Clinical Validation of PITX2 DNA Methylation to Predict Outcome in High-Risk Breast Cancer Patients Treated with Anthracycline-Based Chemotherapy

Manfred Schmitt, Olaf G. Wilhelm, Aurelia Noske, Gabriele Schricker, Rudolph Napieralski, Martina Vetter, Michaela Aubele, Jonathan Perkins, Jürgen Lauber, Kurt Ulm, Christoph Thomssen, John W.M. Martens, Wilko Weichert, Marion Kiechle

Research output: Contribution to journalArticlepeer-review

8 Scopus citations

Abstract

Background: Breast cancer patients at high risk for recurrence are treated with anthracycline-based chemotherapy, but not all patients do equally benefit from such a regimen. To further improve therapy decision-making, biomarkers predicting outcome are of high unmet medical need. Methods: The percent DNA methylation ratio (PMR) of the promoter gene coding for the Paired-like homeodomain transcription factor 2 (PITX2) was determined by a validated methylation-specific real-Time polymerase chain reaction (PCR) test. The multicenter study was conducted in routinely collected archived formalin-fixed paraffin-embedded (FFPE) tissue from 205 lymph node-positive breast cancer patients treated with adjuvant anthracycline-based chemotherapy. Results: The cut-off for the PITX2 methylation status (PMR = 12) was confirmed in a randomly selected cohort (n = 60) and validated (n = 145) prospectively with disease-free survival (DFS) at the 10-year follow-up. DFS was significantly different between the PMR ≤ 12 versus the PMR > 12 group with a hazard ratio (HR) of 2.74 (p < 0.001) in the validation cohort and also for the patient subgroup treated additionally with endocrine therapy (HR 2.47; p = 0.001). Conclusions: Early-stage lymph node-positive breast cancer patients with low PITX2 methylation do benefit from adjuvant anthracycline-based chemotherapy. Patients with a high PITX2 DNA methylation ratio, approximately 30%, show poor outcome and should thus be considered for alternative chemotherapy regimens.

Original languageEnglish
Pages (from-to)425-433
Number of pages9
JournalBreast Care
Volume13
Issue number6
DOIs
StatePublished - 1 Dec 2018
Externally publishedYes

Keywords

  • Breast cancer
  • PITX2 DNA methylation
  • Therapy prediction

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