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Old 07-29-2010, 01:41 PM   #3
gdpawel
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New Paradigms of Cancer Treatment

Gene expression (signature) assays are panels of markers that can predict the likelihood of cancer recurrence in various populations. Functonal profiling assay is a test for drug activity against a tumor. Pharmacogenomic testing is a test to identify patients who are likely to have the most toxicity.

By testing the gene expression markers of a patient, oncologists can identify those patients unlikely to benefit from adjuvant chemotherapy from those that would. If the patient needs adjuvant chemotherapy, by testing the patient's tumor cells and testing the patient toxicity tolerance, the oncologist can select drugs that have a higher probability of being effective for an individual patient rather than selecting drugs based on the average responses of many patients in large clinical trials.

What a cancer patient would like ideally, is to know whether they would benefit from adjuvant chemotherapy. If so, which active drugs have the highest probability of working and are relatively non-toxic in a given patient.

Whether a patient would benefit from adjuvant therapy depends on two things: (1) whether the tumor is "destined" to come back in the first place and (2) whether the tumor is "sensitive" to drugs which might be used to keep it from coming back.

The gene expression (signature) marker assays actually could be calibrated to provide information both about the possibility of recurrence and also chemosensitivity. The problem is dissecting one from the other. Studies to date have just looked at whether people had a recurrence.

You can identify gene expression patterns (via assays) which correlate with this. But it can be hard and even impossible to tell what exactly you are measuring: is it intrinsic aggressiveness of the tumor? sensitivity to adriamycin? sensitivity to cyclophosphamide? sensitivity to taxol? sensitivity to tamoxifen? You find a gene expression panel which correlates with something, but picking apart the pieces is hard.

You can begin to do this if you combine gene expression studies (molecular profiling) with cell culture studies (functional tumor cell profiling). Use the functional profiling as the gold standard to define the difference between sensitivity and resistance. Then see which pattern correlates with which for individual tumors and individual drugs.

When the decision is made to treat a patient with chemotherapy, most patients are treated with a combination of drugs. The "functional profiling" method differs from existing DNA and RNA tests in that it assesses the activity of a drug upon combined effect of all cellular processes, using several metabolic and morphologic endpoints. Other tests, such as those which identify DNA or RNA sequences or gene expression signatures of individual proteins often examine only one component of a much larger, interactive process.

No gene-based test can discriminate differing levels of anti-tumor activity occurring among different therapy drugs. Nor can available gene-based tests identify situations in which it is advantageous to combine the new "targeted" drugs with other types of cancer drugs. So far, only cell-based functional profiling has demonstrated this critical ability.

Not only is this an important predictive test, it is also a unique tool that can help to identify newer and better drugs, evaluate promising drug combinations, and serve as a "gold standard" correlative model with which to develop new DNA, RNA, and protein-based tests that better predict for drug activity.

Genomic testing is not the answer, without cell "function" analysis. Functional tumor cell profiling has its own very sophisticted program to discover gene expression microarrays which predict for responsiveness to drug therapy. The way to identify informative gene expression patterns is to have a gold standard and that cell-based functional profiling assays are by far the most powerful, efficient, useful gold standard to have. It grasps the potential value of the assays today to individualize therapy.

And then you come to the 1,000 pound gorilla of a question: What effect will the different individual drugs have in combination in different, individual tumors? This is where cell-based functional profiling assays will always be able to provide uniquely valuable information. But it's not one versus the other. The best thing is to combine these different tests in ways which make the most sense. One month's worth of herceptin + avastin costs $8000. That's without any docetaxel and blood cell growth factors and anti-emetics. If nothing else, we can't afford too much trial and error treatment.

There are hundreds of different therapeutic drug regimens which any one or in combination can help cancer patients. The system is overloaded with drugs and underloaded with the wisdom and expertise for using them. We have produced an entire generation of investigators in clinical oncology who believe that the only valid form of clinical research is to perform "well-designed," prospective, randomized trials in which patients are randomized to receive one empiric drug combination versus another empiric drug combination.

The problem is not with using the prospective, randomized trial as a research instrument. The problem comes from applying this time and resource-consuming instrument to address hypotheses of trivial importance (do most cancers prefer Coke or Pepsi?). The failure of 30 years' worth of clinical trials research into "one-size-fits-all" therapy will eventually force a consideration of new approaches. All the more reason to "test the tumor" first - properly.
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