In defense of Oncotype DX

[gdpawel]

The genetic analysis of Oncotype DX predicts which women will have a greater chance of breast cancer recurrence. The test looks at 21 genes that influence the behavior of breast cancer cells. Until this test, it had been difficult to pinpoint which women would benefit most from chemotherapy, and those which wouldn’t.

This new gene expression profiling test enables the oncologist and breast cancer surgeon to more accurately determine who should be treated and who should not be treated with chemotherapy, but they cannot predict chemo response.

This laboratory test is a tool for the oncologist. The oncologist should take advantage of all the tools available to him/her to treat a patient. And since studies show that only 25-30% of patients do respond to chemotherapy that is available to them (and even less for "targeted" drugs), there should be due consideration to looking at the advantage of molecular and cellular assay tests to the resistance that has been found to chemotherapy drugs.

This test can 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 pre-tested with a "functional" bio-marker (a cell-based assay using an EGFRx™ Anti-Tyrosine Kinase Profile) 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.

New anti-cancer 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 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.

The drugs are called anti-EGFR drugs or tyrosine kinase inhibitors. When the drugs work, they can be highly beneficial, causing tumor shrinkage or promoting stable disease and extending survival. However, targeted therapy drugs like tyrosine kinase inhibitors only work for a small percentage of the patients who receive them. Further, 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™ Anti-Tyrosine Kinase Profile assay can prospectively report to a physician specifically which chemotherapy agent would benefit a high risk cancer patient by testing that patient's "live" cancer cells. Drug sensitivity profiles differ significantly among cancer patients even when diagnosed with the same cancer. Knowing the drug sensitivity profile of a specific cancer patient allows the treating oncologists to prescribe chemotherapy that will be the most effective against the tumor cells of that patient.

Every breast cancer patient should have her own unique chemotherapy trial based on consultation of pathogenic profiles and drug sensitivity testing data. 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.

These new genetic and cellular-based tests have enormous implications for the short-term future of cancer research in general, and is one of the truly great cancer breakthroughs of our time.

http://weisenthalcancer.com/Patient%20Pages/EGFRXPatients.htm

[tousled1]

I agree with the statement:

"Every breast cancer patient should have her own unique chemotherapy trial based on consultation of pathogenic profiles and drug sensitivity testing data."

Unfortunately upon initial diagnosis of breast cancer, patients rely solely on what their oncologist recommends. Women don't do research on breast cancer and its treatments until after they receive a diagnosis. By that time, they are already in some form of treatment. Once a breast cancer patient is in treatment that is when the research starts to happen. Then and only then can a breast cancer patient be informed enough to question treatment and ask why other options are not being pursued.

[gdpawel]

I know exactly what you mean, going through it with my wife ten years ago. Ideally, we would conduct such research before the treatments are administered, but we usually don't have the luxury of time to learn what oncologists are not telling us when it matters most. Perhaps, if we keep trying, we can finally break the mold. We have to learn to ask more questions and seek more answers. Since writing "New Paradigms of Cancer Treatment" almost three years ago, I've been trying to help break that mold.

Researchers have seen that whether a tumor was a breast, lung or ovarian tumor, it didn't correlate to how the cancers interacted with standard anticancer drugs. Their findings suggest that traditional cancer treatments, which have established different drug regimens for breast, lung or ovarian cancer, should be replaced with therapies that use drugs deemed to be of highest benefit based on the tumor's pharmacologic and whole cell profile. Treatment choice would be determined by how each patient's tumor reacts to anticancer drugs, regardless of the tumor's anatomical origin.

The drug effect is independent of where the tumor came from in the body. Under current treatment selection methods virtually no chemotherapeutic drug has been successful in more than 50 percent of patients with advanced cancer. But instead of considering a drug that works only ten percent of the time a failure, it would be better to consider such a drug effective for one in ten tumors and to search for the agents among the current arsenal of chemotherapeutic drugs that will work for the rest.

Having a good tumor-drug match not only would improve survival rates, it would be cost-effective, and the high cost of the newer cancer therapies reinforces the necessity of choosing the right therapy the first time around. It's not a question of either/or. It is a combination of genetic and whole cell profiling that will give patients their own unique chemotherapy trial.

[Christine MH-UK]

Hi GDPawel,

I think that the scientific community has now come around to the idea of matching treatments to patients, partly because so much progress has been made against her2 breast cancer by treating as its own distinct form. Thank you for the support you have given this idea.

I wonder if you have heard about the Defeat Cancer Project running on the World Community Grid? It is using computer power donated from hundreds of thousands of volunteers worldwide to see which chemotherapy regimes have worked best for the different varieties of breast cancer. The program runs like a screen saver in the background. The only requirement is that your computer has to have 750 MB of RAM. They set this requirement really high to ensure that the program would not affect the performance of volunteers' computers. My computer, alas, doesn't have so much power, so I work on the other projects, folding proteins involved in human diseases and find new AIDS drugs, instead. The World Community Grid's programs have never given me any problems and are an easy way to contribute to medical research.

[panicked911]

There is no question that we would all benfit from individualized treatment when it comes to cancer and as we all know cancer is not one disease but a collection of many under umbrella.
With that said, the oncotype test is a wonderfull tool for those BC patients who are NOT her2 positive. As one oncologist put it to me she has NEVER seen an oncotype typ test come back other than "high" for Her2 patients of which some ( especially those who are triple positives) probably should not have been.
When weighing the high cost ($3,000 plus) of which for most of us it is NOT covered by insurance - versus the inaccuarancy when dealing with her2 cells, it just does it make sense. Adds nothig to the treatment picture.

Susanne

[gdpawel]

Christine. I am familiar with this. It's been going on now for several years. I haven't heard any follow up, progress reports, etc. Over the past few years, gene expression profiling has been suggested as the best or only way of determining ex vivo drug sensitivity. However, the cliinical application of these DNA content and RNA assays have been shown to correlate only with "response" and not "survival." And due to almost all patients being treated with combination chemotherapy, this methodology cannot even be calibrated without the use of cell culture assays. The EGFRx (TM) assay can actually integrate all the gene expression into one convenient test result.

This new test can predict accurately for the survival of patients treated with the targeted drugs because it uses a variety of metabolic and apoptotic measurements to determine if a specific drug was successful at killing the patient's cancer cells. In other words, it differs from existing DNA and RNA tests in that it assesses the activity of a drug upon combined effect of all cellular processes, using several metabolic (cell metabolism) and morphologic (structure) endpoints. Other tests, such as those which identify DNA or RNA sequences or gene expression of individual proteins often examine only one component of a much larger, interactive process.

The is important because the EGFRx (TM) test, which can be applied to many emerging targeted cancer drugs (like Tykerb and Sutent), could help solve the growing problem of knowing which patients should receive costly, new treatments that can have harmful side-effects and which work for some but not all cancer patients who receive them. The test can discriminate between the activity of different targeted drugs and identify situations in which it is advantageous to combine the targeted drugs with other types of cancer drugs.

Susanne. As far as your oncologist's experience, I do know that these tests are complex procedures, fraught with the potential for error and misinterpretation. The results are only meaningful to the extent that the laboratory in question is experienced and diligent in its quality assurance practices. I know that it is compared to lab tests that pinpoint a germ so the right antibiotic can be prescribed, called Bacterial Culture and Sensitivity Testing (it is a "gold standard"). I know the test is expensive, but a number of insurers cover it because it often prevents even more costly and unnecessary chemo. I remember in 2000, Medicare was not paying for Pet Scans for metastatic disease analysis. A combination unenhanced/enhanced MRI was the only test they were paying for this. Although the MRI came up with something, I did not want to do waitful-watching. I wanted to find out now. So I paid for the Pet Scan out of my pocket; it was my spouse's life.

[gdpawel]

Medicare Contractor Establishes Reimbursement Coverage Policy for Cell Culture Assay Tests

National Heritage Insurance Company (NHIC), the contractor that administers Medicare programs in California, has established a positive coverage policy for Cell Culture Assay Tests known as Chemosensitivity (Resistance) Testing or Oncologic In Vitro Chemoresponse Assays for a tumor specimen from a Medicare patient obtained anywhere within the United States, but submitted for testing by one of the approved laboratories located within Southern California. Medicare bills for this testing are billed through NHIC because the test is conducted by the approved laboratories in California.

This pre-test can help see what treatments have the best opportunity of being successful for "high" risk cancer patients. The test measures the response of "live" tumor cells to drug exposure. Following this exposure, the assays measure both cell metabolism and cell morphology (Functional Profiling). 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. Assays based on "cell-death" occur in the entire population of tumor cells.

This cell culture assay technology has been clinically validated for the selection of optimal chemotherapy regimens for individual patients. It is a laboratory analysis based on tumor tissue profiling that uses "fresh" human tumor biopsy or surgical specimen to determine which drugs or combinations of chemotherapeutic agents have the highest likelihood of response for individual cancer patients.

Following the collection of "fresh" tumor cells obtained from surgery or tru-cut needle biopsies, a cell culture assay is performed on the tumor sample to measure drug activity (sensitivity and resistance). This will pinpoint which drug(s) are most effective. Tissue, blood, bone marrow, and ascites and pleural effusions are possibilities, providing tumor cells are present. At least one gram of fresh tissue is needed to perform the tests, and a special kit is obtained in advance from the lab. The treatment program developed through this approach is known as assay-directed therapy.

Individualized assay-directed therapy is based on the premise that each patient's cancer cells are unique and therefore will respond differently to a given treatment. This is in stark contrast to standard or empiric therapy, which chemotherapy for a specific patient is based on average population studies from prior clinical trials.

The decision had been made that the assay is a perfectly appropriate medical service, worthy of coverage on a non-investigational basis. What is of particular significance is that they abandoned the artificial distinction between "resistance" testing and "sensitivity" testing and are providing coverage for the whole FDA-approved kit. Drug "sensitivity" testing is merely a point a little farther along on the very same continuum which "resistance" testing resides.

Cell cuture assay tests based on "cell-death" have proven very effective in identifying novel treatment combinations for a variety of cancers. The value of cell-death assays is that they can and do accurately predict clinical outcomes and define novel chemotherapeutic synergies. It 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).

The current clinical applications of in vitro chemosensitivity testing is ever more important with the influx of new "targeted" therapies. Given the technical and conceptual advantages of "functional profiling" of cell culture assays together with their performance and the modest efficacy for therapy prediction on analysis of genome expression, there is reason for renewed interest in these assays for optimized use of medical treatment of malignant disease.

The payment provided will be sufficiently realistic that all Medicare patients for whom this testing is indicated will be able to get it with only the routine 20% co-payment, as Medi-gap insurance secondaries are mandated to provide payment for co-pays for Medicare-approved services.

The coverage became effective for claims for services performed on or after February 19, 2007. The decision is posted at:

http://www.medicarenhic.com/cal_prov/articles/chemoassaytest_0107.htm (http://www.medicarenhic.com/cal_prov/articles/chemoassaytest_0107.htm)

NHIC Medicare Services reimburses qualified laboratories in Southern California for cell culture assay tests on a Medicare patient anywhere in the United States.

Likewise, Highmark Medicare Services reimburses a qualified laboratory in Pennsylvania for cell culture assay tests on a Medicare patient anywhere in the United States.

NHIC has jurisdiction over Southern California, so that is who gets billed when the laboratory is located in California.

Highmark has jurisdiction over laboratories in Pennsylvania, so that is who gets billed when the laboratory is located in Pennsylvania.

The coverage decision is posted at:

http://www.highmarkmedicareservices.com/bulletins/partb/news06132007.html (http://www.highmarkmedicareservices.com/bulletins/partb/news06132007.html)

Oncologic In Vitro Chemoresponse Assays

Medicare's National Coverage Decision specifically notes noncoverage on two distinct types of assays: a. human tumor stem cell assay, and b. clonogenic assay. These are what most academic oncologists still mistakenly refer to as chemosensitivity testing.

In October 2003, CMS notified all contractors that the NCD was very specific to those tests and does not include tumor cell sensitivity or resistance testing on any other class of cells other than tumor stem cells. In 2006, Medicare officially recognized cancer chemosensitivity tests as a special test category in Federal Regulations (42 CFR 414.510(b)(3), 71 FR 69705, 12/01/2006).

Two Medicare contractors (NHIC Medicare Services and Highmark Medicare Services) established reimbursement coverage policies for cell culture assay tests, the same way that the Oncotype DX assay is being covered. Medicare bills for Chemosensitivity (Resistance) Testing, from any Medicare patients, anywhere in the United States, are billed through NHIC and Highmark Medicare Services because the test is conducted by approved laboratories in Southern California and one in Pennsylvania. As far as payments for this test, it is just as good as having a NCD. Numerous private payors pay for the tests also.

As with any other laboratory tests in cancer medicine, the determination of the efficacy of cell culture assays is based on clinical correlations (comparisions of laboratory results with patient response). The "standard" of retrospective correlations between treatment outcomes and laboratory results is sufficient in the case of ALL laboratory tests. It is what established FDA-approval for the test kit.

[Jean]

For me the Oncotype DX test was a major factor in saving my life as far as I am concerned. When I was dx. 4/05 all the onc. would not consider herceptin or chemo since my tumor was small. I requested the Oncotype test and the dr. said they did not feel that was part of their bible when making the call on chemo/herceptin. I had to fight and demand it done...when it came back all the dr. now advised chemo/herceptin. Therefore in my case the test assisted me getting the treatment I knew I needed and without it my insurance may not have covered my treatment since dr. would not budge on dx. for herceptin.

Now, this past August all early stagers can have herceptin. What I found so upsetting was here I was - not a dr. or specialist in this field. Just a newly dx. woman - did my research, found this wonderful site read about the trials
with early stagers and herceptin and knew my Ki-67 levels were important and on the very high side. Yet all the good dr. in NY did not at any time believe
that would warrent herceptin. It had gotten to a point where I was told
I was not accepting that I had bc....can you imagine how that feels to be told that!

Approach to treatment is changing but we need it sooner. How many women
who were early stagers advanced in a very short time frame to stage IV. For me it just sounds like common sense to treat on the character of the tumor
I am hoping that in a short span of time this will be the standard of care and women will be treated on the basis of "Their tumor" and not due to size or the silly notion that if the node is negative that is a lottery ticket. Maybe 25 years ago the belief that if the node was neg. all was just wonderful.
Well now we know that tumor cells travel via the blood sytem. This is a nasty disease, I hate it and fight it with all my energy.

As an early stager I cannot tell you how angry I was at the attitude of dr's
who just passed you off as your okay since you are an early stager. - why should any woman have to advance to a later stage. Yes, it is true that catching this devil early helps but then again that is like saying you are a litte bit pregnant. I want this disease wiped out or at best under control, hopefully I will.

Jean

[Bev]

Thanks all. Very good to hear this discussed. BB

[AlaskaAngel]

I'm glad to see more discussion about it too. Jean's post is the only personal narrative I've seen so far anywhere that demonstrates the problem with making judgements about HER2 positive cancer treatment by small size, and the importance of using tests like Oncotype dx for those patients to consider additional therapy.

But as Susanne says, from everything I've seen, most HER2 positives who are in the grey area based on nodes/size end up with test results from these expensive tests that favor the use of chemotherapy -- and no one so far seems to use any method to separate out those such as the strongly HR+ HER2 positives who are less likely to benefit from chemotherapy and more likely to benefit from hormonal therapy and perhaps targeted therapy. Again, the TAILOR-X trial is going to tell us which HR+ non-HER2's can do without chemotherapy by use of other therapies, but what is in the works to distinguish the HER2's who don't need itand might be better off to use an ovarian ablation/AI/something like trastuzumab and/or lapatinib?

AlaskaAngel

[gdpawel]

It amazes me not only that some private insurance carriers don't like to pay for cell culture assay tests but that they don't emphatically mandate it as a requirement for obtaining chemotherapy reimbursement against ill-directed treatments.

The validation standard that private insurance companies is accepting from "molecular" profiling tests is "accuracy" and not "efficacy." The "bar" has been instantly lowered. No longer will it be essential to prove that the use of a diagnostic test improves clinical outcomes, all they have to do for these "molecular" profiling tests is prove that the test has a useful degree of "accuracy." However, at the same time, the validation standard they want for "cell-based" profiling tests is "efficacy."

The "cell-based" profiling tests have the same entitlement to be judged by the same validation standard as "molecular" profiling tests. The combination of measuring morphologic (structural) effects and metabolic (cell metabolism) effects constitutes measuring the "profile" at the whole cell level. It must be noted that both types of dignostic tests are just that, "tests" and not treatment.

Profit, as we have seen, is a powerful motivating force. Among the private payors, at least, the profit motive is entirely consistent with the goal of the test, which is to identify efficacious therapies irrespective of drug mark-up rates.

The evidence in support of these assays is more than sufficient to justify the funding of validation trials, if any more truly are needed, as claimed - speciously and self-servingly - by the medical establishment.

Everyone is scared to death - and rightly so - at what is going to happen to the healthcare economic system with the introduction of increasingly expensive new drugs that benefit only a small percentage of patients who receive them, hence the headlong rush to develop tests to identify molecular predisposing mechanisms whose presence still does not guarantee that a drug will be effective for an individual patient.

Nor can they, for any patient or even large group of patients, discriminate the potential for clinical activity among different agents of the same class, such as Sutent, Tarceva, Iressa, and Nexavar.

The FDA could benefit too, as they find themselves under increasing pressure to allow new drugs into marketplace while at the same time protecting the safety of potential recipients of those drugs as well as the financial interests of those who will have to pay for them.

It explains the new paradigm of requiring a companion diagnostic as a condition for approval of new targeted therapies. The pressure, in fact, is so great that the companion diagnostics they've approved often have been mostly or totally ineffective at identifying clinical responders (durable and otherwise) to the various therapies.

I think that in both of these areas - private insurance carriers and the FDA - there is a very real opportunity to make a substantial impact and contribution, an interest in saving the healthcare system perhaps billions of dollars a year (and thereby the healthcare system itself) by ensuring that expensive treatments are used appropriately.

Committee chairpersons, committee members and persons in congress who may have personal interests not only in discovering new cancer treatments - everybody wants that - but also, in the "here and now," using currently-available cell culture assay technologies to improve the effectiveness of existing drugs and save lives today by administering the right drug to the right patient at the right time.

[AlaskaAngel]

Hello gdpawel,

I'm happy to see the beginnings of better ways to deal with these issues too. (See Julie2 post about this method earlier today, and Lolly's post about this method earlier today in the Articles forum.) The down side is that the last person to know about this test is the newly diagnosed patient with bc until too late, when the only tumor tissue they have is already fixed. Correct me if I am wrong, but I gather that this test requires fresh tissue.

As you say, it still is important for us to raise the awareness so that we can help others who perhaps are newly diagnosed to consider having it done at time of surgery.

AlaskaAngel

[gdpawel]

As stated above, "One gets more accurate information when using intact RNA isolated from "fresh" tissue than from using degraded RNA, which is present in paraffin-fixed tissues. The same holds true with cell culture assay tests. "Fresh" sample of the patient's tumor from surgery or an "excisional" biopsy are grown in test tubes and tested with various drugs. Surgeons and pathologists don't have a huge problem with doing this sort of thing. The patient is just asking for more information. Drugs that are most effective in killing the cultured cells are then recommended for treatment.