As we enter the era of "personalized" medicine, it is time to take a fresh look at how we evaluate treatments for cancer patients. More emphasis should be put on matching treatment to the patient. Patients would certainly have a better chance of success had their cancer been chemo-sensitive rather than chemo-resistant, where it is more apparent that chemotherapy improves the survival of patients, and where identifying the most effective chemotherapy would be more likely to improve survival.
Findings presented at the 41st Annual Meeting of the European Society for Clinical Investigation in Uppsala, Sweden, April 18, 2007, concluded that "functional profiling" with cell culture assays is relevant for the study of both "conventional" and "targeted" anti-neoplastic drug agents (anti-tumor and anti-angiogenic activity of Iressa, Tarceva, Sutent, Nexavar, and Avastin in primary cultures of "fresh" human tumors).
Cell Culture Assays with "cell-death" endpoints can show disease-specific drug activity, are useful clinical and research tools for "conventional" and "targeted" drugs, and provide unique information complementary to that provided by "molecular" tests. There have been more than 25 peer-reviewed publications showing significant correlations between cell-death assay results and patient response and survival.
Many patients are treated not only with a "targeted" therapy drug like Tarceva, Avastin, or Iressa, but with a combination of chemotherapy drugs. Therefore, existing DNA or RNA sequences or expression of individual proteins often examine only one compenent of a much larger, interactive process. The oncologist might need to administer several chemotherapy drugs at varying doses because tumor cells express survival factors with a wide degree of individual cell variability.
There is a tactic of using biopsied cells to predict which cancer treatments will work best for the patient, by taking pieces of live "fresh" tumor tissue, applying different chemotherapy treatments to it, and examining the results to see which drug or combination of drugs does the best job killing the tumor cells. A cell culture assay test with "functional profiling," using a cell-death endpoint, can help see what treatments will not have the best opportunity of being successful (resistant) and identify drugs that have the best opportunity of being successful (sensitive).
"Funtional profiling" measures the response of the tumor cells to drug exposure. Following this exposure, they measure both cell metabolism and cell morphology. The integrated effect of the drugs on the whole cell, resulting in a cellular response to the drug, measuring the interaction of the entire genome. No matter which genes are being affected, "functional profiling" is measuring them through the surrogate of measuring if the cell is alive or dead.
For example, the epidermal growth factor receptor (EGFR) is a protein on the surface of a cell. EGFR-inhibiting drugs certainly do target specific genes, but even knowing what genes the drugs target doesn't tell you the whole story. Both Iressa and Tarceva target EGFR protein-tyrosine kinases. But all the EGFR mutation or amplificaton studies can tell us is whether or not the cells are potentially susceptible to this mechanism of attack. They don't tell you if Iressa is better or worse than Tarceva or other drugs which may target this. There are differences. The drugs have to get inside the cells in order to target anything. So, in different tumors, either Iressa or Tarceva might get in better or worse than the other. And the drugs may also be inactivated at different rates, also contributing to sensitivity versus resistance.
As an example of this testing, researchers have tested how well a pancreatic cancer patient can be treated successfully with a combination of drugs commonly used to fight lung, pancreatic, breast, and colorectal cancers. The pre-test can report prospectively to a physician specifically which chemotherapy agent would benefit a cancer patient. Drug sensitivity profiles differ significantly among cancer patients even when diagnosed with the same cancer.
The "funtional profiling" technique makes the statistically significant association between prospectively reported test results and patient survival. It can correlate test results that are obtained in the lab and reported to physicians prior to patient treatment, with significantly longer or shorter overall patient survival depending upon whether the drug was found to be effective or ineffective at killing the patient's tumor cells in the laboratory.
This could help solve the problem of knowing which patients can tolerate costly new treatments and their harmful side effects. These "smart" drugs are a really exciting element of cancer medicine, but do not work for everyone, and a test to determine the efficacy of these drugs in a patient could be the first crucial step in personalizing treatment to the individual.
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According to a study by Dr. Holly Gallion, published in the International Journal of Gynecological Cancer (IJGC) researchers using the Chemo FX Assay by Precision Therapeutics, identified which chemo agent would be most lethal to an individual patient's cancer. In the study of 256 women with recurrent ovarian cancer, the time women went before a worsening of their disease was two to three times longer if they were treated with an assay-sensitive drug compared to an assay-resistant drug. The bottom line is the assay is able to predict the patient's response to treatment. The Chemo FX is a (cell-death) assay test. Their study adds to the already large body of evidence of the accuracy of cell culture assays in ovarian cancer.
The assay determines which agents are most potent against a specific tumor and what concentration works best. No more hit or miss in the patient. Armed with that information, the treating physician and patient can proceed with a chemo regimen likely to work right out of the gate and subjecting the patient to less toxicity. If the assay finds that the tumor responds to none of the currently avialable treatments, a patient could then be referred to a clinical trial before a history of less useful treatments rules her out as a clinical trial candidate.
In light of the precious little in the way of guidance from clinical trials with respect to best empiric treatment, oncologists give treatments knowing full well that only a certain percentage of patients will receive a benefit from any given medicine. They subject patients to one combination chemotherapy after another, just going from one journal paper to another journal paper. They need information about the characteristics that predict which patients are more likely to respond well. The empirical approach, which is based on medical journal articles, epidemiology and economics, doesn't tell doctors how to personalize their care to individual patients. Physicians' decisions need to be based on personal experience, clinical insights, and medical training.
Cell culture assay measures the net effect of all processes within the cancer, acting with and against each other in real time, and it tests living cells actually exposed to drugs and drug combinations of interest. Tens of thousands of individual patient specimens are currently being submitted for testing by more than 1,000 clinical oncologists, surgeons and pathologists annually in the U.S. It is certainly each practitioner's prerogative to order these tests. It seems probable that a self-educated oncologist, genuinely on the cutting-edge would tend to be aggressive in actual treatment beyond mere rhetoric, and make use of running tests on a "fresh" tumor specimen before selecting a chemotherapy option.
Gallion, H. H., W. A. Christopherson, et al. (Jan/Feb 2006). "Relationship between ex vivo chemosensitivity assay and progression free interval in ovarian cancer." International Journal of Gynecological Cancer
PubMed lists a paper that reports an increase from 35% to 65% response rate for recurrent ovarian cancer patients when cell culture assay tests were used to select the chemotherapy drugs. The P values (P=.005, etc.) given are measures of the statistical significance of the findings. The smaller the number, the higher the statistical significance. "P" refers to the probability that the finding is due to random chance. So, high P values are bad. P values of 5% or less are deemed to be statistically significant. All of the P values reported in this study indicate that the results are, indeeed, statistically significant.
(Am J Obstet Gynecol. 2003 Nov;189(5):1301-7)
Every month, Cancer Monthly summarizes the latest clinical results of cancer therapies presented by oncologists, researchers, and other cancer professionals working in over 340 hospitals and research institutions around the world. With this information, patients can compare treatments, have more meaningful discussions with their doctors, and ultimately, make more informed treatment decisions.
A simple lab test that could customize chemotherapy to the patient and save lives. When science takes a back seat: public posturing, private bargains, and scandal, set in the cancer industry.
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Privately, as a student of Cell Function Analysis, I can say the "science" in this book is very real.
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