ADDITIONAL INFORMATION REGARDING OVARIAN CANCER BY GREG PAWELSKI
Cell Culture Assay Technology
A genomic test can help to find out if a cancer patient will benefit from chemotherapy or not, and if they do (high risk patients), further pre-tests like cell culture assays can help see what treatments have the best opportunity of being successful. A cell culture assay measures the response of the tumor cells to drug exposure. Following this exposure, one of these assays measures both cell metabolism and cell morphology (Whole Cell 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.
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.
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.
ASCO's 2004 position paper focused on an older cell-growth assay method and not on a newer cell-death method, which is the most relevant biological measure. Their panel made no attempt to distinguish cell-death from cell-growth techniques. Their conclusions simply did not apply to cell-death assays. In fact, cell-death assay results have consistently correlated with response, time to progression, and overall survival.
The ASCO paper focused solely on a lack of prospective, randomized clinical trials proving superior outcomes with assay-directed therapy, a standard not met by ER/PR testing, HER2 protein or gene analysis, or any other clinical test in cancer medicine, and has seldom been met by even the eimpiric chemotherapy treatments supported by ASCO. Were they to apply the standard measure of predictive test accuracy, the results of their analysis would have been much different and in favor of the use of cell-death assays in clinical practice.
This omission was so significant that Medicare contractor, National Heritage Insurance Company (NHIC) which spent six months reviewing everything about the cell culture assay, including all of the ASCO arguments, and upon reviewing all available information, approved Medicare coverage for the tests as Oncologic in Vitro Chemoresponse Assays. They made the courageous decision to reverse trend and noted that the ASCO paper had failed the consider any of the many studies which support the predictive accuracy of cell death-based in vitro chemosensitivity testing.
As part of this favorable coverage decision, NHIC carefully documented the historical progression of Medicare policy dating from the "colony assays" of the 1970's to the noncoverage-National Coverage Decision regarding "stem cell" assays (1980), to the 1999 National Medicare Coverage Advisory Committee review, to the initial coverage by NHIC in the late 2000, to the present comprehensive review, culminating in this favorable Local Coverage Decision.
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 are finally abandoning the artificial distinction between "resistance" testing and "sensitivity" testing and are providing coverage for the whole FDA-approved kit.
Cell cuture assay tests based on cell-death have proven very effective in identifying novel treatment combinations for a variety of cancers. It is unfortunate that ASCO had not carried out studies to assess the value of cell-death assays, because they can and do accurately predict clinical outcomes and define novel chemotherapeutic synergies. In many cases, these same tests have induced highly durable remissions in patients whom current medical literature have deemed otherwise hopeless.
(Note) Medicare coverage is available for Chemosensitivity (Resistance) Testing 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 California.
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.
Fresh Tumor Cells
These cellular-based pre-tests can report prospectively to a physician specifically which chemotherapy agent would benefit a cancer patient by testing that patientās "live" cancer cells. One gets more accurate information when using intact RNA isolated from "fresh" tissue than from using degraded RNA, which is present in paraffin-fixed tissue.
A "fresh" sample tumor can be obtain from surgery or biopsy (Tru-cut needle biopsies). For newly diagnosed patients, the test is most reliable before a tumor has been exposed to chemotherapy. However, patients that have failed previous chemotherapy treatment, the test still can be done once a patient waits at least four weeks. A FDA-approved kit is obtained from the lab for the surgeon or pathologist.
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.
National Heritage Insurance Company found that even back in 1999, the Medicare Advisory Panel concluded that cell culture assay tests offered "clinical utility." After listening to detailed clinical evidence, the Medicare Coverage Advisory Committee (MCAC) found that these assay systems can aid physicians in deciding which chemotherapies work best in battling an individual patient's form of cancer.
MCAC's laboratory and diagnostic services panel heard presentations from experts regarding the clinical data associated with the assay systems. The panel questioned presenters carefully on clinical performance, study findings, literature analyses, and patient impact of the tests. After considering the evidence, the panel conclued that the tests demonstrated clinical utility for directing therapy.
Although Medicare had been reimbursing for cell culture drug "resistance" tests since 2000, it wasn't until the beginning of this year they abandon the artificial distinction between "resistance" testing and "sensitivity" testing and are providing coverage for the whole FDA-approved kit.
Chemo Assay Test
Reference: Various Bio-Assay Laboratories
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Last Updated On: 07/01/2007
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