High Level Of EGFR Expression In Lung Cancer Is A Predictor For Improved Survival With Cetuximab Plus Chemotherapy

The molecular pathology of cancer

The cell-block technique is useful for special stains and immunohistochemistry (IHC) and can give morphological (structural) details by preserving (in paraffin wax) the architectural patterns. However, when it comes to drug selection, investigators can only measure those analytes (substance or chemical constituent) in paraffin wax that they know to measure. If you are not aware of and capable of measuring a biologically relevant event, you cannot seek to detect it. The cell-lines in paraffin-embedded tissue can change over time. These proliferating populations of cells are biologically distinct in their behavior from "fresh" live cells that comprise human tumors.

Tissue that is frozen, miniced, fixed, formalin-fixed or paraffin-embedded (cell-lines) have always played and continue to play an important role in drug screening and drug development. The problem is that cell-lines do not predict for disease or patient specific drug effects (drug selection). If you can kill lung cancer cell-lines with a given drug, it doesn't tell you anything about how the drug will work in real-world, clinical lung cancer (real-world conditions). But they can learn certain things about general drug biology through the study of cell-lines. As a general rule, studies from established cell-lines, tumor cells are cultured and manipilated so they continue to divide. But this is not reflective of the behavior of the fresh tumor samples (live samples derived from tumors) in primary culture, much less in the patient.

When cells are pre-cultured in monolayers, the assay endpoint is detachment of cells from the surface of the culture plates, which corrlates with with loss of viability. However, when monolayer assays are testing a subcultured cell population, studies by the NCI Navy medical oncology branch did not find that monolayer assays performed on pre-cultured, pre-amplified tumor cells clearly gave clinically relevant results. Studies by Teicher and Kerbel in mouse tumors showed that in vitro drug activity correlated with in vivo drug activity when tumors were tested in vitro as three dimensional clusters, but not when they were tested in two dimensional monolayers.

In a nutshell, cancer cells utilize cross talk and redundancy to circumvent therapies. They back up, zig-zag and move in reverse, regardless of what the sign posts say. Using genomic signatures to predict response is like saying that Dr. Seuss and Shakespeare are truly the same because they use the same words. The building blocks of human biology are carefully construed into the complexities that we recognize as human beings. However appealing gene profiling may appear to those engaged in this field it will be years, perhaps decades, before these profiles can approximate the vagaries of human
cancer.

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