Has anyone an opinion (or exprience with) on CCDRT test for chemo resistance [Archive]

Nguyen

03-01-2007, 09:34 PM

Back in 97 when my wife was first diagnosed, we used CCDRT with Dr. Weisenthal group. Unfortunately we used it after her first chemo combination, CAF, which did not work well. CCDRT predicted that CAF has 20% chance of working, and taxane or navelbine had 80% chance. Both turned out to be true in my wife case. There're data for other combinations as well.

The process was not difficult, although we didn't have a large chunk of tumour, so we couldn't test all combinations available at that time. Dr. Weisenthal was frank and easy to talk too. Wish I listened to him regarding to high dose chemo (HDC) with stem cell rescue. HDC data were bogus, falsified by a researcher.

Anyway, one can think of CCDRT as an "ultra high level gene test", yet more encompassing, since the chemo are tested directly against the whole of your tumour cells. Without restating both the fore/against arguments, I think if one approaches CCDRT by using the highest percentage combination first, then it'd be o.k. Additionally, where data (direct gene data predicting chemo effectiveness) are available, if one can correlate these data with CCDRT data, then more confident in both methods can be realized.

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Linda's treatment history:

01/2005 - current: Herceptin and Femara
07/2004: It returned again via several small nodules in the lung
10/2002: NED (via CT and CA27.29)!
10/2001 - 01/2005: Femara, (Fosamax)
12/2000 - 10/2001: Herceptin and Navelbine
12/2000: lung metastatic was diagnosed (a few small nodules)
02/1998 - 12/2000: Daily Tamoxifen
05/1997 - 04/1998: Modified Radical Mastectomy, many many cycles of chemo regiments (CAF,Taxol, Carpoplatin, Thiotepa, Navelbine, Taxotere), including HDC, and radiation
05/1997: First diagnosed with BC stage 3A (7cm 9/13 nodes) , ER+, PR+, HER2 +, poorly differetiated, nuclear grade 3.

gdpawel

11-15-2007, 10:34 AM

The Weisenthal Cancer Group has finally developed a website for patient communications relating to its clinical services (The Human Tumor Assay Journal site is the more arcane science version).

http://weisenthalcancer.com/index.htm (http://weisenthalcancer.com/index.htm)

The Q/A link is now at Quick Facts:

http://weisenthalcancer.com/Patient%20Pages/QuickFacts.htm (http://weisenthalcancer.com/Patient%20Pages/QuickFacts.htm)

CCDRT (aka Functional Tumor Cell Profiling) is the name of the FDA-approved kit for the cell culture assay. The current status of Cell Culture Drug Resistance Testing (Functional Tumor Cell Profiling):

http://weisenthalcancer.com/Shared%20Pages/current_status_of_cell_culture_d.htm (http://weisenthalcancer.com/Shared%20Pages/current_status_of_cell_culture_d.htm)

The Medicare coverage became effective for claims for services performed on or after February 19, 2007. The decision is posted at:

http://www.medicarenhic.com/cal_prov/articles/chemoassaytest_0107.htm

At one time, the goal of cancer treatment was to inhibit unregulated cell "growth." In the last fifteen years, to goal is to induce cell "death" in order to successfully conquer cancer. The much older "cell-growth" assays measure a drug's ability to inhibit cell "growth" and only succeeds in eliminating drugs that would "not work" for a patient. The more modern "cell-death" assays measure the ability of chemotherapy drugs to induce cell death (apoptosis) in a tumor biopsy from a patient.

The (EDR) cell-growth assay is much less useful than are the various cell-death assays for the purpose of identifying effective treatment regimens. It doesn't mean that the information provided by the EDR assay is not helpful, it's that there are better ways of getting more useful information like higher evaluability rates, more drugs tested per specimens, multiple drug concentrations tested, and more extensive clinical validation of assay results.

In other words, the EDR cannot "accurately" predict for drug "sensitivity." This kind of assay is specifically designed to identify "inactive" drugs and should not be used to identify "active" drugs. Assays based on "cell-death" occur in the entire population of tumor cells, as opposed to only in a small fraction of the tumor cells occurring in "cell-growth" assays. The various "cell-death" assays correlate very well with each other on direct comparisions of different methods.

The EDR assay is performed by "growing" a portion of the cancer tumor in the presence of different chemotherapy drugs in the laboratory. If cancer cells grow in the presence of a very high (extreme) dosage of a chemotherapy drug, the cancer is unlikely to respond to that drug in the patient's body. By eliminating "inactive" drugs from the therapy regimen, use of the EDR assay avoids exposing patients to the toxicity of those drugs that are "unlikely" to be effective in treating the tumor.

The Medicare reimbursable "cell-death" assays are not growing anything. They are testing a drug or combinations of drugs with cells that are in their natural state (live or fresh). Three dimensional tumor cell clusters. Clusters maintain natural cell-cell interactions.

When the decision is made to treat a patient with chemotherapy, most patients are treated with a "combination" of drugs. When correlating various "cell-death" assays, the "whole cell" is profiled, assessing the activity of a drug (or combination) upon combined effect of "all" cellular processes, using several metabolic and morphologic endpoints. This is more important than using tests which identify DNA or RNA sequences or gene expression of individual proteins that 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 (like Herceptin and Avastin) with other types of cancer drugs. So far, only functional profiling with "cell-death" assays has demonstrated this critical ability. Tests indicating that a tumor culture is "sensitive" to a particular agent do not guarantee clinical effectiveness, but it substantially increases the likelihood that the agent will be beneficial.

A personalized treatment plan would be cheaper than the conventional (empiric) treatment protocol. Treating a patient with a drug (or combination) that is most beneficial (sensitive), the first time around, eliminating most or all of the meds to manage side effects, and eliminating drugs that would be "resistant" to the cancer cells. This can spare the patient from unnecessary toxicity associated with ineffective treatment and offers a better chance of tumor response resulting in progression-free and overall survival.

Chemosensitivity vs Chemoresistance

A published study in ovarian cancer raised the question of the distinction between "chemosensitivity" and "chemoresistance" (drug resistance). The distinctions are largely semantic and not of useful clinical relevance. Resistance is the relative absence of sensitivity and sensitivity is the relative absence of resistance.

The Matsuo, et al study (Int J Cancer. 2009 Dec 1;125(11):2721-7) and another study presented at the 2009 ASCO meeting (J Clin Oncol 27:15s, 2009 suppl; abstr 5504) showed no useful correlation between the "extreme drug resistance" (cell-growth assay) endpoint and any clinical outcome in ovarian cancer. While the Matsuo, et al study showed highly significant correlations between the chemosensitive (cell-death assay) endpoint and both progression-free and overall survival.

Several things are evident:

1. In all individual studies, patients treated with drugs classified as “sensitive” had a higher response rate than that for all the patients in each individual study.

2. In all individual studies, patients treated with drugs classified as “resistant” had a lower response rate than that for all the patients in each individual study.

3. In all individual studies, patients treated with drugs classified as “sensitive” had a "much" higher response rate than for patients treated with drugs classified as “resistant.”

4. Averaging up all of the studies, patients treated with drugs classified as “sensitive” had an 8-fold higher response rate than patients treated with drugs classified as “resistant.”

All of the above data point to the fact that differences between “chemosensitivity” and “chemoresistance” are entirely semantic and that the proper role for these assays is to direct attention towards agents in the “sensitive” (“low resistance”) group and away from agents in the “resistant” (“low sensitivity” group).

When clinically relevant and accepted drugs may have the same efficicay, and a tumor is "resistant" to one of them, it is within the standard of care to give the drug with the least "resistance" and/or the drug with the most "sensitivity."

My personal belief is in having additional support of drug patient-specific activity as determined by extensive laboratory pre-tests to bolster the clinical justification of the drug(s) chosen, with no economic ties to outside healthcare organizations; recommendations made without financial or scientific prejudice.

http://www.ncbi.nlm.nih.gov/pubmed/19530239?ordinalpos=19&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum

http://www.asco.org/ASCOv2/Meetings/Abstracts?&vmview=abst_detail_view&confID=65&abstractID=32065