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The EGFRx Assay

gdpawel's picture
gdpawel
Posts: 538
Joined: May 2001

A class of anti-cancer drugs, called tyrosine kinase inhibitors (TKIs) or anti-EGFR drugs, selectively targets cells within the body that have a specific molecular defect that is believed to cause dangerous cell behaviors such as uncontrolled proliferative growth and high metastatic potential – behaviors that typically are associated with aggressive cancer. The defect occurs within the interior of the cell in a region that is called the tyrosine kinase domain and it involves a complicated chemical process called EGFR signaling.

When tyrosine kinase inhibitors work, they can be highly beneficial, causing tumor shrinkage or promoting stable disease and extending survival. However, as with most of the newer, targeted therapy drugs, tyrosine kinase inhibitors only work for a small percentage of the patients who receive them. In various studies, response rates in single-agent and combined anti-EGFR drug therapy ranged from around 10% to 66%, depending upon the cancer type and the patient population involved. The drugs are expensive and have been associated with toxic side effects. No molecular (gene-based) test has been proven to tell reliably who will benefit from anti-EGFR treatment.

The EGFRx functional profile has been shown to correlate highly with patient response to anti-EGFR treatment and with overall patient survival. Reported prospectively, EGFRx functional profiling results reliably identify patients who do or do not respond to treatment with anti-EGFR drugs and also those who achieved superior survival after treatment.

The EGFRx targeted therapy profile includes analysis of the following targeted drugs: erlotinib (Tarceva), gefitinib (Iressa), sorafenib (Nexavar), and sunitinib (Sutent). For certain types of cancer, a drug called imatinib (Gleevec), which works in a very different way, may be tested.

As we enter the era of "personalized" medicine, it is time to take a fresh look at how we evaluate treatments for cancer patients. More emphasis should be put on matching treatment to the patient. Patients would certainly have a better chance of success had their cancer been chemo-sensitive rather than chemo-resistant, where it is more apparent that chemotherapy improves the survival of patients, and where identifying the most effective chemotherapy would be more likely to improve survival.

Findings presented at the 41st Annual Meeting of the European Society for Clinical Investigation in Uppsala, Sweden, April 18, 2007, concluded that "functional profiling" with cell culture assays is relevant for the study of both "conventional" and "targeted" anti-neoplastic drug agents (anti-tumor and anti-angiogenic activity of Iressa, Tarceva, Sutent, Nexavar, and Avastin in primary cultures of "fresh" human tumors).

Cell Culture Assays with "cell-death" endpoints can show disease-specific drug activity, are useful clinical and research tools for "conventional" and "targeted" drugs, and provide unique information complementary to that provided by "molecular" tests. There have been more than 25 peer-reviewed publications showing significant correlations between cell-death assay results and patient response and survival.

Many patients are treated not only with a "targeted" therapy drug like Tarceva, Avastin, or Iressa, but with a combination of chemotherapy drugs. Therefore, existing DNA or RNA sequences or expression of individual proteins often examine only one compenent of a much larger, interactive process. The oncologist might need to administer several chemotherapy drugs at varying doses because tumor cells express survival factors with a wide degree of individual cell variability.

There is a tactic of using biopsied cells to predict which cancer treatments will work best for the patient, by taking pieces of live "fresh" tumor tissue, applying different chemotherapy treatments to it, and examining the results to see which drug or combination of drugs does the best job killing the tumor cells. A cell culture assay test with "functional profiling," using a cell-death endpoint, can help see what treatments will not have the best opportunity of being successful (resistant) and identify drugs that have the best opportunity of being successful (sensitive).

"Funtional profiling" measures the response of the tumor cells to drug exposure. Following this exposure, they measure both cell metabolism and cell morphology. The integrated effect of the drugs on the whole cell, resulting in a cellular response to the drug, measuring the interaction of the entire genome. No matter which genes are being affected, "functional profiling" is measuring them through the surrogate of measuring if the cell is alive or dead.

For example, the epidermal growth factor receptor (EGFR) is a protein on the surface of a cell. EGFR-inhibiting drugs certainly do target specific genes, but even knowing what genes the drugs target doesn't tell you the whole story. Both Iressa and Tarceva target EGFR protein-tyrosine kinases. But all the EGFR mutation or amplificaton studies can tell us is whether or not the cells are potentially susceptible to this mechanism of attack. They don't tell you if Iressa is better or worse than Tarceva or other drugs which may target this. There are differences. The drugs have to get inside the cells in order to target anything. So, in different tumors, either Iressa or Tarceva might get in better or worse than the other. And the drugs may also be inactivated at different rates, also contributing to sensitivity versus resistance.

As an example of this testing, researchers have tested how well a pancreatic cancer patient can be treated successfully with a combination of drugs commonly used to fight lung, pancreatic, breast, and colorectal cancers. The pre-test can report prospectively to a physician specifically which chemotherapy agent would benefit a cancer patient. Drug sensitivity profiles differ significantly among cancer patients even when diagnosed with the same cancer.

The "funtional profiling" technique makes the statistically significant association between prospectively reported test results and patient survival. It can correlate test results that are obtained in the lab and reported to physicians prior to patient treatment, with significantly longer or shorter overall patient survival depending upon whether the drug was found to be effective or ineffective at killing the patient's tumor cells in the laboratory.

This could help solve the problem of knowing which patients can tolerate costly new treatments and their harmful side effects. These "smart" drugs are a really exciting element of cancer medicine, but do not work for everyone, and a test to determine the efficacy of these drugs in a patient could be the first crucial step in personalizing treatment to the individual.

Literature Citation: Eur J Clin Invest 37 (suppl. 1):60, 2007

kaitek
Posts: 156
Joined: Aug 2006

Thanks gdpawel for the advice. I will look more into the test. Phil noted that most insurance companies won't readily pay for the test. Is this something you guys would demand on first cause and not wait until it gets to second line?

gdpawel's picture
gdpawel
Posts: 538
Joined: May 2001

kaitek. All I can honestly say is, if I had the chance to do it all over again, with what I know now, I would have had my wife receive this testing. If I would have had that testing before they attempted to give her Taxol + Carboplatin, it would have shown that the cancer cells were resistent to the combination and would have received other drugs that would have been synergistic (sensitive) to her disease (perhaps single-agent Carboplatin).

Even this week, there was good news with more "predictive" tests coming aboard. A new genomic test that will tell physicians which lung cancer patients will benefit from chemotherapy and which ones do not need to be unnecessarily exposed to toxic chemotherapy cocktails.

When tumors are detected early and removed surgically, many cancer patients undergo chemotherapy to lower the chance that the cancer will recur. However, for the majority of cancer patients, the cancer will not recur regardless of whether they receive chemotherapy. So they are exposed needlessly to the treatment, which can cause myelosuppression, mucositis, cardiac problems, peripheral neuropathy, central neurotoxicity, or even leukemia. Doctors cannot tell, however, which patients needed the chemotherapy.

Because of this, there is a good portion of cancer patients that are either undertreated or overtreated because there was no adequate information on who will recur. This is another new test to enhance the ability to distinguish between low risk and high risk patients. Patients in the high-risk group, who would benefit from chemotherapy can then be tested to see what treatments have the best opportunity of being successful, and offers a better chance of tumor response resulting in progression-free survival, while those in the lower-risk groups can be spared the unnecessary toxicity, particularly associated with ineffective treatment.

Every cancer patient should have his/her own unique chemotherapy trial based on consultation of pathogenic profiles and whole cell profiling. Research and application of these tests are being encouraged by growing patient demands, scientific advances and medical ethics. These tests are not a luxury but an absolute necessity, and a powerful strategy that cannot be overlooked.

Improving cancer patient diagnosis and treatment through a combination of cellular and gene-based testing will offer predictive insight into the nature of an individual's particular cancer and enable oncologists to prescribe treatment more in keeping with the heterogeneity of the disease. The biologies are very different and the response to given drugs is very different.

As far as the costs (respectfully), how much is a loved-one worth, when you do cancer treatment right?

kaitek
Posts: 156
Joined: Aug 2006

Gdpawel,

Not until I read your in-depth advice on chemosensitivity testing somewhere did I learn you lost your wife to cancer. You have my condolences and I feel for your loss.

I, too, want the best treatment and doctors for my mom. Reading other people's treatment gives me insights as to how other medical professionals approach treating lung cancer. It is completely intuitive chemosensitivity making sense in determing the best and proper treatment instead of a trial-and-error approach.

I'm gathering, though, this chemosensitivity and even the EGFR testing is not routine in the protocol of cancer therapy because of insurance issues? I would think doctors would naturally rely on pre-testing to target therapies specific to the individual. As they know, everyone is different.

Evidently, my mother's oncologist isn't among that new wave. So that means I would have to demand for the testing? And pay out of our pocket? You're right, life is priceless.

I'm just clueless about this and I confess I am relying on the expertise of the oncologist - save for what I've been able to glean from my own research and people like yourself.

Thanks for replying.

kaitek
Posts: 156
Joined: Aug 2006

A followup to my pursuing the idea of chemoresistance (my mother's thoracic surgeon corrected me on the exact term) and EGFR test: He said that for a chemoresistance test, which he and his colleagues would do normally, a large enough tumor sample must be obtained, which would require major operation or surgery. My mother's surgery was minimally invasive with the biopsy and pleurodesis. He did, however, confirm that a sample was sent for determination of an EGFR mutation, of which the results haven't been received yet. To ensure I wouldn't lose hope or be disappointed should the test not be favorable, he stressed that those tests aren't foolproof, meaning that those without the EGFR mutation do survive despite the presence of the mutation leading to better treatment with Tarceva. (If I got the specifics mixed up, it's on my end and not his.) I guess his point was for me to not put too much stock on those tests as the end-all, be-all for effective cures. Cures can be personalized, individualized and targeted with other methods, as well.

Point taken that the trial-and-error approach is needless.

gdpawel's picture
gdpawel
Posts: 538
Joined: May 2001

Just a point of information about the difference between chemoresistance and chemosensitivity. All available cell culture assays are able to report drug "resistance" information. Resistance implies that when a patient's cancer cells are exposed to a particular chemotherapy agent in the laboratory, the cancer cells will continue to live and grow. Some chemosensitivity assays also are able to report drug "sensitivity" information. Sensitivity implies that when a patient's cancer cells are treated with a particular chemotherapy agent in the laboratory, that agent will kill the cancer cells or inhibit their proliferation.

The extreme drug resistance assay (EDR) cannot "accurately" predict for drug sensitivity. This kind of assay is specifically designed to identify "inactive" drugs and should not be used to identify "active" drugs. Even the reports on this assay state that the assay results should "not" be used to identify "active" drugs.

The goal of all chemosensitivity tests is to determine the response of a patient's cancer cells to proposed chemotherapy agents. Knowing which chemotherapy agents the patient's cancer cells are resistant to is important. Then, these options can be eliminated, thereby avoiding the toxicity of ineffective agents. In addition, some chemosensitivity assays predict tumor cell sensitivity, or which agent would be most effective. Choosing the most effective agent can help patients to avoid the physical, emotional, and financial costs of failed therapy and experience an increased quality of life.

The traditional criteria ever used to evaluate laboratory tests has been the predictive "accuracy" of the test. None of the available laboratory tests used in the selection of treatments for cancer patients have ever been tested for "efficacy." This includes Her2/neu, immunohistochemical staining for tumor classification, estrogen/progesterone receptor, Oncotype DX, EGFR amplication/mutation, cell culture assay tests, or CT, MRI and Pet Scans to measure tumor response to treatment. The only data supporting any of them relate to test "accuracy," and there is a total lack of information regarding test "efficacy."

The test is showing the "effaciousness" of a particular drug, the test itself doesn't have to show it is "effacious." It just has to show it is "accurate" to standards set by the FDA.

Yes, I did lose my wife to improper chemotherapy use. If I had the chance to do it all over again, with what I know now, I would have had her receive a cell culture assay. If I had, before they attempted to give her Taxol + Carboplain, it would most likely have shown that her cancer cells were resistent to the combination and would have received other drugs that would have been synergistic (sensitive) to her disease (perhaps single-agent Carboplatin or single-agent Leukeren, the drug she received for her first primary cancer in 1972).

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