The EGFR stands at the origin of a major signaling pathway involved in the growth of breast cancer. Two of the four receptors in this pathway, epidermal growth factor receptor type 1 (HER1) and epidermal growth factor receptor type 2 (HER2, also referred to as HER2/neu or ErbB2), are promising targets for new treatments.

In about 20% of patients with breast cancer, the tumor overexpresses HER2. Herceptin, a humanized monoclonal antibody that targets the extracellular domain of HER2, is effective as adjuvant therapy and as treatment for metastatic disease in patients with HER2-positive breast cancer.

Tykerb, an orally administered small-molecule inhibitor of the tyrosine kinase domains of HER1 and HER2, has antitumor activity when used as a single agent in patients with HER2-positive inflammatory breast cancer or HER2-positive breast cancer with central nervous system (CNS) metastases that are refractory to Herceptin. This finding is important because HER2-positive tumors frequently spread to the CNS, where the tumor is sheltered from Herceptin and most chemotherapeutic agents.

Other targeted therapies also show great promise in the treatment of breast cancer. Avastin is a monoclonal antibody against the vascular endothelial growth factor (VEGF). Tumors can be effectively controlled by targeting the network of blood vessels that feed them. Tumor growth is dependent on angiogenesis. Angiogenesis is dependent on VEGF. Avastin directly binds to VEGF to directly inhibit angiogenesis. Within 24 hours of VEGF inhibition, endothelial cells have been shown to shrivel, retract, fragment and die by apoptosis. In addition to VEGF, researchers have identified a dozen other activators of angiogenesis, some of which are similar to VEGF.

Although these targeted therapies are initially effective in certain subsets of patients, the drugs eventually stop working, and the tumors begin to grow again. This is called acquired or secondary resistance. This is different from primary resistance, which means that the drugs never work at all. The change of a single base in DNA that encodes the mutant protein has been shown to cause drug resistance.

Initially, tumors have the kinds of mutations in the EGFR or VEGF gene that were previously associated with responsiveness to these drugs. But, sometime tumors grow despite continued therapy because an additional mutation in the gene, strongly implies that the second mutation was the cause of drug resistance. Biochemical studies have shown that this second mutation, which was the same as before, could confer resistance to the EGFR or VEGF mutants normally sensitive to these drugs.

It is especially interesting to note that the mutation is strictly analogous to a mutation that can make it tumor resistant. For example, mutations in a gene called KRAS, which encodes a signaling protein activated by EGFR, are found in 15 to 30 percent of certain cancers. The presence of a mutated KRAS gene in a biopsy sample is associated with primary resistance to drugs. Tumor cells from patients who develop secondary resistance to a drug like Tarceva after an initial response on therapy did not have mutations in KRAS. Rather, these tumor cells had new mutations in EGFR. This further indicates that secondary resistance is very different from primary resistance.

All the EGFR/VEGF mutation or amplification studies can tell us is whether or not the cells are potentially susceptible to this mechanism of attack. They don't tell you if one drug is better or worse than some other drug which may target this. There are differences. The drug has to get inside the cells in order to target anything.

EGFR/VEGF-targeted drugs are poorly-predicted by measuring the ostansible targets, but can be well-predicted by measuring the effect of the drug on the "function" of live cells.

Literature Citation:
PLoS Medicine, February 22, 2005
Eur J Clin Invest 37 (suppl. 1):60, 2007

For the last two decades, the hallmark of medical treatment for cancer has been intravenous cytotoxic chemotherapy. The drugs targeted rapidly dividing cells, including cancer cells and, of course, certain normal cells (cancer cells and healthy cells). Traditional chemotherapy does not have any mechanism to distinguish between them.

In the last few years, 'targeted' therapies are becoming a component of treatment. 'Targeted' therapy is designed to block a specific gene or protein that has a critical role in the survival, growth, invasion, or metatasis of a specific cancer cell. It takes advantage of the biologic differences between cancer cells and healthy cells by 'targeting' faulty genes or proteins that contribute to the growth and development of cancer.

In other words, 'targeted' treatments fight cancer by correcting or modifying defective 'pathways' in a cancer cell. In healthy cells, each 'pathway' is tightly controlled. For instance, healthy cells are allowed to divide into new cells, and damaged cells are destroyed. However, in cancerous cells, certain points in the 'pathway' become disrupted, usually through a genetic mutation (change in form).

Designing "targeted" anticancer drugs begins with identifying the genes or proteins that are specific to the development of cancer and testing whether blocking those genes or proteins gets rid of the cancer. Genetic (molecular) tests are instrumental in accomplishing this task.

However, understanding 'targeted' treatments begins with understanding the cancer cell. Every tissue and organ in the body is made of cells. In order for cells to grow, divide, or die, they send and receive chemical messages. These messages are transmitted along specific 'pathways' that involve various genes and proteins in a cell.

Genetic testing examines a single process within the cell or a relatively small number of process. The aim is to tell if there is a theoretical predispostion to drug response. Cell-based testing not only examines for the presence of genes and proteins but also for their 'functionality' (their interaction with other genes, proteins, and processes occurring within the cell, and for their response to 'targeted' drugs).

Genetic testing involves the use of dead, formaldehyde preserved cells that are never exposed to 'targeted' drugs. Genetic tests cannot tells us anything about uptake of a certain drug into the cell or if the drug will be excluded before it can act or what changes will take place within the cell if the drug successfully enters the cell.

Genetic tests cannot discriminate among the activities of different drugs within the same class. Instead, it assumes that all drugs within a class will produce precisely the same effect, even though from clinical experience, this is not the case. Nor can Genetic tests tell us anything about drug combinations.

Cell-based testing looks at 'fresh' living cancer cells. It assesses the net result of all cellular processes, including interactions, occurring in real time when cancer cells actually are exposed to specific anti-cancer drugs. It can discriminate differing anti-tumor effects of different drugs within the same class. It can also identify synergies in drug combinations.

When considering a 'targeted' cancer drug which is believed to act only upon cancer cells that have a specific genetic defect, it is useful to know if a patient's cancer cells do or do not have precisely that defect. Although presence of a 'targeted' defect does not necessarily mean that a drug will be effective, absence of the targeted defect may rule out use of the drug.

As you can see, just selecting the right test to perform in the right situation is a very important step on the road to personalizing cancer therapy. Sometimes a drug will inhibit the 'target' but not stop the growth of cancer. Not all genes and proteins have a critical role in the survival and growth of cancer cells.

The are many pathways to altered cellular (forest) function, hence all the different 'trees' which correlate in different situations. Improvement can be made by measuring what happens at the end of all processes (the effects on the forest), rather than the status of the individual trees (pathways/mechanisms). You still need to measure the net effect of all processes, not just the individual molecular (gene/protein) 'targets.'

*** Edited 5/14/2008 4:44:03 PM UTC by gdpawel***