in a multi-centre setting in collaboration with the European Organisation for Research and Treatment of Cancer (EORTC) PathoBiology group

Sabine Maier, Inko Nimmrich, Thomas Koenig, Serenella Eppenberger-Castori, Inga Bohlmann, Angelo Paradiso, Frédérique Spyratos, Christoph Thomssen, Volkmar Mueller, Jörg Nährig, Francesco Schittulli, Ronald Kates, Ralf Lesche, Ina Schwope, Antje Kluth, Almuth Marx, John W M Martens, John A. Foekens, Manfred Schmitt, Nadia Harbeck

Research output: Contribution to journalArticle

Abstract

Our aim was to identify and validate DNA-methylation markers associated with very good outcome in node negative, hormone receptor positive breast cancer patients after adjuvant endocrine therapy which might allow identifying patients who could be spared the burden of adjuvant chemotherapy. Using a methylation microarray, we analysed 117 candidate genes in hormone receptor-positive tumours from 109 breast cancer patients treated by adjuvant tamoxifen. Results were validated in an independent cohort (n = 236, 5 centres). Independent methodological validation was achieved by a real-time polymerase chain reaction (PCR)-based technique. DNA methylation of PITX2 showed the strongest correlation with distant recurrence. Its impact on patient outcome was validated in the independent cohort: 86% of patients with low PITX2 methylation were metastasis-free after 10 years, compared to 69% with elevated PITX2 methylation. Moreover, PITX2 methylation added significant independent information to established clinical factors. All clinical and technical findings were confirmed by quantitative DNA-methylation PCR. These results provide strong evidence that DNA-methylation analysis allows clinically relevant risk assessment in tamoxifen-treated primary breast cancer. Based on PITX2 methylation, about half of hormone receptor-positive, node-negative breast cancer patients receiving adjuvant tamoxifen monotherapy can be considered low-risk regarding development of distant recurrences and may thus be spared adjuvant chemotherapy. In addition, these low-risk postmenopausal patients seem to respond sufficiently well to tamoxifen so that they may not require up-front aromatase inhibitor therapy.

Original languageEnglish
Pages (from-to)1679-1686
Number of pages8
JournalEuropean Journal of Cancer
Volume43
Issue number11
DOIs
Publication statusPublished - Jul 2007

Keywords

  • Breast cancer
  • DNA methylation
  • Outcome prediction

ASJC Scopus subject areas

  • Cancer Research
  • Hematology
  • Oncology

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    Maier, S., Nimmrich, I., Koenig, T., Eppenberger-Castori, S., Bohlmann, I., Paradiso, A., Spyratos, F., Thomssen, C., Mueller, V., Nährig, J., Schittulli, F., Kates, R., Lesche, R., Schwope, I., Kluth, A., Marx, A., Martens, J. W. M., Foekens, J. A., Schmitt, M., & Harbeck, N. (2007). DNA-methylation of the homeodomain transcription factor PITX2 reliably predicts risk of distant disease recurrence in tamoxifen-treated, node-negative breast cancer patients - Technical and clinical validation in a multi-centre setting in collaboration with the European Organisation for Research and Treatment of Cancer (EORTC) PathoBiology group. European Journal of Cancer, 43(11), 1679-1686. https://doi.org/10.1016/j.ejca.2007.04.025