Personalized Medicine

Personalized medicine aims to identify patients who require treatment and subsequently select the right therapy based on individual factors and tumor characteristics, i.e. personalized medicine targets to identify the right patients for the right therapy. Prognostic biomarkers provide information on the risk of disease recurrence whereby predictive ones will inform the physician of the potential clinical response of the patient to a given cancer therapy.

In personalized medicine biomarkers are used to predict prognosis (prognostic biomarkers) and treatment success (predictive biomarkers).

High risk breast cancer

One in eight to ten women will get breast cancer during their lifetime. More than 460,000 women in Europe are newly diagnosed with breast cancer each year, with about 50% characterized as high-risk.

Therapy concepts for early breast cancer depend on prognostic risk classification, i.e. pending on the risk for disease recurrence patients will be treated more or less aggressively.

Prognostic risk classification by clinico-pathological assessment includes risk factors such as axillary lymph node status, tumor size, tumor grade, hormone-receptor status, patient age and Human Epidermal Growth Factor Receptor 2 (HER2)-status. While for patients at low and at high risk treatment recommendations are straightforward, the risk-benefit analysis for chemotherapy in patients at intermediate risk is challenging. Multigene signatures help to further stratify the intermediate risk group into low-risk (endocrine therapy, no systemic chemotherapy needed) and high-risk (indication for systemic chemotherapy) categories.

Patients with early breast cancer at high risk for disease recurrence require systemic chemotherapy. Anthracycline-based chemotherapy is considered standard of care according to national and international guidelines. As for any systemic chemotherapy, anthracyclines are associated with considerable side effects such as cardiac toxicity as well as secondary hematological malignancies (Azim et al., Annals of Oncology (2011) 22, 1939-1947).

Selection of the right patients for anthracycline-based chemotherapy vs. alternative chemotherapy (e.g. DC or P or CMF) is now supported by the PITX2-assay. The assay provides information to the treating physician, which patients are likely to benefit from anthracycline-based chemotherapy and which are not.

Response prediction by PITX2 DNA-methylation provides valuable information on who has a high probability to benefit from anthracycline-based chemotherapy versus who should be considered for alternative chemotherapy regimen.

PITX2 DNA-methylation, a prognostic and predictive biomarker

DNA-methylation is a common and early event in cancer indications, including breast cancer. DNA-methylation is observed in regulatory regions of specific genes and affects gene expression. The pituitary homeobox gene 2 (PITX2) is one of these regulatory genes and the methylation status of the PITX2 promotor has been shown to be prognostic for disease-free survival (DFS) and overall survival (OS) in various indications (see literature list PITX2)

Significant evidence has accumulated about PITX2 serving as prognostic and predictive biomarker in breast cancer, especially in hormone-receptor positive disease.

PITX2 hypermethylation predicts poor patient outcome

In patients with high-risk, lymph-node-positive, estrogen/progesterone-receptor positive, HER2-negative breast cancer treated with adjuvant anthracycline-based chemotherapy, PITX2-hypermethylation predicts high risk of disease recurrence, PITX2 hypomethylation identifies patients with high probability to benefit.

High PITX2-methylation predicts high risk of disease recurrence in hormone-receptor positive breast cancer.

The therascreen PITX2 Assay

The therascreen PITX2 RGQ PCR Kit has been developed by Therawis Diagnostics together with its development partner Qiagen using reliable RGQ PCR technology and routinely available FFPE tissue.

The therascreen PITX2 RGQ PCR Kit has been CE-certified in Feb-2018. The assay separates high-risk, lymph node-positive, estrogen receptor-positive and Her2-negative breast cancer patients, who are more vs. less likely to benefit from anthracycline-based chemotherapy (see assay validation).

The assay is a unique DNA methylation test that determines the percent methylation ratio (PMR) in promoter 2 of the pituitary homeobox transcription factor 2 (PITX2) gene as a novel biomarker. The kit has been optimized to detect and differentiate between methylated and unmethylated areas within the PITX2 promoter and is characterized by the following properties.

 

  • Clinically validated CE-certified IVD (in-vitro diagnostic)

  • Limit of Detection (LOD): PMR 4 to PMR 92

  • Range of linearity: PMR 5 to PMR 50

  • Simple and efficient workflow with Ready-to-use solutions and reaction mixes

  • Sample to Insight in <48 hours

 

Automated software using Rotor-Gene AssayManager v2.1 for quick and easy results interpretation

therascreen PITX2 RGQ PCR Kit – workflow

The therascreen PITX2 RGQ PCR assay is a CE-certified test. The whole workflow from sample to insight is performed using readily available kits within 48 hours.

Kits can be ordered on the manufacturer’s homepage (further details see manufacturer’s homepage)

therascreen PITX2 RGQ PCR requirements:

For test performance the following sample material is required:

  • 5 µm unstained slides of formalin-fixed, paraffin-embedded breast cancer tissue material

  • Surface area of at least 100 mm²

Clinical validation

Overall 205 patients (ER+, PR+, N+, HER2-) were included in a prospective analysis using archived formalin-fixed paraffin-embedded (FFPE) tissues.

Thereof, 60 FFPE samples were used to confirm a pre-defined PMR cut-off value of 12 which separates patients who benefit more versus less likely from anthracycline based chemotherapy with or without endocrine therapy.

The remaining 145 samples were used to clinically validate the PMR cut-off of 12. Applying 10-year follow-up as primary study endpoint, patients with low PMRs (≤ 12) demonstrated increased disease-free survival, patients with high PMRs (>12) showed a statistically significant shorter disease-free survival.

The PMR cut-off of 12 has been validated in high-risk luminal B-patients. This cut-off is optimized to identify patients with high versus low probability to benefit from anthracycline-based chemotherapy.

Contact

Therawis Pharma GmbH

Therawis Diagnostics GmbH

Grillparzerstrasse 14

81675 Munich Germany

Tel.: +49 (0) 89 41 42 45 57 0

Fax. +49 (0) 89 41 42 45 57 40

E-Mail: info@therawis.com

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