[gdpawel]

Thanks Lani. Very important point. These cellular-based pre-tests can report prospectively to a physician specifically which chemotherapy agent would benefit a cancer patient by testing that patient’s "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.