PITX2 DNA-Methylation: Predictive versus Prognostic Value for Anthracycline-Based Chemotherapy in Triple-Negative Breast Cancer Patients

Rudolf Napieralski; Gabriele Schricker; Gert Auer; Michaela Aubele; Jonathan Perkins; Viktor Magdolen; Kurt Ulm; Moritz Hamann; Axel Walch; Wilko Weichert; Marion Kiechle; Olaf G Wilhelm

doi:10.1159/000510468

PITX2 DNA-Methylation: Predictive versus Prognostic Value for Anthracycline-Based Chemotherapy in Triple-Negative Breast Cancer Patients

Breast Care (Basel). 2021 Oct;16(5):523-531. doi: 10.1159/000510468. Epub 2020 Dec 17.

Authors

Affiliations

¹ Therawis Diagnostics GmbH, Munich, Germany.
² Department of Oncology-Pathology, Karolinska Institute, Stockholm, Sweden.
³ QIAGEN Manchester Ltd., Manchester, United Kingdom.
⁴ Department of Gynecology and Obstetrics and Comprehensive Cancer Center (CCCTUM), Klinikum Rechts der Isar, Technische Universität München, Munich, Germany.
⁵ Institute of Medical Informatics, Statistics and Epidemiology, Technische Universität München, Munich, Germany.
⁶ Department of Gynecology Rotkreuzklinikum München, Munich, Germany.
⁷ Research Unit Analytical Pathology, Helmholtz Zentrum München, Munich, Germany.
⁸ Institute of Pathology, Klinikum Rechts der Isar, Technische Universität München, Munich, Germany.

Abstract

Background: PITX2 DNA methylation has been shown to predict outcomes in high-risk breast cancer patients after anthracycline-based chemotherapy. To determine its prognostic versus predictive value, the impact of PITX2 DNA methylation on outcomes was studied in an untreated cohort vs. an anthracycline-treated triple-negative breast cancer (TNBC) cohort.

Material and methods: The percent DNA methylation ratio (PMR) of paired-like homeodomain transcription factor 2 (PITX2) was determined by a validated methylation-specific real-time PCR test. Patient samples of routinely collected archived formalin-fixed paraffin-embedded (FFPE) tissue and clinical data from 144 TNBC patients of 2 independent cohorts (i.e., 66 untreated patients and 78 patients treated with anthracycline-based chemotherapy) were analyzed.

Results: The risk of 5- and 10-year overall survival (OS) increased continuously with rising PITX2 DNA methylation in the anthracycline-treated population, but it increased only slightly during 10-year follow-up time in the untreated patient population. PITX2 DNA methylation with a PMR cutoff of 2 did not show significance for poor vs. good outcomes (OS) in the untreated patient cohort (HR = 1.55; p = 0.259). In contrast, the PITX2 PMR cutoff of 2 identified patients with poor (PMR >2) vs. good (PMR ≤2) outcomes (OS) with statistical significance in the anthracycline-treated cohort (HR = 3.96; p = 0.011). The results in the subgroup of patients who did receive anthracyclines only (no taxanes) confirmed this finding (HR = 5.71; p = 0.014).

Conclusion: In this hypothesis-generating study PITX2 DNA methylation demonstrated predominantly predictive value in anthracycline treatment in TNBC patients. The risk of poor outcome (OS) correlates with increasing PITX2 DNA methylation.

Keywords: Anthracyclines; Biomarker; Chemotherapy; DNA methylation; Homeodomain proteins/genetics; PITX2; Therapy prediction; Treatment outcome; Triple-negative breast cancer/neoplasms; Tumor/genetics.