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Chemosensitivity testing- found this while searching for a cost

Posts: 295
Joined: Apr 2010

January 20, 2005 - 3:21am
Chemotherapy Sensitivity and Resistance Assays

When a patient has an infection, doctors often send a sample of infected blood or tissue to a lab where they can grow the bacteria and see which antibiotics are most effective (called Bacterial Culture and Sensitivity Testing). Chemosensitivity testing is an attempt to do something similar for cancer; fresh samples of the patient's tumor from surgery or a biopsy are grown in test tubes and tested with various drugs. Drugs that are most effective in killing the cultured cells are recommended for treatment. It is highly desirable to know what drugs are effective against your particular cancer cells before highly-toxic agents are systemically administered to your body.

One approach to individualizing patient therapy is chemosensitivity testing. Chemosensitivity assay is a laboratory test that determines how effective specific chemotherapy agents are against an individual patient's cancer cells. Often, results are obtained before the patient begins treatment. This kind of testing can assist in individualizing cancer therapy by providing information about the likely response of an individual patient's tumor to proposed therapy. Chemosensitivity testing may have utility at the time of initial therapy, and in instances of severe drug hypersensitivity, failed therapy, recurrent disease, and metastatic disease, by providing assistance in selecting optimal chemotherapy regimens.

All available chemosensitivity assays are able to report drug 'resistance' information. Resistance implies that when a patient's cancer cells are exposed to a particular chemotherapy agent in the laboratory, the cancer cells will continue to live and grow. Some chemosensitivity assays also are able to report drug 'sensitivity' information. Sensitivity implies that when a patient's cancer cells are treated with a particular chemotherapy agent in the laboratory, that agent will kill the cancer cells or inhibit their proliferation.

The goal of all chemosensitivity tests is to determine the response of a patient's cancer cells to proposed chemotherapy agents. Knowing which chemotherapy agents the patient's cancer cells are resistant to is important. Then, these options can be eliminated, thereby avoiding the toxicity of ineffective agents. In addition, some chemosensitivity assays predict tumor cell sensitivity, or which agent would be most effective. Choosing the most effective agent can help patients to avoid the physical, emotional, and financial costs of failed therapy and experience an increased quality of life.

Fresh samples of the patient's tumor from surgery or a biopsy are grown in test tubes and tested with various drugs. Drugs that are most effective in killing the cultured cells are recommended for treatment. Chemosensitivity testing does have predictive value, especially in predicting what 'won't' work. Patients who have been through several chemotherapy regimens and are running out of options might want to consider chemosensitivity testing. It might help you find the best option or save you from fruitless additional treatment. Today, chemosensitivity testing has progressed to the point where it is 85% - 90% effective.

Chemosensitivity testing might help you find the best option, or save you from fruitless additional treatment. Another situation where chemosensitivity testing might make particularly good sense is in rare cancers where there may not be enough experience or previous ideas of which drugs might be most effective.

Finally, there has been a veritable deluge of new approvals of cytotoxic drugs in recent years as the tortuous FDA process has been speeded and liberalized. In many cases a new drug has been approved on the basis of a single very very narrow indication. But these drugs may have many useful applications - and it's going to take years to find out. Chemosensitivity testing offers a way of seeing if any of these new drugs might apply to your specific cancer.

Another Name

Cell Culture Drug Resistance Testing (Chemotherapy Sensitivity and Resistance Assays) refers to laboratory testing of a patient's own cancer cells with drugs that may be used to treat the patient's cancer. A group of lab tests known as human tumor assay systems (HTAS) can aid oncologists in deciding which chemotherapies work best in battling an individual patient's form of cancer. The assay is a lab test performed on a biopsy specimen containing living cancer cells. It's used to determine the sensitivity or resistance of malignant cells to individual chemotherapy agents. Depending on how well the tumor cells respond to each chemotherapy agent, they are rated as sensitive, resistant or intermediate to chemotherapy. The concept is that you are better off using a chemotherapy drug that your tumor reacts to strongly than one your tumor resists.

There have been over 40 publications in peer-reviewed medical literature showing correlations between cell-death assay test results and the results of clinical chemotherapy in more than 2,000 patients. In every single study, patients treated with drugs active in the assays had a higher response rate than the entire group of patients as a whole. In every single study, patients treated with drugs inactive in the assays had lower response rates than the entire group of patients. In every single study, patients treated with active drugs were much more likely to respond than patients treated with inactive drugs, with assay-active drugs being 7 to 9 times more likely to work than assay-inactive drugs. A large number of peer-review publications also reported that patients treated with assay-tested 'active' drugs enjoyed significantly longer survival of cancer than patients with assay-tested 'negative' drugs.

How May a Patient Arrange to Have Their Tumor or Leukemia Tested?

Both fluid and solid tumor specimens may be sent out via Federal Express or another overnight courier service for testing at one of more than a dozen labs around the country. Note that the choice of a lab is not a geographical consideration, but a technical consideration. All of the labs are experienced and capable of providing very useful information. However, the labs vary considerably with regard to technologies, approach to testing, what they try to achieve with the testing, and cost. By investing a little time on the phone speaking with the lab directors, you should have enough knowledge to present the concept to the patient's own physician. At that point, the best thing is to ask the physician, as a courtesy to the patient, to speak on the phone with the director of the laboratory in which you are interested, so that everyone (patient, physician, and laboratory director) understand what is being considered, what is the rationale, and what are the data which support what is being considered.

Some Resistance

The fact that some doctors don't agree isn't stopping many cancer patients from taking this matter into their own hands, and sending their live path specimens off to one of the above private labs for assay-testing to be done. There has been much discussion about whether assay (in vitro) tests are of any use, as the in vivo response to a drug may very well be different in the body than in the petri dish. But, they said the same for Bacterial Culture and Sensitivity Testing. Doctors cannot remember a time when they didn't have this technology. It is a 'gold' standard. So will Chemosensitivity Testing.

Source: Human Tumor Assay Journal

Caregivers of Leukemia Patients ›

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Posts: 273
Joined: May 2001
April 25, 2006 - 10:12am
Re: Chemo Sensitivity and Resistance Assays
The traditional criteria ever used to evaluate laboratory tests has been the predictive 'accuracy' of the test.

None of the available laboratory tests used in the selection of treatments for cancer patients have ever been tested for 'efficacy'. This includes estrogen receptor, progesterone receptor, Her2/neu, immunohistochemical staining for tumor classification, bacterial culture and sensitivity testing, CT, MRI and FDG Pet Scans to measure tumor response to treatment.

There is no literature establishing clinical 'efficacy' of these laboratory tests, because the costs of such clinical trials are prohibitive, granting agency support is non-existent, and no other analogous tests have been or will likely ever be subjected to such an unreasonably high bar criterion for clinical use.

The only data supporting any of them relate to test 'accuracy', and there is a total lack of information regarding test 'efficacy'. (randomized trials with outcome measurements for diagnostic tests)

Also, no one is seriously proposing that any of the molecular tests now available (Oncotype DX, EGFR amplification/mutation) should have to be proven 'efficacious', as opposed to merely 'accurate', before they are used in clinical decisions regarding treatment selection.

The American Society of Clinical Oncology (ASCO) reviews of cell culture assay tests for establishing clinical 'efficacy' specifically excluded all studies reporting the predictive 'accuracy' of the tests. In other words, they excluded reports that only reported correlations between assay results and clinical outcomes.

Instead, ASCO reviews included old, previously-reviewed studies comparing outcomes of patients who had treatment based on assay results versus patients with empirically chosen therapy. The criteria of laboratory assay 'efficacy', as opposed to laboratory assay 'accuracy' sound reasonable, but it is unprecendented with regard to any other laboratory test ever evaluated.

Cell culture assay tests have been well proven to have predictive 'accuracy' with that of estrogen receptor, progesterone receptor, Her2/neu and the newer molecular tests. In light of the precious little in the way of guidance from clinical trials with respect to best empiric therapy (where the only thing that has been proven to correlate with treatment decisions is reimbursement to the prescribing oncologist) and the importance of basing cancer treatment at least in part on patient preferences, it is entirely reasonable to support judicious application of laboratory tests which have been well characterized with respect to test 'accuracy'. These are diagnostic tests and should be held to that criteria, and not to that of therapy.

These laboratory tests are a tool for the oncologist. The oncologist should take advantage of all the tools available to him/her to treat a patient. And since studies show that only 25-30% of patients do respond to chemotherapy that is available to them, there should be due consideration to looking at the advantage of human tissue assay tests to the resistance that has been found to chemotherapy drugs.

Cell culture drug resistance testing is for preventing use of known anti-cancer drugs that are not likely effective in the specific tumor. Cell culture drug sensitivity testing tries to determine specific drug and dose effectiveness. The distinction between sensitivity and resistance is more semantic than substantive.

In virtually all forms of cancer, clinical trials have failed to identify best drug regimens for use in all individuals with a given form of cancer.

Oncologists have been documented to use reimbursement (payment to the oncologist) as the most important criterion for selecting between the large array of otherwise equally acceptable regimens. (Jacobson, M.,O'Malley, A.J., Earle, C.C., et al. Health Affairs 25(2):437-443, 2006) & (Patterns of Care: 2005,Vol 2,Issue 1)

The established criterion on which to judge all laboratory tests used to help in the selection of cancer treatment is test 'accuracy' and not test 'efficacy'.

Cell culture assay tests with cell-death endpoints have been exceedingly and reproducibly well established to be usefully 'accurate' in correlation with and predicting for clinical outcomes, including tumor response and patient survival.

There should an expansion of Medicare and private insurance reimbursement to promote even greater utilization and development of laboratory-based mechanisms, like cell culture assays, for improving the match between tumors and an ever-increasing number of partially effective and very expensive drug therapies.

Posts: 295
Joined: Apr 2010

Chemo sensitivity testing
Has anyone asked their oncologist to have this testing done? I mentioned it at the last visit and wasn't sure it the doctor was going to follow through. He said out of the 4 patients who have requested it, only one came back.

WHAT? Why do I find it shocking that he has done this for only 4 people?
The nurse from the office called two days ago and said we would be responsible for the cost if the ins. will not pay for it. We have to go in and sign a paper before anything can be ordered. Fine.

Why am I annoyed by what to me is ignorance or lack of compassion? Let's do chemo and try the 'guess and check theory' in the meantime the immune system suffers and 'hopefully' the chemo is working.

I scheduled an appt. for my husband to see an integrative doctor on the 28 of this month. He doesn't specialize in cancer, but I hope he can give my husband some options other than more pills. I realize my husband may have to take chemo for a long time, but am hopeful there is a way to lessen the side effects.

chicoturner's picture
Posts: 285
Joined: Apr 2009

Is this not the same of similar to the testing for KRAS mutation genes? I know my onc had that test performed with samples of my tumor. It was determined that certain drugs would not effectively work for my colon cancer. I know many others on this site who have had this same testing. Thanks for the information. Jean

Posts: 295
Joined: Apr 2010

No, my husband was also tested for the KRAS gene and does not have it, therefore Erbitux should work. However if he exhausts other treatments, I'm hoping there will be more therapies out there that are effective. Erin

gdpawel's picture
Posts: 525
Joined: May 2001

Chemotherapy Sensitivity and Resistance Assays (now called Chemoresponse by the federal government) are not the same testing for KRAS mutation genes.

Molecular profiling, those which identify DNA or RNA sequences or expression of individual genes or proteins (like KRAS) often examine only one component of a much larger, interactive process. It may tell you whether or not the cells are "potentially" susceptible to one pathway of attack or anothers. It cannot tell you if one inhibiting drug (Erbitux in this case) is better or worse than another which may target the mutation.

Functional profiling (with a Chemorsponse assay) takes the advantage of looking at the entire cell to measure the interaction of the entire genome (not just one pathway or a couple of pathways). There are many pathways to altered cellular (forest) function (hence all the different "trees" which correlate in different situations). In functional profiling, the whole cell measures what happens at the end (the effects on the forest), rather than the status of the individual trees (genes or proteins).

Why Some Cancers Stop Responding to Erbitux

Epidermal Growth Factor (EGF) is a receptor on many normal tissues/cells, and also on many cancer cells. It is a growth hormone, locally secreted by cells. It attaches to a receptor on the cell membrane called Epidermal Growth Factor Receptor (EGFR). It then activates so-called signalling pathways within the cell, a cascade of biochemical events, including phosphorylation of proteins, leading to cell growth/proliferation/division. One type of an enzyme which is involved in the pathway which is involved in protein phosphorylation is called tyrosine kinase.

The monoclonal antibodies like Erbitux (cetuximab) are "enormous" molecules. These very large molecules don't have a convenient way of getting access to the large majority of cells. Plus, there is multicellular resistance, the drugs affecting only the cells on the outside may not kill these cells if they are in contact with cells on the inside, which are protected from the drug. The cells may pass small molecules back and forth.

Erbitux (cetuximab) is a "targeted" therapy, in that it halts the growth of certain cancers by zeroing in on a signaling molecule critical to the survival of those cancer cells. Although this "targeted" therapy is initially effective iin a subset of patients, the drug can eventually stop working, and the tumor begins to grow again.

This is called acquired or secondary resistance. This is different from primary resistance, which means that the drug never worked at all. The change of a single base in DNA that encodes the mutant EGFR protein has been shown to cause drug resistance. Drug resistance evolves by multiple mechanisms.

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

The report states, “We expected that patients with the genetic mutation would not respond to cetuximab, and that is what we found,” said Goldberg, who is also physician-in-chief of the N.C. Cancer Hospital. However, even the patients in the study whose tumors did not harbor the KRAS mutation did not benefit significantly from the combination therapy and the standard treatment proved to have the best results."

EGF-targeted drugs like Erbitux (cetuximab) are poorly-predicted by measuring the ostensible target (EGFR), but can be well-predicted by measuring the effect of the drugs on the function of "live" cells.

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

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CGP=Cancer Genome Project

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