Oncologic In Vitro Chemoresponse Assays

[gpawelski]

Patients, physicians, insurance carriers, and the FDA are all calling for predictive tests that allow for rational and cost-effective use of chemotherapeutic drugs. Given the technical and conceptual advantages of Cell Culture Assays together with their performance and the modest efficicay of therapy prediction on analysis of genome expression, there is reason for a renewal in the interest for these assays for optimized use of medical treatment of malignant disease.

Researchers have seen that whether a tumor was a breast tumor, prostate tumor, lung tumor or lymphoma, it didn't correlate to how the cancers interacted with standard anticancer drugs. Their findings suggest that traditional cancer treatments, which have established different drug regimens for brain, prostate, lymphoma or ovarian cancer, for example, should be replaced with therapies that use drugs deemed to be of highest benefit based on the tumor's pharmacologic profile. Treatment choice would be determined by how each patient's tumor reacts to anticancer drugs, regardless of the tumor's anatomical origin.

The drug effect is independent of where the tumor came from in the body. Under current treatment selection methods virtually no chemotherapeutic drug has been successful in more than 50 percent of patients with advanced cancer. But instead of considering a drug that works only ten percent of the time a failure, it would be better to consider such a drug effective for one in ten tumors and to search for the agents among the current arsenal of chemotherapeutic drugs that will work for the rest. Having a good tumor-drug match not only would improve survival rates, it would be cost-effective, and the high cost of the newer cancer therapies reinforces the necessity of choosing the right therapy the first time around.

Conventionally, oncologists make chemotherapy treatment recommendations on the basis of published reports of clinical trials and a patient's health status and treatment preferences in choosing chemotherapy regimens. But the statistical results of these population-based studies might not apply to an individual. For many cancers, more than one standard treatment exists. Physicians select drugs based on their personal experience, possible side effects and the patient's condition, among other factors. However, the system is overloaded with drugs and underloaded with wisdom and expertise for using them.

In patients with cancer, it is often difficult to select an effective treatment because the tumor develops resistance to many drugs. Currently, physicians select an empirically-selected drug and must wait about six months to see whether it is effective on a particular patient. For many cancers, especially after a relapse or when a particular treatment is ineffective, more than one standard treatment exists.

A chemo-induced gene mutation can happen when the original chemo received does not work. The cancer comes back. When it does this, the cancer comes back more aggressively. The mutagenic effects (changes in form) of chemotherapy on a genetically-unstable tumor, drives the tumor into a state of more aggressive behavior. You might kill off a whole lot of cancer, only to cause a mutation in the remaining cancer, such that the remaining cancer behaves in a more aggressive fashion.

Cancers that are a product of these genetic mutations release cells from the usual controls of proliferation and survival, making them so much harder to fight it. Following this mutation, the cancer cells acquire the ability to proliferate without the normal restraints. As the cancer grows, it may infiltrate and destroy the surrounding tissue, and metastasize by penetrating into blood vessels, lymph nodes, and body cavities. Distant metastasis via the bloodstream may affect virtually any organ (the lungs, bones, liver, adrenals, and even the brain).

There are patients who have progressive disease after first-line therapy, only to enjoy a dramatic benefit from second or even third line therapy, and these patients would have been much better served by receiving the most probable active treatment the first time around. By utilizing cell culture assays, oncologists can choose the treatment which is most likely to work or that is what their patients want.

With cell culture assays, 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.

Cell culture assays are 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. These assays 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 cell culture 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. However, some assays 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.

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. 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 narrow indication. But these drugs may have many useful applications, and a cell culture assay offers a way of seeing if any of these new drugs might apply to your specific cancer.

A cell culture 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.

In studies, patients treated with drugs "active" in the assays had a higher response rate than the entire group of patients as a whole. Patients treated with drugs "inactive" in the assays had lower response rates than the entire group of patients. 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.

Both fluid and solid tumor (200mg or 10mm in size) 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. Some private laboratories have been offering these assays as a non-investigational, paid service to cancer patients, the average cost being about $2,000, in a situation where 20 different drugs and combinations are tested, at two drug concentrations in three different assay systems.

Assay-tests could be performed from ovarian cancer cells in pleural fluid (fluid from the cavity that surrounds the lungs) which is evidence of Stage IV ovarian cancer, or from Ascites (an abnormal accumulation of fluid in the abdomen), and of course lymph nodes. The labs will provide you and your physician with in depth information and research on the testing they provide.

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.

These cell culture assays are not intended to be scale models of chemotherapy in the patient, anymore than the barometric pressure is a scale model of the weather. But it's always more likely to rain when the barometer is falling than when it is rising, and chemotherapy is more likely to work in the patient when it kills the patient's cancer cells in the laboratory. It is no different than any other medical test in this regard.

These tests have been extensively validated for "accuracy," without any controversy whatsoever. In more than 40 peer-reviewed publications, in a wide range of human tumors, ranging from acute and chronic leukemia to ovarian and breast cancer, patients treated with drugs which were active in the assays were more likely to respond to treatment than the group as a whole and dramatically more likely to respond to treatment than patients treated with drugs which were not active in the assays, with there being a 7 to 9 fold advantage to treatment with assay "positive" drugs, compared to assay "negative" drugs. In a number of studies, patients treated with assay "positive" drugs enjoyed significant survival advantages, as well.

The criteria always used to evaluate medical tests is the "accuracy" of the tests and not the "efficacy" of the tests. There is no single test (laboratory or radiographic or anything else) used in cancer which has been proven to be "efficacious" in prospective randomized trials, where patients are managed with and without the benefit of the information provided by the tests, and treatment outcomes compared. The only information which has ever been obtain is how accurate the tests are, and the accuracy of the cell culture assays compares favorably with that of other similar tests used in cancer medicine. Critics of the testing are demanding a standard of proof which is truly unprecedented, and which has not been met by all of the other tests used in cancer medicine.

The test is showing the "effaciousness" of a particular drug, the test itself doesn't have to show it is "effacious." It just has to show it is "accurate" to standards set by the FDA. Most of the cancer treatments used have not met the standard of proof demanded of a cell culture assay, which is a test and not a treatment. The degree to which "standard" cancer chemotherapy has been "proven" to be more efficacious than other forms of treatment has been overstated, overassumed, and over-sold.

Having some foreknowledge of a given chemo agent's expected result before its administration would benefit the individual patient. The cost of drugs is enormous. Patients are followed with serial CT scans, MRI's and even Pet Scans, just to see if a tumor is growing or shrinking. Not to mention the hospitalizations for toxicity, bone marrow tranfusions, etc. The point is, the cost of ineffective therapy is truly enormous and all cell culture assays are particularly good at identifying ineffective therapy, and some are good at identifying effective therapy. The biggest criticism of cell culture assays is its standard for proving its value - improving overall survival.

http://weisenthalcancer.com/Patient%20P ... kFacts.htm

[gpawelski]

Good review papers exist on cell culture assays and are increasingly appreciated, understood and applied by the private sector and European clinicans and scientists. The literature on these assays have not been understood by many NCI investigators and by NCI-funded university investigators, because their knowledge was almost always geared towards an assay technique (cell-growth) that hasnt' been used in private labs for over fifteen years now.

NCI studies never determine if "fresh" tumor assays worked. All of the considerable literature which supports the use of these assays in patient management has been based on true "fresh" tumor (non-passaged) cell assays.

Some years ago, NCI made an attempt to study "assay-directed" therapy of lung cancer. The study was a failure because it was done with established permanent cell lines (instead of fresh cells), which have been conclusively proven to have no predictive value at all with respect to the clinical activity spectrum. The result was a dismal 11% response.

The NCI used "cell lines" because the major expertise of the investigators who carried out any study was in the creation of cancer cell lines, and they wanted to see if they could perform assays on these cell lines to use in patient therapy. The results showed they were able to test successfully only 22% of specimens received, including only 7% of primary lesions.

This contrasts with a 75% overall success rate reported by earlier investigators who used the same assay system in "fresh" tumor and a routinely obtained >95% success rate using improved (cell death) methods available today.

The NCI spent $15 million on a single-cell suspension "fresh" tumor assay with cell proliferation (cell growth) rather than cell death as an endpoint. When that didn't work, they folded their hand and specifically discouraged future applications of cell culture testing in their grant and contract guidelines, dating from the late 1980's. They never supported any drug development work based on primary cultures of three dimensional cell clusters with cell death endpoints, which very nicely recapitulate known disease specific activity endpoints.

Then later, there were sophisticated programs to discover gene expression microarrays which predict for responsiveness to drug therapy. The NCI has a huge lab working on microarrays to look for patterns of mRNA and protein expression which are predictive of chemotherapy response. They spent 2 years trying to find patterns which correlated using the NCI's various established ovarian "cell lines."

They thought they had something, but when they started to apply them to "fresh" tumor specimens, none of the results in the "cell lines" was applicable to the "fresh" tumors. Everything they worked out in the "cell lines" was not worth anything and they had to start over from square one.

However, the limitations and non-applicability of the NCI efforts, failed to realize that the way to identify informative gene expression patterns is to have a "gold standard" and the (cell-death) cell culture assays are by far the most powerful, efficient, useful "gold standard" to have, adding the potential value of the assays to individualize cancer therapy.

It was routine for the NCI to append statements to grant and contract initiative announcements that applications relating to cell culture assays were strongly discouraged. Dan Von Hoff published a paper around 1990 in which he stated that clinical trials of cell culture assays would never be supported. And the cooperative groups have utterly refused to do the studies. Why should they? Five times as much work for much less (financial) reward.

There was an enormous amount of published, peer-reviewed research documenting the "accuracy" of cell culture assays. Scores of studies in thousands of patients. Based on both response and survival, but all of it excluded from the ASCO and insurance industry reviews. And it's the only evidence existing to validate any other medical test used as an aid in drug selection.

Disallow the introduction of published, peer-reviewed evidence documenting accuracy. While allowing the introduction of hearsay, unstated, undocumented, undescribed, unpublished, unpeer-reviewed non-evidence.

And the fact that "proving" efficacy in one situation would do nothing to prove efficacy in any other situation. This is why the FDA demands clinical trials data showing efficacy for each and every indication relating to drugs.

Let's say a plan assay-directed clinical trial in relapsed NSCLC proves efficacy. All we prove is that it improves things for one small indication. Relapsed NSCLC, not ovarian cancer. And it gets worse. The year after the close of the study, two new drugs become available and the assay-directed clinical study only proves efficacy with the old drugs. It doesn't prove efficacy involving the new and improved drugs. A constantly moving target. So then you say, just go out and get a grant to do another one.

[gpawelski]

Recent findings presented at the ASCO GI cancer meetings in Orlando, FL concluded that Functional Profiling (whole cell profiling) with cell culture assays is relevant for the study of both traditional and targeted antineoplastic agents.

Functional profiling with cell culture assays for targeted drug therapy

Recent findings presented at the ASCO GI cancer meetings in Orlando, FL concluded that Functional Profiling (whole cell profiling) with cell culture assays is relevant for the study of both traditional and targeted antineoplastic agents.

Functional profiling (FP) with cell culture assays for targeted drug therapy.

Sub-category: Translational research

Category: Colon and Rectum

Meeting: 2007 Gastrointestinal Cancers Symposium

Abstract No: 440

Author(s): L. M. Weisenthal

Abstract: Introduction: We studied the relevance of FP for standard and targeted drugs.

Methods: Drugs were tested against fresh human tumor microclusters, with 96 hr drug exposures and multiple FP endpoints (MTT, DISC, resazurin, and/or ATP).

Results: In 65 previously chemonaive stage 4 colon cancer patients, those with FP assays showing 5FU results in the most resistant tertile had inferior overall survival, compared to pts without 5FU resistance (303 days vs. 686 days, H.R. 2.1, 95% C.I. 1.2 - 5.0, P2=0.011). In subset analysis restricted only to 53 pts who subsequently died (eliminating potential surgical cures), the respective results were 292 vs 493 days, HR 1.5 - 6.9, P2=0.0021. We applied FP to test targeted agents, including gefitinib, erlotinib, sunitinib, sorafenib, and bevacizumab. Gefitinib was tested against > 700 fresh tumor specimens; we reported striking correlations between gefitinib activity and overall pt survival in non-small lung cancer (2006 ASCO Annu Mtg, Abst 17117). Gefitinib and erlotinib are moderately cross resistant (R2=0.48, n paired comparisons=190). Gefitinib/sunitinib (R2=0.20, n=46) and erlotinib/sunitinib (R2=0.12, n=44) are largely non-cross resistant. We also developed a new microvascular viability assay (MVVA) to test microvascular cells present in tumor clusters. In the MVVA, bevacizumab was tested in 81 fresh tumor specimens (including 15 GI). Bevacizumab was nontoxic to the tumor cells, but often strikingly toxic to microvascular cells present within the same tumor clusters. Grading on a 0-4 scale, there was absent (Gr 0) effect in 23 specimens, weak (Gr 1-2) effect in 28, and a strong (Gr 3-4) effect in 26. In contrast to bevacizumab, neither sunitinib (n=87) nor sorafenib (n=20) showed selective effects against microvascular cells compared to tumor cells.

Conclusions: We cannot rule out a cytostatic effect of sunitinib or sorafenib on tumor microvascular cells. However, our results imply that the antitumor effects of bevacizumab are predominately mediated through antimicrovascular effects, while effects of sunitinib and sorafenib may be mediated largely through tumor cell apoptosis. We conclude that FP is relevant for the study of both traditional and targeted antineoplastic agents.

http://breastca.asco.org/portal/site/AS ... ctID=10630

[gpawelski]

It must be realized that cell culture assays are complex procedures, fraught with the potential for error and misinterpretation. The results are only meaningful to the extent that the laboratory in question is experienced and diligent in its quality assurance practices. A patient interested in this testing should not hesitate to ask specific questions and to require specific answers of the laboratories under consideration.

The "extreme drug resistance" (EDR) method of cell culture assay testing uses "cell proliferation" (cell growth) as the endpoint of testing. This method cultures tumor cells in the presence of single chemotherapy drugs and observes in the presence of a very high (extreme) dosage which drugs prevent the tumor cells from growing. In numerous cases, a report generated by this method can show drugs that best prevented the "growth" of tumor can be the same drugs that failed in previous chemotherapy. This type of assay method would not provide clinically useful information (other than to know why previous drugs failed - they were resistant to the tumor). The EDR assay is not useful for the purpose of identifying "effective" treatment regimens.

The other method of cell culture assay testing uses "cell death" (apoptosis) as the endpoint of testing. The test exposes tumor cells to chemotherapy drugs and observes which drugs actually "killed" tumor cells. It can identify which combination of drugs that are able to "kill" tumor cells in the laboratory. Cell death assays are better at getting more useful information -- namely: (1) higher evaluability rates, (2) more drugs tested per specimens, (3) multiple drug concentrations tested using multiple complementary endpoints, and (4) more extensive clinical validation of assay results. 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." Cell-death assays correlate very well with each other on direct comparisions of different methods.

Different Types of Cell-Death Assays

The TCR Assay

ChemoFX Assay

The MiCK Assay

HDRA Assay

EVA Assay

DiSC Assay

MTT Assay

ATP Assay

Fluorescein Diacetate Assay

Cell death assays focus more on the discrimination between a relatively lower probability of response on one hand and a relatively higher response on the other hand. Basically, identify each and every drug as being either "good prognosis," "poor prognosis," or "average prognosis," with the advantage of a good prognosis over a poor prognosis drug as being (on average) 7:1, meaning a good prognosis drug is 7 times as likely to work as a poor prognosis drug. Results used in a "positive" way to "select" the drugs most likely to work.

A "fresh" sample tumor can be obtain from surgery or biopsy (Tru-cut needle biopsies). Tissue, blood, bone marrow, and ascites and pleural effusinos are possibilities, providing tumor cells are present, and only live cells can be used. At least one gram of fresh biopsy tissue is needed to perfom the tests, and a special kit must be gotten in advance from the lab. Arrangements have to be made with the surgeon and/or pathologist for preparation and sending of the specimen.

Upgrading clinical therapy by using drug sensitivity assays measuring "cell death" of three dimensional microclusters of live "fresh" tumor cells, can improve the conventional situation by allowing more drugs to be considered. Drug sensitivity tests support the idea that a marginal benefit in terms of overall survival is observed in cancer patients with normal prognoses, but there are marked survival benefits for cancer patients with poor prognoses.

The key to improving drug sensitivity tests is related to the number and types of drugs tested. The more anti-cancer drug types there are in the selective arsenal, the more likely the system is to prove beneficial. In order to acquire sufficient data, tumors should be tested with at least two assay endpoints, and most often three, for sensitivity tests in any one patient. On average, up to twenty drugs and combinations at two concentrations in three different assay systems, is an effective way to avoid false-positive or false-negative data. Careful choice of drug doses and administration intervals also improves outcomes.

Drug sensitivity assays do not harm patients in any way except in terms of cost. Every cancer patient should have his/her own unique chemotherapy trial based on consultation of pathogenic profiles and drug sensitivity testing data. Research and application of drug sensitivity assays are being encouraged by growing patient demands, scientific advances and medical ethics. Drug sensitivity tests are not a luxury but an absolute necessity, and a powerful strategy that cannot be overlooked. Having some foreknowledge of a given agent's expected result before its administration would benefit the individual patient.

[jcawork]

I know you have posted this before for us, but I don't think you understand our challenge.

Most of us if on the board, have already been dx. A biopsy has already been taken, is in slide form and its too late for us to get solid or liquid specimen to do this testing. Most of us would of course want this testing and a more targeted chemo.

Getting this info out to the crazed, upset, freaked out beginer who is just getting ready to have their biopsy would be the target audience. I have no idea how this group would get this info. When you first learn you have LC, but not specifically what kind because you have not had the biopsy yet would be the ideal time because you are making arrangements to get your biopsy etc....

Thats who needs this info.

Jen

[gpawelski]

Educating those who have the ears to listen is not always an easy task. Medicine is often so slow to change, it ends up taking creative and independent individuals to start the real changes. One needs to start somewhere, helping patients conceptualize cancer more accurately, so they could better understand the way to approach their choice of treatment regime.

[gpawelski]

Medicare Contractor Establishes Reimbursement Coverage Policy for Cell Culture Assay Tests

National Heritage Insurance Company (NHIC), the contractor that administers Medicare programs in California, has established a positive coverage policy for Cell Culture Assay Tests known as Chemosensitivity (Resistance) Testing or Oncologic In Vitro Chemoresponse Assays for a tumor specimen from a Medicare patient obtained anywhere within the United States, but submitted for testing by one of the approved laboratories located within Southern California. Medicare bills for this testing are billed through NHIC because the test is conducted by the approved laboratories in California.

This pre-test can help see what treatments have the best opportunity of being successful for "high" risk cancer patients. The test measures the response of "live" tumor cells to drug exposure. Following this exposure, the assays measure both cell metabolism and cell morphology (Functional Profiling). 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. Assays based on "cell-death" occur in the entire population of tumor cells.

This cell culture assay technology has been clinically validated for the selection of optimal chemotherapy regimens for individual patients. It is a laboratory analysis based on tumor tissue profiling that uses "fresh" human tumor biopsy or surgical specimen to determine which drugs or combinations of chemotherapeutic agents have the highest likelihood of response for individual cancer patients.

Following the collection of "fresh" tumor cells obtained from surgery or tru-cut needle biopsies, a cell culture assay is performed on the tumor sample to measure drug activity (sensitivity and resistance). This will pinpoint which drug(s) are most effective. Tissue, blood, bone marrow, and ascites and pleural effusions are possibilities, providing tumor cells are present. At least one gram of fresh tissue is needed to perform the tests, and a special kit is obtained in advance from the lab. The treatment program developed through this approach is known as assay-directed therapy.

Individualized assay-directed therapy is based on the premise that each patient's cancer cells are unique and therefore will respond differently to a given treatment. This is in stark contrast to standard or empiric therapy, which chemotherapy for a specific patient is based on average population studies from prior clinical trials.

The decision had been made that the assay is a perfectly appropriate medical service, worthy of coverage on a non-investigational basis. What is of particular significance is that they abandoned the artificial distinction between "resistance" testing and "sensitivity" testing and are providing coverage for the whole FDA-approved kit. Drug "sensitivity" testing is merely a point a little farther along on the very same continuum which "resistance" testing resides.

Cell cuture assay tests based on "cell-death" have proven very effective in identifying novel treatment combinations for a variety of cancers. The value of cell-death assays is that they can and do accurately predict clinical outcomes and define novel chemotherapeutic synergies. It 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).

The current clinical applications of in vitro chemosensitivity testing is ever more important with the influx of new "targeted" therapies. Given the technical and conceptual advantages of "functional profiling" of cell culture assays together with their performance and the modest efficacy for therapy prediction on analysis of genome expression, there is reason for renewed interest in these assays for optimized use of medical treatment of malignant disease.

The payment provided will be sufficiently realistic that all Medicare patients for whom this testing is indicated will be able to get it with only the routine 20% co-payment, as Medi-gap insurance secondaries are mandated to provide payment for co-pays for Medicare-approved services.

The 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/ar ... t_0107.htm

NHIC Medicare Services reimburses qualified laboratories in Southern California for cell culture assay tests on a Medicare patient anywhere in the United States.

Likewise, Highmark Medicare Services reimburses a qualified laboratory in Pennsylvania for cell culture assay tests on a Medicare patient anywhere in the United States.

NHIC has jurisdiction over Southern California, so that is who gets billed when the laboratory is located in California.

Highmark has jurisdiction over laboratories in Pennsylvania, so that is who gets billed when the laboratory is located in Pennsylvania.

The coverage decision is posted at:

http://www.highmarkmedicareservices.com ... 32007.html

[gpawelski]

It amazes me not only that some private insurance carriers don't like to pay for cell culture assay tests but that they don't emphatically mandate it as a requirement for obtaining chemotherapy reimbursement against ill-directed treatments.

The validation standard that private insurance companies is accepting from "molecular" profiling tests is "accuracy" and not "efficacy." The "bar" has been instantly lowered. No longer will it be essential to prove that the use of a diagnostic test improves clinical outcomes, all they have to do for these "molecular" profiling tests is prove that the test has a useful degree of "accuracy." However, at the same time, the validation standard they want for "cell-based" profiling tests is "efficacy."

The "cell-based" profiling tests have the same entitlement to be judged by the same validation standard as "molecular" profiling tests. The combination of measuring morphologic (structural) effects and metabolic (cell metabolism) effects constitutes measuring the "profile" at the whole cell level. It must be noted that both types of dignostic tests are just that, "tests" and not treatment.

Profit, as we have seen, is a powerful motivating force. Among the private payors, at least, the profit motive is entirely consistent with the goal of the test, which is to identify efficacious therapies irrespective of drug mark-up rates.

The evidence in support of these assays is more than sufficient to justify the funding of validation trials, if any more truly are needed, as claimed - speciously and self-servingly - by the medical establishment.

Everyone is scared to death - and rightly so - at what is going to happen to the healthcare economic system with the introduction of increasingly expensive new drugs that benefit only a small percentage of patients who receive them, hence the headlong rush to develop tests to identify molecular predisposing mechanisms whose presence still does not guarantee that a drug will be effective for an individual patient.

Nor can they, for any patient or even large group of patients, discriminate the potential for clinical activity among different agents of the same class, such as Sutent, Tarceva, Iressa, and Nexavar.

The FDA could benefit too, as they find themselves under increasing pressure to allow new drugs into marketplace while at the same time protecting the safety of potential recipients of those drugs as well as the financial interests of those who will have to pay for them.

It explains the new paradigm of requiring a companion diagnostic as a condition for approval of new targeted therapies. The pressure, in fact, is so great that the companion diagnostics they've approved often have been mostly or totally ineffective at identifying clinical responders (durable and otherwise) to the various therapies.

I think that in both of these areas - private insurance carriers and the FDA - there is a very real opportunity to make a substantial impact and contribution, an interest in saving the healthcare system perhaps billions of dollars a year (and thereby the healthcare system itself) by ensuring that expensive treatments are used appropriately.

Committee chairpersons, committee members and persons in congress who may have personal interests not only in discovering new cancer treatments - everybody wants that - but also, in the "here and now," using currently-available cell culture assay technologies to improve the effectiveness of existing drugs and save lives today by administering the right drug to the right patient at the right time.