June 12, 2007

Cancer Drug May Elude Many Women Who Need It

By ANDREW POLLACK

CHICAGO — The breast cancer drug Herceptin is considered the model for the future of medicine tailored to each individual. The drug is given only to the 20 percent of breast cancer patients whose tumors have a particular genetic characteristic.

But now, nearly a decade after the drug’s approval, evidence is emerging that the testing of the tumors can be highly inaccurate or that the wrong cutoff values are being used to determine who qualifies for treatment.

That could mean that as many as 40 percent of women with early breast cancer might benefit from the drug but are not getting it, some experts say. Yet other women may be paying for the drug and risking its side effects unnecessarily.

“This has major practice-changing potential,” Dr. James H. Doroshow of the National Cancer Institute said in a commentary after one presentation at the American Society of Clinical Oncology meeting here last week. But he added that the data were too preliminary to justify changing treatment patterns just yet.

Herceptin, also known as trastuzumab, works by blocking Her2, a protein that can spur growth of tumor cells. It is given only to women whose tumors have abundant amounts of the protein. There are two tests used to determine this. One looks at the amount of the protein on the surface of a sample of tumor cells. The other looks for extra copies of the gene that governs the production of Her2.

But two studies discussed at the oncology meeting found that patients who were considered Her2-negative even using both tests benefited from Herceptin.

Both studies reanalyzed tumor samples from earlier clinical trials showing that Herceptin, if used after a tumor is removed by surgery, cuts the risk of the cancer’s recurring by half. For a woman to have entered those trials, her tumor had to be classified as Her2-positive by a local clinical laboratory.

But scientists have now gone back and retested those preserved tumor samples and found that as many as 20 percent of them were actually Her2-negative. Yet the women with those tumors also experienced a reduction in cancer recurrence from Herceptin, in some cases as great as that in the Her2-positive women.

“This is a revolution compared to what we believed before,” said Dr. Edith A. Perez of the Mayo Clinic, who presented one of the studies. She said the findings raised questions of whether women who were Her2-negative should be tested again.

Some experts were skeptical, saying the number of patients in the two studies was too small to draw firm conclusions. Also, they said, it was not clear if those women were truly Her2-negative, since they had tested positive by the local laboratory.

Dr. Daniel F. Hayes, a breast cancer specialist at the University of Michigan who helped develop guidelines for Her2 testing, said it would be unwise to start giving Herceptin to Her2-negative women because the drug was expensive and raised the risk of heart failure.

But he said the studies called attention to the inconsistent quality of Her2 testing in many small laboratories. Laboratories can use commercially available tests or develop their own.

Dr. Soonmyung Paik, who presented the second study at the cancer conference, said the problem might lie not in sloppy testing but rather in the cutoff used to determine which women get Herceptin.

Dr. Paik, who is with the National Surgical Adjuvant Breast and Bowel Project, said that about 40 percent of women had intermediate levels of Her2. They are now classified as negative but might still derive some benefit from the drug. On the other hand, he said, many women who are Her2-positive do not benefit from Herceptin. So better ways are needed to determine who should be treated.

“To me, the take-home message is that we don’t have a perfect test, unfortunately,” Dr. Paik said.

Dr. Pamela M. Klein, an executive at Genentech, the manufacturer of Herceptin, said the company was continuing to explore how to best identify patients for the drug.

The fact that this uncertainty is occurring so long after the 1998 approval of Herceptin — the paragon of “personalized medicine” — suggests that it will not be so easy to tailor other drugs to patients based on gene or protein tests.

It left some doctors at the conference incredulous and uncertain how to treat their patients.

“Here we are, 10 years into it,” said Dr. Marc L. Citron, an oncologist in Lake Success, N.Y., “and we don’t know how to test for it.”

*** Edited 6/29/2007 7:00:18 AM UTC by gdpawel***

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 a Whole Cell Profiling Assay has demonstrated this critical ability.

Source: Cell Function Analysis

*** Edited 6/29/2007 7:23:23 AM UTC by gdpawel***