Drug curbs relapses, but eligibility tests raise major doubts
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By Judy Peres
Tribune staff reporter
June 5, 2007
Cancer researchers meeting in Chicago had good and bad news Monday for breast-cancer patients who are eligible for treatment with the new-generation drug Herceptin -- at least 40,000 a year in the U.S. alone.
The good news is that Herceptin continues to prevent relapses years after patients stop taking it. The bad news is that the laboratory tests used to determine eligibility appear to be highly inaccurate. That means some women who could benefit from Herceptin don't get it, while others are subjected to the side-effects and high cost of the drug with no hope of a benefit.
"It is a very big deal," said Dr. Larry Norton, head of breast-cancer programs at Memorial Sloan-Kettering Cancer Center in New York.
About one-quarter of breast-cancer patients carry extra copies of a gene called HER2, which makes their tumors more aggressive but also makes them respond to Herceptin, a synthetic antibody that targets the HER2 protein. Herceptin, one of the first in a new generation of targeted cancer drugs, has been shown to reduce the risk of recurrence by about 50 percent. That is a huge benefit, because breast cancer doesn't become life-threatening unless it recurs and spreads to other parts of the body.
On Monday Dr. Edith Perez of the Mayo Clinic location in Jacksonville, Fla., presented trial results showing that, four years after treatment, the women who got Herceptin in addition to chemotherapy were 35 percent more likely to be alive and 52 percent more likely to be relapse-free.
"This is good news for patients," she said.
But one of the slides Perez screened at the annual meeting of the American Society of Clinical Oncology showed that some patients who were classified as HER2-negative got the same benefit as those who tested positive. Perez's data contained too few patients to be statistically significant, but another researcher was scheduled to present similar findings Tuesday in a bigger set of patients.
That caused a buzz among the cancer doctors gathered at McCormick Place, many of whom said the finding raised serious questions about their ability to offer patients the best possible treatment.
Dr. Kathy Albain, director of breast research at Loyola University Health System in Maywood, predicted the data would cause "mass confusion," adding, "It will give me pause to remeasure someone who is initially HER2-negative."
Perez also suggested it might make sense to retest anyone whose first test was negative, just in case it's a false result. "I'm worried about excluding patients who might benefit," she said.
Drug expensive, risky
But Dr. Dennis Slamon of UCLA, who is largely credited with developing Herceptin, noted that false-positive results are also problematic, because the drug costs about $3,000 a month and has sometimes-serious side-effects, including a heightened risk of heart failure.
Dr. Michael Press, a pathologist at the University of Southern California, said as many as one-third of positive antibody tests "could be false-positives."
Slamon called for a high-level task force to figure out how to reduce errors in testing for HER2. As a first step, he said, any negative tumor samples of women who got Herceptin in the clinical trials should be retested by independent, "blinded" pathologists to make sure they're true negatives.
Slamon said there have always been "technical challenges" to determining whether a patient is positive or negative for HER2. One study found that when five pathologists looked at the same slides, they disagreed on the diagnosis in half the cases. "This will bring it to a head," he said, "and that's a good thing."
Early errors found
Shortly after Herceptin was approved by the FDA in 1998, studies began showing that the lab tests to determine if breast-cancer patients should get the drug often yielded false results.
At first it was believed most of the bad results occurred when less-experienced, community laboratories processed the samples or used non-standard test kits. So researchers insisted the tests be performed in a central lab that has processed at least 100 HER2 tests a month for six months.
But Perez said Monday that some of the women who responded to Herceptin in her trial had received negative test results from the central pathology lab that was entrusted with overseeing all the samples.
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Which Patients Should Receive Breast Cancer Drug Herceptin
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.
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