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Nayernia and Bojar: Personalized diagnostics and treatment of breast cancer

Introduction

Breast cancer can exist for long periods as non-invasive or invasive but non-metastatic disease. Early detection of breast cancer, for example by mammography screening, significantly improves a woman’s chances of survival. If breast cancer is diagnosed and treated while it is confined to the breast, the cure rate can approach 100%. However, mammography screening is far from perfect in terms of sensitivity and specificity of cancer detection. There is a significant clinical need for accurate and highly sensitive tests for early detection of breast cancer. Target applications are screening of high-risk groups, particularly younger women (under the age of 50) from high-incidence families, and breast cancer patients to detect the primary metastasis and migratory route, to direct treatment and the early detection of recurrence when screening breast cancer patients.

Preliminary studies

A growing body of evidence supports the notion that only a small subset of cells within a tumour, termed cancer stem cells or tumour-initiating cells, are capable of both tumour initiation and sustaining tumour growth. The importance of cancer stem cell research lies in the possibility of providing new approaches for improved understanding of cancer biology and cancer treatment. We described specific expression of stem-cell protein Piwil2 in breast cancer and its predominant expression in breast cancer stem cells. Piwil2 belongs to the piwi gene family, which is characterized by conserved PAZ and PIWI domains (PPDs) and plays an important role in stem-cell self-renewal, RNA silencing and translational regulation in various organisms ranging from Arabidopsis to humans. PPDs show very strong RNA- and protein-binding activity, evident from studies carried out by various research groups.

In breast cancer, we found predominant expression of Piwil2 in breast cancer stem cells. Stem and progenitor cells are of great interest because it is perceived that these cells are the initial targets for malignant transformation. These findings caution that the success of our efforts in translating cancer stem-cell research into clinical practice depends on how thorough and rigorous we are at characterizing these cells. This leads to molecular targeting of breast cancer stem cells and improving the efficacy of the current anticancer strategies with the aim to sensitize tumours towards conventional therapies and effectively abrogate tumorigenesis. Piwil2, and its molecular pathway, provides an excellent diagnostic base for the establishment of personalized diagnostics and therapy of breast cancer.

ONCOASSAY BREAST development

The ONCOASSAY BREAST (Institute for Molecular Medicine and Cell Therapy, Düsseldorf, Germany) is a hybrid immunohistochemical and genomic test for more accurate characterization of breast cancer. ONCOASSAY BREAST combines the specific advantages of immunohistochemistry with that of the genetic approach by quantitative polymerase chain reaction-based gene expression profiling. The immunohistochemical assessment of prognostic biomarkers is limited to some extent by the semiquantitative nature of the technology. The ability to exactly define the cellular source of the signals in the often heterogeneous cellular environment of the tumour tissue makes up for that disadvantage. An enormous advantage of the immunohistochemical component of the ONCOASSAY BREAST hybrid system is the fact that these biomarkers have been assessed prospectively. The potential drawback of the genetic component, cellular heterogeneity, has been overcome by routinely applying some kind of precise micro-scissors, namely contact- and contamination-free laser microdissection. ONCOASSAY BREAST considers not only the activity of a group of proliferation, apoptosis and oestrogen hormone receptor-associated genes, but also tumour size and lymph node involvement.

The ONCOASSAY BREAST algorithm is based on a total of 30 molecular biomarkers and cancer stem-cell markers complemented by two clinical prognosticators, namely tumour size (pT) and axillary lymph node status (pN). In a two-stage process, our computation model first determines the intrinsic phenotype of the individual tumour (luminal A, luminal B, HER2/neu, triple-negative/basal-like). Subsequently, the risk of recurrence of breast cancer for that specific phenotype is determined, which forms the basis for development of a personalized therapy strategy. All this information is summarized in the OA score (ONCOASSAY score) (Figure 1).

FIGURE 1

The OA score considers tumour size, nodal involvement and activities of tumour-specific genes.

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Figure 2 shows an example of the relationship between the OA score and the risk of disease in oestrogen receptor-positive HER2/neu-negative breast cancers. The OA score varies between 0 and 40. Two important points of reference for treatment decision displayed in the graphics are disease-related events of 10% and 20% after 10 years.

FIGURE 2

The relationship between OA score and risk of disease in oestrogen receptor-positive HER2/neu-negative breast cancer.

Suppl-1-14-fig2.jpg

Figure 3 shows the relation between OA score and disease-related events in triple-negative breast cancer (TNBC). The risk calculation is based on a cohort of 231 consecutively presented TNBCs.

FIGURE 3

The relationship between OA score and risk of disease in TNBC.

Suppl-1-14-fig3.jpg

Based on the abovementioned basic version of ONCOASSAY BREAST, complementary tests (OncoAssay Advanced I–III) will be offered. Depending on the OA score and the breast cancer subtype of the individual (intrinsic phenotype), the complementary tests offer valuable additional information on the optimal individual treatment strategy.





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