For the average layperson, talking about breast cancer is like floating in a bowl of alphabet soup. That’s because breast cancer is not one disease, but many different diseases; each one has its own assigned acronym. It sometimes seems as though the scientific community will run out of letters before they run out of different types of breast cancer.

One particularly aggressive form of breast cancer is HER2-positive, caused by the over-expression of a gene called HER2. This over-expression allows breast cancer cells to grow unregulated. According to Dr. Richard Bender, this is a typical feature of neoplastic cells, meaning cells from which tumors are formed.

Dr. Bender is a clinical oncologist and the Chief Medical Officer for Agendia, a company that has developed a new testing methodology for assessing the risk of recurrence in breast cancer patients. He explained that under normal conditions, growth factors, such as human epidermal growth factor, or HER2, bind themselves to receptors on the surface of a cell so that the cells can grow and survive. However, when there is an over-expression of HER2, it signals into the HER pathway, the course along which signals are carried, and it causes the cells to grow without responding to the body’s normal checks and balances that control the rate at which cells develop.

The amplification, or increase in the number of copies of the HER2 gene, which results in this over-expression, develops as breast cancer cells transition from benign to malignant. Dr. Bender says that another feature of cancer cells is that they express epidermal growth factor receptor (EGFR). This is a stabilizer for another cell membrane protein that feeds a steady supply of glucose to cancer cells, keeping them from devouring themselves. Breast cancer cells express EGFR in either small or large amounts. The over-expression is what creates more malignancy.

Women need to be tested for their HER2 status, according to Dr. Bender, because of the biology of breast cancer. Women under 50 years of age, and particularly those under 40, are especially vulnerable to estrogen-receptor negative and HER2 positive breast cancer. If they are diagnosed with this form of the disease, they are generally prescribed Herceptin, a monoclonal antibody. This type of antibody is produced from immune cells that have all been cloned from a single parent cell. Herceptin works by attaching itself to the HER2 receptors on the surface of breast cancer cells, and stopping them from receiving growth signals.

There are currently two types of testing that are in use. The first is ImmunoHistoChemistry (IHC), in which a stain is applied to the breast cancer cell and the the cell is examined under a microscope to see how intense a reaction there is. The results are graded as 0, 1+, 2+, or 3+.

Dr. Bender noted that, as with anything that is done under a microscope, there is a certain subjectivity when determining test results. The process is further influenced by the staining itself, how long it has been fixed, and the experience level of the laboratory and the pathologist performing the test.

For these reasons, The College of American Pathologists (CAP) and the American Society of Clinical Oncology (ASCO) collaborated in producing guidelines for interpreting the results. One of these guidelines is that women whose test results are 1+ or 2+ need a second level of testing called Fluorescence in Situ Hybridization (FISH).  In this test, chromosomes are spread on a slide and exposed to fluorescent compounds that will glow under certain light. One fluorescent compound sticks to the HER2 genes in a cell and another adheres to chromosome 17 in a cell. The pathologist counts the number of fluorescent spots on the control versus the number of spots on the slide.

In both of these testing scenarios, decisions regarding breast cancer are made based on appearance under a microscope, says Dr. Bender. What his company has done is to develop a testing format that uses gene expression profiling, allowing the pathologist to get at more of the basic biology of the cell. The test, known as MammaPrint, uses a group of breast cancer cells under 5 centimeters in size, with the same estrogen receptors, progesterone receptors, grade, and size, to make a decision about prognosis based on 70 key genes.

Dr. Bender and Agendia will be breaking significant research about the accuracy of this testing methodology on Friday, December 12th, at the San Antonio Breast Cancer Symposium. Current treatment guidelines classify all HER2-positive breast cancer patients at high risk of relapse and recommend Herceptin and chemotherapy. However, a study using MammaPrint found that 16 percent of these women do not need any treatment at all, and some HER2-positive women categorized as high risk are actually low risk for recurrence. In addition, for those who need additional treatment, MammaPrint can predict which tumors will be sensitive to chemotherapy.

The impact of this kind of accuracy in terms of disease management is extremely significant. Categorizing risk, according to Dr. Bender, saves women from unnecessary treatment, and the possibility of morbidity and fatality associated with chemotherapy; it also saves the healthcare system the expense of prolonged treatment.

The test is performed in the Agendia lab in Southern California. Fresh tissue from a tumor is placed in the stabilizing fluid developed by the company, and it remains viable for seven days at room temperature, which means it can be shipped from anywhere in the country. Dr. Bender noted that Agendia has been working to develop an advocacy for this kind of testing among key opinion leaders, local opinion leaders, and local doctors. The company’s goal is to have all physicians aware of the testing methodology by spring 2009.

In the meantime, you can request this test from your own physician. The company’s web site will provide your doctor with information about the efficacy of the test as well as how to order it. It could be the best use of the Internet you’ll ever make.