The Predictive Value of PITX2 DNA Methylation for High-Risk Breast Cancer Therapy: Current Guidelines, Medical Needs, and Challenges

Abstract

High-risk breast cancer comprises distinct tumor entities such as triple-negative breast cancer (TNBC) which is characterized by lack of estrogen (ER) and progesterone (PR) and the HER2 receptor and breast malignancies which have spread to more than three lymph nodes. For such patients, current (inter)national guidelines recommend anthracycline-based chemotherapy as the standard of care, but not all patients do equally benefit from such a chemotherapy. To further improve therapy decision-making, predictive biomarkers are of high, so far unmet, medical need. In this respect, predictive biomarkers would permit patient selection for a particular kind of chemotherapy and, by this, guide physicians to optimize the treatment plan for each patient individually. Besides DNA mutations, DNA methylation as a patient selection marker has received increasing clinical attention. For instance, significant evidence has accumulated that methylation of the PITX2 (paired-like homeodomain transcription factor 2) gene might serve as a novel predictive and prognostic biomarker, for a variety of cancer diseases. This review highlights the current understanding of treatment modalities of high-risk breast cancer patients with a focus on recommended treatment options, with special attention on the future clinical application of PITX2 as a predictive biomarker to personalize breast cancer management.

Figure 1

Clinicopathological risk stratification of breast cancer patients according to St. Gallen criteria. ¹Clinicopathological risk assessment according to St. Gallen consensus panel [, –24]. ²Endopredict®, OncotypeDX®. ET = endocrine therapy; CTX = chemotherapy.

Figure 2

Classification of the high-risk breast cancer subtypes. PITX2 DNA methylation status can serve as a significant predictive biomarker for anthracycline-based chemotherapy in the two major high-risk breast cancer subtypes [44, 66].

Figure 3

5-year disease-free survival rate analysis of TNBC patients treated with anthracycline-based adjuvant chemotherapy. At 5 years of follow up, the TNBC patients were grouped according to their PITX2 DNA methylation value with a cut-off of 6.35 percent methylation ratio (PMR). Low PITX2 DNA methylation status (n = 18) shows a poor disease-free survival rate at 5 years (35.6%); high PITX2 DNA methylation status (n = 38) is associated at 5-year observation time with favorable disease-free survival (83.5%). (p values: log-rank test, p = 0.006; Wilcoxon test, p = 0.003) [66].

Figure 4

Kaplan-Meier survival curves demonstrating metastasis-free survival probability of high-risk breast cancer patients (n = 133). ER+ breast cancer patients with >3 lymph nodes affected were treated with anthracycline-based chemotherapy plus endocrine therapy. Patients were grouped according to their PITX2 DNA methylation score. PITX2 high gene methylation (quartile 4) predicts poor survival and PITX2 low gene methylation (quartiles 1–3) favorable survival (data reanalyzed from [44]).

Figure 5

Predictive significance of PITX2 gene methylation in high-risk breast cancer patients. TNBC and ER+ BC are two biologically different high-risk breast cancer entities. Yet, for both, the PITX2 DNA methylation status has been shown to predict response or failure to anthracycline-based chemotherapy [44, 66]. The controversial results of the favorable clinical significance of PITX2 gene hypermethylation in TNBC patients versus PITX2 gene hypomethylation in ER+ BC patients are outlined. The hypothesis presented is based on published evidence; other, so far unknown, mechanisms may be involved as well. ER+ BC = estrogen receptor-positive breast cancer.