PITX2: A novel biomarker to support breast cancer therapy selection

PITX2 DNA methylation status is a clinically relevant biomarker to predict survival in a variety of cancers, including breast cancer, and is a predictive biomarker for treatment response in high- risk breast cancer patients. Applying PITX2 methylation as a predictive biomarker can help avoid use of chemotherapy in patients that would receive  little or no benefit.

Breast cancer is worldwide the most common cancer in women and the second most common cancer overall, with nearly 1.7 million new cases diagnosed in 2012. This represents about 12% of all new cancer cases and 25% of all cancers in women (1). Based on clinico-pathological factors 25% of patients are considered to be at high risk for relapse. This group includes, among others, patients with triple-negative breast cancer (TNBC, around 10-15% of breast cancers), patients with HER2-overexpression, and estrogen receptor (ER)-positive, HER2-negative patients who present with risk factors for disease recurrence such as affected lymph nodes.

Based on current guidelines patients at high risk for disease recurrence will benefit from adjuvant systemic treatment (2, 13). Anthracycline-based chemotherapy regimens (ANT) (usually in combination with cyclophosphamide) are recommended (4), and efficacy may be further improved with sequential addition of taxanes (14). These chemotherapy regimens cause breast cancer patients to suffer from short-and long-term toxicity. Acute reversible effects associated with chemotherapy include alopecia, nausea, vomiting, fatigue and myelosuppression, whereas long-term and potentially irreversible effects include cardiomyopathy, acute leukemia and neuropathy (3). For selected patients, non-ANT regimen such as classical cyclophosphamide / methotrexate / fluorouracil (CMF) or taxane-monotherapy has been recommended. These non-ANT regimen may decrease toxicity, but are currently used in selected patients only, such as those at higher risk for cardiac complications (15). Until now, there has been lack of reliable biomarkers to help determine which breast cancer patients are most likely to benefit from anthracycline therapy (4). Oncologists are in need of clinically validated predictive biomarkers help to avoid ineffective treatment administration with potentially severe side effects.

Promoter methylation the pituitary homeobox transcription factor 2 (PITX2) gene is a clinical, prognostic biomarker predicting survival in a variety of cancers, including breast, prostate and pancreatic cancer (4–11). PITX2 DNA methylation has also been recently suggested as a predictive biomarker in early breast cancer patients treated with chemotherapy, and can be reliably assessed by real-time PCR technology using DNA extracted from formalin-fixed paraffin-embedded (FFPE) tumor tissue (4, 6, 16). PITX2 methylation has been described in recent studies as a valuable marker for the selection of high-risk breast cancer patients, including TNBC and node positive, breast cancer patients with hormone receptor expression, to be treated with anthracycline-based chemotherapy (4,12). PITX2 DNA methylation levels can be used to stratify breast cancer patients into different chemotherapy regimen groups to help avoid needless patient suffering from toxicity, as well as unnecessary costs. Patients assigned to the non-responder group based on their PITX2 DNA methylation level may be subsequently considered for a non-anthracycline-based or escalated chemotherapy regimen.

QIAGEN supports education and awareness of cutting-edge approaches to improve treatment and increase testing of breast cancer patients. We continue to expand our portfolio of innovative Sample to Insight technologies for oncology biomarker detection, to help caregivers more accurately and efficiently identify the right treatment for the patient. QIAGEN is currently developing the CE-IVD therascreen PITX2 RGQ PCR Kit* for launch later this year which will provide information to help determine the appropriate chemotherapy regimen for high-risk lymph node-positive, estrogen receptor-positive, HER2-negative breast cancer patients. The therascreen PITX2 RGQ PCR Kit is intended for the determination of the percent methylation ratio (PMR) in promoter 2 of the PITX2 gene. The PMR will aid clinicians in the prediction of response to adjuvant anthracycline-based chemotherapy, to avoid patient administration of ineffective treatments which may have severe side effects. The therascreen PITX2 assay fits into QIAGEN’s broad therascreen biomarker assay and service portfolio. QIAGEN’s oncology solutions include convenient biomarker testing, reliable, efficient and cost effective workflows, and secure systems with experienced services and support. Find out more about QIAGEN’s oncology companion diagnostic solutions here.

*QIAGEN’s therascreen PITX2 assay is being prepared for launch in Europe only, and will be for in vitro diagnostic use.

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References:

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  2. 2. Cardoso, F., et al. (2017) 3rd ESO–ESMO International Consensus Guidelines for Advanced Breast Cancer (ABC 3). Annals of Oncology 28 (1): 16-33 and The Breast 31: 244–259. Link
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  15. 15. Wang, S., et al. (2012). Classical CMF regimen as adjuvant chemotherapy for triple-negative breast cancer may be more effective compared with anthracycline or taxane-based regimens. Med Oncol, 29(2): 547–553. Link
  16. 16. Aubele, M., et al. (2017) The Predictive Value of PITX2 DNA-Methylation for High-Risk Breast Cancer Therapy: Current Guidelines, Medical Needs, and Challenges. Disease Markers (in press). Link
Kathryn Collinet

Kathryn Collinet, PhD, is a Technical and Marketing Writer for Personalized Healthcare and Oncology at QIAGEN. She trained as a molecular biologist at the University of Barcelona and the Institute for Research in Biomedicine, where she studied DNA and protein modifications and their influence on chromatin conformation and gene expression. Since 2011 Kathryn has been working in marketing communications for the scientific information and molecular diagnostics industries. Kathryn has a passion for delivering knowledge and insights about molecular and clinical technologies, and their power to impact research and healthcare.

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