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The primary reason for Her2/neu testing in breast cancer is to determine who is most likely to benefit from Herceptin, which is directed against the Her/neu protein. However, the potential benefits and risks of Herceptin have renewed concerns about the reliability of Her2/neu testing and oncologists should be concerned about it. Some studies have shown that the test produces false positives as often as 26% of the time, and may also carry some risk of false negatives.

There are a number of common ways to measure Her2/neu status on breast cancer tissue, and testing for Her2/neu and estrogen receptor (ER) is not all that accurate. Drugs can work in ways that we don't suspect. That is why a "functional" assay (is the cell being killed regardless of the mechanism) is better than a "target" assay (does the cell express a particular target that the drug is supposed to be attacking).

ER is used to determine a number of very important things. Which patients with early breast cancer should receive adjuvant chemotherapy. Whether or not chemotherapy should include hormonal therapy. In the advanced setting, whether chemotherapy should be given versus hormonal therapy. These are all very important decisions in situations where you would flip a coin between your choices and on average, do as well or as poor.

The accuracy of the ER assay was mainly documented by retrospective correlations to clinical response with thousands of patients. Patients who are ER negative have about a 10% chance of responding to hormonal therapy and are more likely to recur after curative surgery. Patients who are ER positive have about a 60% chance of responding to hormonal therapy and were less likely to recur (there were no prospective randomized trials to prove that doing the assay made a difference).

Then came the immunohistochemical (IHC) assay, which could be done in most pathology labs. It was initially validated by comparision of the ER assay, which was done in specialized labs. The IHC assay correlated reasonably well with the ER assay and the IHC assay became the standard. However, no one ever did a prospective or even a retrospective study to show how IHC correlated with and predicted for response to treatment. The ER assay worked and the IHC assay correlates with it, so the IHC is okay to use.

Very recently, there was a study showing how well the IHC assay predicts. In a very small retrospective study, where they could draw the best possible cut off lines after the fact, they found that ER positive patients had a 56% response rate, while ER negative patients had a 20% response rate, correlations which are vastly inferior to those obtained in much bigger and better studies with cell culture assays.

If highly sophisticated labs get such poor correlations, you can imagine the accuracy of tests performed in community hospitals. And yet every patient with breast cancer gets this test and in almost every patient the imformation is used to make much more critical decisions than in the cases of both the Her2/neu assay and cell culture assays.

Recent research has shown that the best way to determine whether a tumor will respond to Herceptin is to look at whether it overexpresses the Her2/neu oncogene, not whether it is making too much Her2/neu protein. And the best way to examine the oncogenes is with FISH (Fluorescence In Situ Hybridization). Because the results of the IHC test can sometimes be ambiguous, many doctors suggest the FISH test for a second opinion.

Tumors that are 3+ positive by IHC and those that test positive by FISH are most likely to benefit from Herceptin. Tumors that test 1+ by IHC are considered Her2/neu negative and those that test 2+ are considered equivical, in which case FISH testing is done to make the determination. Tumors that test negative for Her2/neu by FISH are unlikely to benefit from Herceptin.

Previous studies demonstrated that there is poor agreement between the results from local laboratory-based Her2/neu testing and those of central testing by experienced investigators. There has been poor concordance between community and central laboratory testing, in terms of both Her2 protein expression and gene amplification. Even still, there has been poor concordance in terms of FISH testing in a central laboratory compared to local laboratories, which the prevalent notion regarding FISH is that it is 100% accurate.

It doesn't matter if there is a "target" molecule (protein or receptor) in the cell that the targeted drug is going after, if the drug either won't "get in" in the first place or if it gets pumped out/extruded or if it gets immediately metabolized inside the cell, drug resistance is multifactorial. The advantage of a "functional" whole cell profiling assay is that it can show this in the "population" of cells.

Over the past few years, researchers have put enormous efforts into genetic profiling as a way of predicting patient response to targeted therapies. However, no gene-based test can discriminate differing levels of anti-tumor activity occurring among different targeted therapy drugs. Nor can an available gene-based test identify situations in which it is advantageous to combine a targeted drug with other types of conventional cancer drugs. So far, only cell-based functional profiling has demonstrated this critical ability.

Source: Cell Function Analysis