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Nomogram vs GeneSearch Genetic Test | Breast Cancer August 23, 2007

Posted by ramunas in bio-software, breast cancer, cancer genetics, GeneSearch.
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Several days ago an article from Memorial Sloan-Kettering Cancer Center, NY, USA, presented a user-friendly prediction model (nomogram) based on a large data set to assist in predicting the presence of sentinel lymph node (SLN) metastasis for a specific patient, which is important prognostic factor.

After multivariate analysis with SLN metastasis were associated several factors: age, tumor size, tumor type, lymphovascular invasion, tumor location, multifocality, and estrogen and progesterone receptors [ref.]. The nomogram was accurate, discriminating and properly validated (a model was subsequently applied to 1,545 sequential SLN biopsies.)

Because newly diagnosed breast cancer patients are increasingly interested in information about their disease, this validated nomogram for risk estimation could be useful tool for physicians and patients to accurately predict the likelihood of SLN metastasis.

A nice computerized version (Macromedia Flash 6.0) of the nomogram is available on their website.

This tool, known as a nomogram, can be used to calculate the likelihood that breast cancer that has spread to the sentinel lymph nodes has also spread to additional lymph nodes under the arm (axilla). It is designed to individualize the risk estimate for each patient — a key factor in deciding whether additional surgery is likely to be beneficial, website states.

Obviously, it is not a substitute for medical advise, diagnosis or treatment but seems to be quite useful addition for risk estimation.

Researchers recommends that this tool should be used by physicians only. Patients should use this tool only in consultation with their physicians.

Also, I think it would be of great interest to compare this Breast Cancer Nomogram results with recently FDA approved Johnson&Johnsons GeneSearch™ Breast Lymph Node (BLN) assays results, which claims to detect the spread of breast cancer into the lymph nodes by analyzing the level of metastatic tumor expression markers.


Gene-expression Profiling in Cancer | A Brief Review July 24, 2007

Posted by ramunas in breast cancer, cancer genetics, GeneSearch, MammaPrint, Oncotype DX, sporadic cancer, technology.

It seems I’m getting more and more interested in gene-expression profiling (GEP) oncotests. In the Internet the information about this topic is quite messy and dispersed, so here I will try to draw some focus on this emerging technology (what will be added to a Genetic testing section later).

So, if we want to make gene-expression profiling, or in the other words, to answer an important question – what genes are expressed in a particular cell type of an organism, at a particular time, under particular conditions? [ref.]- first we need to have a sample of a tumor tissue to analyze its RNA pattern (or more precisely, messenger RNA (mRNA)). Here, unlike in mutations search, we’re not interested in DNA. RNA is quite instable molecule, so you need be quite cute and smart to manage preserve and analyse it.

A breast cancer is currently a holy grail for gene-expression profiling research to identify genes associated with breast cancer and to measure their activity in tumor cells, i.e. obtain its gene expression profiles.

Several techniques for measuring gene expression are available: a) a microarray based analysis and b) reverse transcriptase-polymerase chain reaction (RT-PCR). To measure gene expressions with a microarray you need to have a “fresh” (or “unpreserved”) tumor tissue samples. Tumor samples are frequently preserved in this way in Europe. Whereas in the United States tumor samples are more commonly preserved in formalin and embedded in paraffin blocks. Microarray analysis cannot be done on tissue that has been preserved in this way [ref.]. Since our pathologists are accredited by College of American Pathologists, they’re using paraffin blocks as well. Instead, for formalin-fixed and paraffin embedded (FFPE) tumor tissue blocks RT-PCR can be used to measure gene expression.

Therefore its important to know, that because of this difference in common methods of tissue processing has led to the development of tests in Europe and the United States that are quite different from one another, and that are based on measurements of the activity of different sets of genes.

In Europe, using microarray analysis, researchers are studying the usefulness of at least two different groups, or “panels”, of genes in studies on early stage tumors from node negative patients. One is a 70-gene panel, and another is a 76-gene panel. 1,2 Only three genes are common to both panels, while all the others are unique to one test or the otherB. In spite of this difference, both panels have yielded results that appear to be promising,3 and a commercial test based on the 70-gene panel is already available in the United States under the name MammaPrint®. (via)

Based on 76-gene panel Johnson&Jonson’s companies Veridex research, a two genes expression The GeneSearch™ Breast Lymph Node (BLN) Assay test was recently approved dy FDA, and is based on RT-PCR (i.e. for analysis in FFPE).

Common use of FFPE and a need for gene expression profiling using RT-PCR has led researchers in the United States to investigate several other panels of genes that produce too much or too little protein in early stage, node-negative, and estrogen receptor-positive breast cancer cells. A 21-gene panel commercial Oncotype DX test is one of example, which recently was approved by TEC to inform decision making about adjuvant chemotherapy only for a women with estrogen receptor-positive, node-negative, tamoxifen-treated breast cancer.

Let’s have a closer look at these genes [ref.]:

Measurements of five of those 21 genes (Beta-actin, GAPDH, RPLPO, GUS, and TFRC ) are used as “controls” – that is, to verify that the test has not been contaminated or run improperly.

The other 16 genes, which produce their proteins at varying levels in different tumors, include:

  • genes associated with cell proliferation (Ki-67, STK15, Survivin, Cyclin B1, and MYBL2);
  • genes associated with cellular invasion (Stromolysin 3, and CathepsinL2);
  • genes associated with HER2 activity (GRB7 and HER2);
  • genes associated with estrogen activity (ER, PR, Bc12, and SCUBE2); and
  • three other genes with distinctly different activity in cancer cells (GSTM1, BAG1, and CD68).

This Oncotype DX panel has only a single gene overlap with the 70-gene MammaPrint® panel. The reason for such diversity between gene panels under investigation are because of differences in tissue preparation, differences in laboratory methodologies, and differences in measurement techniques. At present, these gene-expression profile tests have only been validated on stored sample tissue.

Whether one of the existing panels will prove to be significantly superior to others, or whether newer panels will emerge that have better predictive power remains to be seen. It is clear that additional validation studies and more clinical experience are needed to establish the reliability of gene expression profiling for predicting tumor recurrence and response to specific treatments (ref.)


Johnson & Johnson Genetic Testing | FDA Approved July 18, 2007

Posted by ramunas in breast cancer, cancer genetics, GeneSearch, genetic testing, sporadic cancer.

Did you know that “baby friendly” company Johnson&Johnson has in vitro diagnostics oncology products company called Veridex? Yesterday U.S. Food and Drug Administration (FDA) approved the first intra-operative and gene-based test to detect the spread of breast cancer into the lymph nodes. Its GeneSearch™ Breast Lymph Node (BLN) assay (for in vitro use only) can detect the spread of cancer into the lymph nodes more accurately than existing rapid methodologies and, as a result, has the potential to reduce the need for stressful and costly second surgeries for breast cancer patients.

The GeneSearch™ Breast Lymph Node (BLN) Assay may be used in conjunction with sentinel lymph node biopsy for a patient who has been counseled on use of this test and has been informed of its performance. False positive results may may be associated with increased morbidity. False negative and inconclusive test results may be associated with delayed axillary node dissection. Clinical studies so far are inconclusive about a benefit from treatment based on findings of breast cancer micrometastases in sentinel lymph nodes. [via]

It claims to detect metastases greater than 0.2mm in nodal tissue removed from sentinel lymph node biopsies of breast cancer patients and gives rapid, reproducible, objective results, which can be used to guide the intra-operative or post-operative decision to remove additional lymph nodes.

It’s based on reverse transciptase polymerase chain reaction (RT-PCR) assay that detects metastatic tumor expression markers: Mammaglobin (MGB1) and Cytokeratin 19 (KRT19) , which are present in higher level in breast cancer, but not in nodal tissue (i.e. tissue specific RNA expression).

In clinical trials with more than 300 patients in the U.S. that compared performance of GeneSearch(TM) with commonly performed intra-operative test procedures, GeneSearch(TM) correctly identified 95.6 percent of patients who had metastases in their lymph nodes. This high accuracy in finding metastases was statistically superior to the most commonly performed intra-operative test procedure. The new, gene-based technology of the GeneSearch(TM) test allows for the analysis of 50 percent of the sentinel node, versus five percent of tissue typically examined under a microscope for evidence of cancer cells. Test results from GeneSearch(TM) can be produced in 35 to 40 minutes during the initial surgical procedure versus two to three days with tissue pathology. (via)

The test is intended for use of customers, patients and healthcare professionals in the United States. It is also CE marked and is commercially available in the EU.

Breast cnacer is the most common cancer and the second leading cause of cancer death in western world. The average lifetime riks for a woman in the western world (or populational risk) varries from 1 in 8-10.
More than 40,000 women in the U.S. die from breast cancer annually and given level of accuracy, GeneSearch(TM) has the potential to prevent the need for costly and traumatic second surgeries for as many as 5,200 additional breast cancer patients in the U.S. each year. [via]