WEDNESDAY, FEBRUARY 13, 2002

"Herceptin and Other New Therapies: Promise Fulfilled?"

We now believe that cancer is a direct or indirect result of changes in the genes. Genes encode all the proteins that are made by the cell. They also have regulatory elements which tell whether the protein will be made by the gene. In the late 1970s it was determined that viruses can cause cancer in animals like mice, cats and birds. About this time, the tools for cloning became available. The ability to manipulate genes by cutting them out of one place and putting them in another was revolutionizing. Michael Bishop and Harold Varmus cloned the first oncogene called SARK. Oncogenes are altered versions of our normal genes. These genes can be changed in a variety of ways to become activated: by multiplication or chomosomal translocation, in which one half of a chromosome crosses over to another half to form a fusion gene or mutation. Radiation and carcinogens also can produce changes in the genes. Genes which are involved in the growth and development of the cells can cause problems if mutated or stuck in the "on" position, contributing to the development of cancer.

In 1981, researchers at MIT and NIH simultaneously discovered a gene found in rats that developed neuoblastoma (brain tumors) when given specific carcinogens. They called the gene "neu" because it was a neural tumor. A few years later it was discovered that the human homologue was very similar to a growth factor receptor (called HER, for human epithelial receptor). This new gene called HER2/neu was found to be amplified or overexpressed in 20% of breast cancer cells. Dennis Slaymon at UCLA, found that amplification of the gene was related to a worse outcome and lead to more protein being made, such that HER2/neu can be considered a causative agent in breast cancer. In 1987 a variety of people (including Dr. Tripathy) started to discover how this oncogene works. No one had identified the normal role of HER2/neu, nor identified the ligand which binds the receptor and causes it to activate. Instead it was thought that if antibodies could be made to the receptor they might bind to the receptor and cause it to activate. Researchers at Genentech, working at night, developed an antibody was developed called antibody 45. It not only bound the receptor, but activated the signalling cascade. It was very exciting to discover that the antibody inhibited a growth factor receptor that seemed to be important in cancer. A small phase I study was done. It was found that 10% of patients responded to the antibody, but it left open the question of the normal biology of HER2/neu. If it was to be targeted with an antibody that would modulate it’s function, not knowing the actual biologic function might be a set-up for unknown side effects in the future. Knockout experiments were done on mice in which genes were taken away by an enzyme. The consequence was that the embryo did not form neurologic and cardiac systems and the animal did not make it to birth. This is typical of oncogenes which are very active in the embryo. In normal development, genes are turned on in embryogenesis and then turned off in adult life. If they are turned on again, it can cause uncontrolled growth. In normal epithelial cells, HER2/neu is expressed in very low levels. In 1992 the Herceptin trials were started. All patients had tumors which expressed HER2/neu. 15% of patients who had been heavily pretreated responded, but 30% of patients who had not had prior chemotherapy responded. Another study comparing chemo alone to chemo plus Herceptin, showed a clear benefit and a survival advantage with the addition of Herceptin. Most patients eventually developed a resistance to Herceptin, but on the average they lived longer—an important finding. Then patients began to get cardiac symptoms. This was unexpected as HER2/neu is almost never expressed in heart cells. With very sensitive techniques, small levels of HER2/neu were found in cardiac cells. Patients who already have stressors on their heart are more likely to develop cardiac symptoms. Other side effects sometimes seen are throat tickle, slight cough, looser bowel movements. Using Herceptin in early stage breast cancer is problematic because of the potential cardiac problems. We are now trying to find combinations of drugs to use with Herceptin which will act synergistically.

Can you go off Herceptin and then return? There have not been large trials looking at this. The general practice is to keep Herceptin going until there is progression or until the cardiac ejection fraction drops.

Can a patient’s HER2/neu status change? It is possible for status to change when the patient becomes metastatic, but it is more likely that testing procedures have changed and become more accurate. It is advisable for the metastatic patient to get testing done on the new tumor block because at this time most test results are based on the primary tumor. The best way to look at HER2/neu is to test the DNA which tends to be robust rather than protein staining which tends to degrade over time.

If you progress on Herceptin can it be used in combination with other drugs? You can produce synergy--an increased response with both drugs used together, as opposed to either one used individually--in the laboratory. Taxotere and Navelbine tend to be the most synergistic. We have yet to prove this with patients.

What does it mean to be 2+ or 3+? This simply refers to the amount of HER2/neu that is on the surface. There are two ways to test for HER2/neu: immunohystic chemical staining which uses an antibody to bind the protein, which is stained brown. Under the microscope this stained area is apparent if the protein is present. The amount and intensity of the stain is graded: 1+ or 2+ or 3+. This reading can be very subjective. Pathologists who do a lot of this reading are most proficient. Even with proficiency, there will be a certain number of false positives. The FISH (Flourescence In Situ Hybridization) test is more accurate.

Do you know at what degree of overexpression patients begin to respond to Herceptin? Some arbitrary cutoffs have been made. If you have more than two times the normal gene content, that is considered amplified, but there is a gray zone here. At best only about 35% of patients respond to Herceptin who are 3+. A 2+ would give you only about a 10% chance of response. With 1+, there is virtually no chance of a response.

At what level of cardiac ejection should you consider Herceptin? You want to start out with what would be considered a normal cardiac ejection factor. With women, it should be above 45%. Another thing to look for is a drop in the ejection factor; if it started at 60% and dropped to 45%, it would be cause for concern—might want to consider withholding the Herceptin.

Can you explain the correlation between estrogen receptor and Herceptin, and why are there not many clinical trials regarding the combination? There are current trials involving both Tamoxifen and aromatase inhibitors (Arimidex and Letrozole) in combination with Herceptin. The relationship is not well understood, but there is some evidence that Tamoxifen may not be as effective for women who are both ER+ and HER2/neu+ , whereas this is not the case with the aromatase inhibitors. This indicates that there may be some relationship between the two pathways. Placing the HER2/neu oncogene into ER+ cells can make them resistant to Tamoxifen.

Please define "ligand". A ligand is a protein that binds receptors. It is specific to the receptor, i.e., insulin binds the insulin receptor, epidermal growth factor binds the epidermal growth factor receptor (EGFR), etc. Kinase inhibitors like Tarceva and Iressa are drugs that bind the EGFR and prevent the cascading effect of the protein. These drugs are very effective with head and neck cancer, but have not been very effective in breast cancer.

Are drugs most effective in combination? Unless you have clear evidence to the contrary, it is better to use drugs sequentially that in combination. The toxicities are less. There are exceptions, with some drugs showing a survival advantage in combination: Taxotere/Xeloda and Herceptin/Taxol are two examples.

How do you define "asymptomatic" in Stage IV? This is very subjective, you must ask the patient how they feel. Something which shows up on a scan, like a supraclavicular lymph node recurrence or liver metastasis can still be asymptomatic if the patient does not report any symptoms. However, usually the greater the tumor burden, the more symptoms.

Without symptoms, when would you start the patient on chemotherapy? Metastatic disease is very different from early stage disease. With breast cancer, the sooner you treat early stage, the better off you are. With metastatic disease, this is not the case. Generally nothing is lost to survivorship if the treatment is a little delayed, especially if the patient is asymptomatic. Taking the drug with the higher response rate does not mean you will live longer.

Is there a role for radiation therapy in supraclavicular metastasis? In general, we do not use radiation with metastatic disease unless there are symptoms in the bone. If the only spread of the disease is supraclavicular, it might be treated as local disease.

What about Herceptin and brain mets? There was a study that suggested a higher likelihood of brain metastasis. One hypothesis is that just living longer because of the Herceptin may contribute to the possibility of brain mets. Another is that Herceptin goes almost everywhere, but does not cross the blood/brain barrier because it is a large molecule. It is not likely that Herceptin is inducing brain cancer.