Multicenter study using paraffin-embedded tumor tissue testing PITX2 DNA methylation as a marker for outcome prediction in tamoxifen-treated, node-negative breast cancer patients

Nadia Harbeck, Inko Nimmrich, Arndt Hartmann, Jeffrey S. Ross, Tanja Cufer, Robert Grützmann, Glen Kristiansen, Angelo Paradiso, Oliver Hartmann, Astrid Margossian, John Martens, Ina Schwope, Antje Lukas, Volkmar Müller, Karin Milde-Langosch, Jörg Nährig, John Foekens, Sabine Maier, Manfred Schmitt, Ralf Lesche

Research output: Contribution to journalArticlepeer-review

Abstract

Purpose: We recently reported DNA methylation of the paired-like homeodomain transcription factor 2 (PITX2) gene to be strongly correlated with increased risk of recurrence in node-negative, hormone receptor-positive, tamoxifen-treated breast cancer patients using fresh frozen specimens. Aims of the present study were to establish determination of PITX2 methylation for routine analysis in formalin-fixed paraffin-embedded (FFPE) breast cancer tissue and to test PITX2 DNA methylation as a biomarker for outcome prediction in an independent patient cohort. Patients and Methods: Real-time polymerase chain reaction (PCR) technology was validated for FFPE tissue by comparing methylation measurements in FFPE specimens with those in fresh frozen specimens from the same tumor. The impact of PITX2 methylation on time to distant metastasis was then evaluated in FFPE specimens from hormone receptor-positive, node-negative breast cancer patients (n = 399, adjuvant tamoxifen monotherapy). Results: Reproducibility of the PCR assay in replicate measurements (rs ≥ 0.95; n = 150) and concordant measurements between fresh frozen and FFPE tissues (rs = 0.81; n = 89) were demonstrated. In a multivariate model, PITX2 methylation added significant information (hazard ratio = 2.35; 95% CI, 1.20 to 4.60) to established prognostic factors (tumor size, grade, and age). Conclusion: PITX2 methylation can be reliably assessed by real-time PCR technology in FFPE tissue. Together with our earlier studies, we have accumulated substantial evidence that PITX2 methylation analysis holds promise as a practical assay for routine clinical use to predict outcome in node-negative, tamoxifen-treated breast cancer, which might allow, based on future validation studies, the identification of low-risk patients who may be treated by tamoxifen alone.

Original languageEnglish
Pages (from-to)5036-5042
Number of pages7
JournalJournal of Clinical Oncology
Volume26
Issue number31
DOIs
Publication statusPublished - Nov 1 2008

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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