Gene Expression of Metastatic Breast Cancer
A 70-Gene Signature Profile Used for Clinical Diagnosis
Oct 21, 2008
DNA microarray is a technique that has recently revolutionized many aspects of cancer research. This technique is used to compare expression patterns of thousands of genes between different cells. Cancer researchers use a tumor's "gene expression profile" or "gene signature" to distinguish tumor cells from a healthy cells or from another tumor subtype.
DNA Microarray Analysis
DNA Microarray analysis involves placing up to several thousand genetic probes in an ordered "array" of tiny spots on a glass slide. These probes are then put in contact with RNAs (Ribonucleic Acids) extracted from cells of a tumor sample and labeled with a fluorescent dye. Each probe encountering a complementary RNA will then fluoresce and the corresponding spots on the array become fluorescent. The fluorescent array is analyzed by computer programs that provide researchers with a readout of which genes are more or less expressed in the tumor sample in comparison to another sample.
For a clinical use, this type of approach is often criticized due to its lack of reproducibility, among different cohorts of patients or among different research centers. Reproducibility and reliability are important factors for a new clinical tool to be approved by the FDA (Food Drug Administration) before going to clinic.
DNA Microarray Applied to Breast Cancer Prognostic
In 2002, Laura van t Veer and Marc J Van de Vijer from the Netherlands Cancer Institute, in the study " Gene expression profiling predicts clinical outcome of breast cancer" (Nature, 415, 530-536) have used a DNA microarray technology to analysis 261 breast cancer samples. They compared samples from patients developing or not metastasis and identified several genes which they called "poor prognosis" profile and were associated with likelihood of developing distant metastases within 5 years of treatment. Another profile was associated with patients who did not develop metastases by 5 years, called the "good prognosis" profile.
Reproducibility in Several Series of Patients
The researchers performed an additional microarray analysis, in 2002, and two recent independent analysis in 2006 and 2008 in the studies titled "A gene–expression signature as a predictor of survival in breast cancer" (N Engl J Med 347:1999-2009, 2002), "Validation and clinical utility of a 70-gene prognostic signature for women with node-negative breast cancer" (J Natl Cancer Inst 98:1183-1192, 2006) and "Validation of 70-gene prognosis signature in node-negative breast cancer" (Breast Cancer Treat, sept 2008). In the three studies, the gene profiles efficiently predicted which patients were at risk for developing distant metastases or surviving within 5 years or 10 years.
Good Prognostic Signature is Associated With Longer Survival and Abscence of Distant Metastasis
In their most recent study, the researcher showed about 94% of patients with a "good prognosis" profile survived 10 years. In comparison, 51% of patients with a "poor prognosis" profile survived 10 years. In addition, only 14% of patients with a "good" profile developed distant metastases by 10 years after initial therapy in comparison to 50% of patients with a "poor" profile.
The Gene-Signature Outperformed the Clinical Parameters
The researchers also compared the efficiency of their gene-prognosis profile with currently used clinical parameters for predicting outcome of disease.They showed that this signature profile outperformed the clinical parameters.
This third study validates the clinical usefulness of their approach as a prognostic clinical tool tailoring therapy for breast cancer; most important, it could support treatment decisions. For this purpose, a molecular diagnostic test, named MammaPrint®, has already been approved by the FDA for marketing and is offered by Agentia (Amsterdam, The Netherlands), the company cofounded by Laura van t Veer,
