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Old 12-02-2010, 09:44 AM
gdpawel gdpawel is offline
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Default Crizotinib in NSCLC

Reports have described the striking activity of the oral investigational drug Crizotinib in tumors that harbor a specific mutant protein (enzyme) known as anaplastic lymphoma kinase (ALK). In 5.5% of NSCLC patients, a specific mutation known as EML4-ALK rearrangement results in activation of this gene and the development of this cancer, no others. The response rate was 57% with a disease control rate of 87% at eight weeks.

"This response rate is unprecedented in lung cancer," said Anil Potti, MD, associate professor of medicine at Duke University in Durham, North Carolina, speaking at an earlier ASCO meeting. The patients taking part in this clinical trial had already failed on 2 previous chemotherapies, and their chances of responding to a third chemotherapy would be at best 10%, although others have question whether Crizotinib will yield equally strong responses as the first therapeutic intervention or whether a combined approach will be more beneficial.

They note that although only 5% of NSCLC patients had tumors that responded to crizotinib, this represents a substantial number of potential patients. But to find these patients and others with mutations that have responded to other drugs (EGRF, KRAS), there will need to be an acceptance of "genotyping as a standard practice," they write.

The lead author of this study, Eunice Kwak, MD, PhD, from the Massachusetts General Hospital Cancer Center in Boston, said that more recent data from this trial have shown that patients receiving Crizotinib had a progression-free survival of 9.2 months, which compares very favorably with what would be expected with chemotherapy.

The high response rate of ALK NSCLC patients to Crizotinib is very exciting, he said, but he added that it is in line with what has been seen before with targeted agents, such as erlotinib and gefitinib in EGRF NSCLC. Together, these 2 genotypes account for about 20% of all lung cancer (5% ALK and 15% EGRF), so there are still many patients who do not have the benefit of this targeted approach.

Several more genotypes are under study, but many of these are rare (found in only 2% to 3% of patients). "But the elephant in the room is KRAS mutations, found in about 35% of lung cancer patients. So far, there is no agent that targets this," he said. Several have been tried but have failed. "What we need is a Crizotinib-type drug for every patient," he added.

Another paper discusses the problem of resistance to Crizotinib (a mutation in the ALK protein that conferred a resistance to the drug). The appearance of Crizotinib-resistance mutation indicates that additional ALK inhibitors will be required to target EML4-ALK mutants that are insensitive to Crizotinib in a clinical setting.

There is the possibility that a series of ALK inhibitors will be needed to overcome emerging resistance and will require close collaboration between basic scientists and clinicians. A number of new ALK inhibitors are already in the pipeline, including AP26113. Earlier this year at the American Association for Cancer Research annual meeting, it was reported that AP26113 overcomes mutations in EML4-ALK that confer resistance to Crizotinib.

Citation: N Engl J Med. 2010;363:1693-1703, 1727-1733, 1734-1739, 1760-1762.

Xalkori (crizotinib) is an anaplastic lymphoma kinase (ALK) and a c-ros oncogene1, receptor tyrosine kinase (ROS1) inhibitor, approved for treatment of some NSCLC. It has an aminopyridine structure and functions as a protein kinase inhibitor by competitive binding within the ATP-binding pocket of target kinases.

About 4% of patients with NSCLC have a chromosomal rearrangement that generates a fusion gene between EML4 (echinoderm microtubule-associated protein-like4) and ALK, which results in constitutive kinase activity that contributes to carcinogenesis and seems to drive the malignant phenotype.

Patients with this gene fusion are typically younger non-smokers who do not have mutations in either EGFR (epidermal growth factor receptor) gene or in the K-ras gene. A companion diagnostic test that will help determine if a patient has the abnormal ALK or ROS1 gene, a genetic test called the Vysis ALK Break Apart FISH Probe Kit.

Note:

Clinical Benefit Rate (CBR) and Disease Control Rate (DCR) are defined as the percentage of patients with advanced or metastatic cancer who have achieved complete response, partial response and stable disease to a therapeutic intervention in clinical trials of anticancer agents. CBR and DCR are commonly reported in many clinical trials in abstracts, papers, meeting presentations and media releases. The frequent use of these measures of drug activity presents the question of whether CBR and DCR are useful additional endpoints in early clinical trials, and if they can reasonably predict the success of an agent in subsequent, adequately powered, randomized trials. There are no comprehensive analyses to demonstrate that CBR or DCR add to the value of traditional response/activity endpoints in early clinical trials. Data from phase II clinical trials in which the CBR or DCR are reported suggest that CBR or DCR provides ambiguous information that likely exaggerates the anticancer activity of the therapy. The terms 'disease control' and 'clinical benefit' in the context of non-randomized trials are themselves disingenuous because neither tumor regression nor stable disease, defined without any consideration of duration of effect or reduction of symptoms appropriate for the specific patient population, are evidence of these endpoints in an individual patient (Curr Opin Investig Drugs. 2010 Dec;11(12):1340-1).

Reporting disease control rates or clinical benefit rates in early clinical trials of anticancer agents: useful endpoint or hype?

[url]http://www.ncbi.nlm.nih.gov/pubmed/21268434
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Old 12-02-2010, 10:06 AM
gdpawel gdpawel is offline
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Default Re: Crizotinib (Xalkori) in NSCLC

Although hailed as an unprecedented response rate by Anil Potti, MD, associate professor of medicine at Duke University (Gene-Guided Chemotherapy Research Questioned [url]http://cancerfocus.org/forum/showthread.php?t=3174), the results of the Crizotinib study reflect the power of pre-selection of candidates for treatment.

Dr. Robert Nagourney, MD PhD, medical and laboratory director at Rational Therapeutics in Long Beach, CA, suggests in context, these results are not superior to those that were recently reported at the 2010 ASCO Annual Meeting using conventional chemotherapies pre-selected by functional profiling analysis. With a response rate of 62%, a time to progression of 9.5 months and a median overall survival of 20.3 months, results were actually better. More notably, their results were obtained with conventional chemotherapeutics, not novel compounds.

What is most striking about the Crizotinib results is the capacity of pre-selection to demonstrably improve response rates. Yet, these results only apply to a distinct minority of patients. The results that were reported at ASCO reflect the activity of chemotherapy applicable to the remaining 95 percent of NSCLC patients. It is also highly likely that functional profiling analysis will select Crizotinib candidates as well, or better, than the mutational analysis utilized for patient selection in the study reported above.

For comparison, Rational Therapeutics' response rates for erlotinib (Tarceva) as a single agent are superior to the response rates for patients selected based on EGFR mutational analysis. In addition, secondary mutations have already been identified that confer resistance to Crizotinib, which likely confound durable remissions for this and related drugs.

While Dr. Nagourney applauds the results of the Crizotinib trial, he feels it important that all lung cancer patients have the benefit of pre-selection. Whether they fit into the 5 percent described in this report, or the 95 percent covered in our clinical trial.

Targeted therapies are classes of drugs that target specific pathways considered tumorigenic. Among the pathways initially targeted were the epidermal growth factor receptor (EGFR) and the closely related Her2. Shortly after the introduction of EGFR and Her2 directed therapies came the development of drugs that target another critical pathway, mTOR.

Hundreds of compounds are now under development intended to more accurately hone in on the pathways of interest in patients' tumors. Regrettably, while the selective application of drugs like: Tarceva for EGFR mutants, Herceptin for Her2 over-expressers, and Crizotinib for EML4-ALK mutants, are much more effective in patients with these gene expressions, these are a select few examples of linear thinking, in that this gene is associated with this disease state and can be treated with this drug.

Many, if not most cancers will prove to be demonstrably more complicated. Genomic trials can only succeed if we first know the gene of interest and second know that its (over) expression alone is pathogenetic for the disease entity. Even meeting these conditions is likely to result in comparatively brief partial responses due to the crosstalk, redundancy and complexity of human tumor signaling pathways, the "targets" of these new drugs.

To address these complexities, functional analytic platforms that examine outcomes, not targets, are needed. This bottom-up approach has now enabled cell-based assay labs to explore the activity of novel compounds. When investigators develop interesting "small molecules," these labs examine the disease specificity, combinatorial potential and sequence dependence of these compounds in short-term cultures to provide meaningful insights that can then be addressed on genomic and proteomic platforms. This reduces the time required to take these new agents from bench to bedside.

Citation: J. Clin Oncol 28:7s, 2010 (Abstract No. 7617)

Poster from Rational Therapeutics Lung Cancer ASCO Presentation

[url]http://robertanagourney.wordpress.com/2010/06/23/poster-from-rational-therapeutics-lung-cancer-asco-presentation/#respond

Alimta (pemetrexed)-based chemotherapy in patients with advanced, ALK-positive non-small cell lung cancer

[url]http://www.ncbi.nlm.nih.gov/pubmed/22887466
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Old 04-13-2011, 09:15 AM
gdpawel gdpawel is offline
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Default Why test for EGFR, KRAS, ALK pathways?

Targeted drugs are specifically designed to block one or more critical pathways (EGFR, KRAS, ALK, etc.) involved in cancer-cell growth and metastases. The development of these therapies stem from advances in molecular biology that have permitted the identification of qualitative and quantitative differences in gene expression between cancer cells and normal cells.

The new agents range from antibodies to small molecules. The interaction of the antibody or drug with its target inhibits pathways that are essential for cell proliferation or metastasis or activates pathways that culminate in cell death (apoptosis). Since these targets are usually specific for or overexpressed in cancer cells, the new agents generally have fewer side effects than most conventional chemotherapeutic agents.

Testing for these pathways (molecular profiling), those which identify DNA, or RNA sequences or expression of individual genes or proteins often examine only one component of a much larger, interactive process. It doesn't matter if there is a target molecule 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.

For example, the EGFR (epidermal growth factor receptor) 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. All the EGFR mutation studies can tell us is whether or not the cells are potentially susceptible to this pathway of attack.

It doesn't tell you if one EGFR inhibiting drug is better or worse than another which may target this pathway. There are diffferences. The drugs have to get inside the cells iin order to target anything. In different tumors, either one EGFR inhibiting drug might get in better or worse than another. And the drugs may also be inactivated at different rates, also contributing to sensitivity versus resistance.

You can though take the advantage of profiling the entire cell to measure the interaction of the entire genome (not just one pathway or a couple of pathways). There are many pathways to altered cellular (forest) function (hence all the different 'trees' which correlate in different situations).Functional profiling the whole cell measures what happens at the end (the effects on the forest), rather than the status of the individual trees.

Cancer is a complex disease and needs to be attacked on many fronts. Improving cancer patient treatment through proper drug selection will enable oncologists to prescribe treatment more in keeping with the heterogeneity of the disease. The biologies are very different from patient to patient and the response to given drugs is very different.

Literature Citation:
PLoS Medicine, February 22, 2005
Eur J Clin Invest 37 (suppl. 1):60, 2007
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Old 05-04-2011, 01:53 PM
gdpawel gdpawel is offline
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Default Genotyping as a standard practice?

The particular sequence of DNA that an organism possess (genotype) does not determine what bodily or behaviorial form (phenotype) the organism will finally display. Among other things, environmental influences can cause the suppression of some gene functions and the activation of others. Our knowledge of genomic complexity tells us that genes and parts of genes interact with other genes, as do their protein products, and the whole system is constantly being affected by internal and external environmental factors.

In fact, the gene may not be central to the phenotype at all, or at least it shares the spotlight with other influences. Environmental tissue and cytoplasmic factors clearly dominate the phenotypic expression processes, which may in turn, be affected by a variety of unpredictable protein-interaction events. This view is not shared by all molecular biologists, who disagree about the precise roles of genes and other factors, but it signals many scientists discomfort with a strictly deterministic view of the role of genes in an organism's functioning.

Genetic profiles are able to help doctors determine which patients will probably develop cancer, and those who will most likely relapse. However, it cannot be suitable for specific treatments for "individual" patients. The NCI has concluded (J Natl Cancer Inst. March 16, 2010), it cannot determine treatment plans for patients. It cannot test sensitivity to any of the targeted therapies. It just tests for "theoretical" candidates for targeted therapy.

All DNA or RNA-type tests are based on "population" research (not individuals). They base their predictions on the fact that a higher percentage of people with similar genetic profiles or specific mutations may tend to respond better to certain drugs. This is not really "personalized" medicine, but a refinement of statistical data.

Contrary to analyte-based genomic and proteomic methodologies that yield static measures of gene or protein expression, functional profiling provides a window on the complexity of cellular biology in real-time, gauging tumor cell response to chemotherapies in a laboratory platform.

By examining drug induced cell death, functional analyses measure the cumulative result of all of a cell's mechanisms of resistance and response acting in concert. Thus, functional profiling most closely approximates the cancer phenotype.

Insights gained can determine which drugs, signal transduction inhibitors, or growth factor inhibitors induce programmed cell death in individual patients' tumors. Functional profiling is the most clinically validated technique to predict patient response to drugs and targeted agents.

Epigentics may have important implications for the treatment of cancer. The cell-based functional profiling platform has the capacity to measure genetic and epigenetic events as a functional, real-time adjunct to static genomic and proteomic platforms.

By examining small clusters of cancer cells (microspheroids or microclusters) in their native state, it can provide a snapshot of the response of tumor cells to drugs, combinations and targeted therapies, mimicking what will happen in the body.

The proteomic platform does not clarify how the response to targeted drugs compares with that to chemotherapy, combinations, or other targeted therapies. There is a challenge to identify which patients the targeted treatment will be effective.

The analysis is unique in that each microspheroid (microcluster) examined contains all the complex elements of tumor biosystems found in the human body and have a major impact on clinical response. Cell function analysis is a conduit that connects novel drugs to clinicians and patients in need.

There are any number of variables that affect drugs, including the rate of excretion of the drugs by the kidneys and liver, protein binding and a myriad of other biological factors. In the body, these cells interact with and are supported by other living cells, both malignant and non-malignant cells. That is why cell-death functional profiling assays study cancer cells in microspheroids or microclusters.

Three-dimensional (3D) tissue culture methods have an invaluable role in tumor biology and provides very important insights into cancer biology. As well as increasing our understanding of homeostasis, cellular differentiation and tissue organization, they provide a well defined environment for cancer research in contrast to the complex host environment of an in vivo model.

In lung cancer, well- and moderately-differentiated tumors are slow-growing tumors, while poorly-differentiated tumors are fast-growing (high-grade) tumors, thus very aggressive. So, poorly-differentiated, fast-growing tumors are generally treated with chemotherapy, while slow-growing ones (well- and moderately-differentiated) can be treated with biotherapy (targeted therapy).

Due to their enormous potential, 3D tumor cultures are currently being exploited by many branches of biomedical science with therapeutically orientated studies becoming the major focus of research. Recent advances in 3D culture and tissue engineering techniques have enabled the development of more complex heterologous 3D tumor models.
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Old 05-05-2011, 09:28 AM
gdpawel gdpawel is offline
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Default The Era of Genomics

Dr. Robert Nagourney, one of the pioneers of cell-based functional analysis, has often described his personal misgivings surrounding the application of gene profiles for the prediction of response to therapeutics. His initial concerns regarded the oversimplification of biological processes and the attempt of analyte-driven investigators to ascribe linear pathways to non-linear events.

The complexities of human tumor biology took a wayward turn with the publication of a lead article in Nature by the group from Harvard under Dr. Pier Paulo Pandolfi. Dr. Nagourney sat in as Dr. Pandolfi reviewed his work during the Pezcoler Award lecture, held Monday, April 4, 2011, in Orlando at the American Association for Cancer Research (AACR) meeting.

What Dr. Pandolfi’s group found was that gene regulation is under the control of messenger RNA (mRNA) that are made both by coding regions and non-coding regions of the DNA. By competing for small interfering RNAs (siRNA) the gene and pseudogene mRNAs regulate one another. That is to say that RNA speaks to RNA and determines what genes will be expressed.

To put this in context, Dr. Pandolfi’s findings suggest that the 2% of the human genome that codes for known proteins (that is, the part that everyone currently studies) represents only 1/20 of the whole story. Indeed, one of the most important cancer related genes (known as PTEN), is under the regulation of 250 separate, unrelated genes. Thus, PTEN, KRAS and, for all we know, all genes, are under the direct regulation and control of genetic elements that no one has ever studied.

This observation represents one more nail in the coffin of unidimensional thinking of drawing straight lines from genes to functions. This further suggests that attempts on the part of gene profilers to characterize patients likelihoods of response based on gene mutations are not only misguided but, may actually be dishonest.

The need for phenotype analyses like the EVA-PCD (functional profiling) performed at Rational Therapeutics has never been greater. As systems biologists point out, complexity is the hallmark of biological existence. Attempts to oversimplify phenomena that cannot be simplified, have, and will continue to, lead us in the wrong direction.

Citations:

J. Clin Oncol 28:7s, 2010 (Abstract No. 7617)

Poliseno, L., et al. 2010. A coding-independent function of gene and pseudogene mRNAs regulates tumor biology. Nature. 2010 Jun 24; 465(7301):1016-7.
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Old 08-30-2011, 11:19 AM
gdpawel gdpawel is offline
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Default Gene Test For Xalkori (crizotinib) To Cost $1,500 Per Patient

The U.S. Food and Drug Administration (FDA) approved crizotinib (Xalkori), a drug that shrinks tumors in lung-cancer patients with a rare genetic abnormality, the latest molecularly targeted therapy to win a rapid approval from the agency. Patients with this cancer would be identified by a genetic test made by Abbott Laboratories that was also approved, and then take the pills twice a day.

As reported in Forbes, Xalkori will cost $9,600 per patient per month, meaning it could cost $80,000 or more for the average patient. But Xalkori is only effective in about 5% of patients whose tumors have a mutation in a gene called ALK. A biotech executive states the real cost of the drug is $9,600 plus 25 ALK tests, because that's how many patients will need to be screened for one to actually get Xalkori.

Forbes stresses that given those costs, it’s easy to see how DNA sequencing in cancer might have a market in the future. That’s one of the big potential markets for companies like Illumina, Complete Genomics, and Life Technologies, which are sequencing whole human genomes at a cost of $5,000 or less. Those technologies could carry extra pathology costs, too.

The question of whether to consider spending $3,000 or more for a cell-based functional profiling test is interesting, especially with the lastest press release from Pfizer about their new drug Xalkori (crizotinib). The drug will cost $9,600 per patient per month and the gene test for it will cost $1,500 per patient.

There are lots of things which determine if drugs work, beyond the existence of a given target (like ALK for Xalkori). Does the drug even get into the cancer cell? Does it get pumped out of the cell? Does the cell have ways of escaping drug effects? Can cells repair damage caused by the drug? Do combinations of drugs work in ways which can't be predicted on the basis of static gene expression patterns?

Tumor biology is a lot more complex than we'd like it to be. Cancer is more complex than its gene signature. Many common forms of cancer present as a host of mutated cells, each with a host of mutations. And they're genetically unstable, constantly changing. That's why so many cancers relapse after initially successful treatment. You kill off the tumor cells that can be killed off, but that may just give the ones that are left a free reign.

The idea of searching for clinical responders by testing for a single gene mutation seems like a nice theoretical idea, but you may have to test for dozens of protein expressions that may be involved in determining sensitivity/resistance to a given drug. Because if you miss just one, that might be the one which continues cancer growth. And at $1,500 a pop, that's a lot of dough, on top of the inflated price of the single drug!

The key to understanding the genome is understanding how cells work. The ultimate driver is "functional" pre-testing (is the cell being killed regardless of the mechanism) as opposed to "target" pre-testing (does the cell express a particular target that the drug is supposed to be attacking). While a "target" test tells you whether or not to give "one" drug, a "functional" pre-test can find other compounds and combinations and can recommend them, all from the one test.

Source: Cell Function Analysis

[url]http://hopepracticedhere.wordpress.com/2012/05/02/persistence-over-acceptance/
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Old 09-12-2011, 12:21 AM
gdpawel gdpawel is offline
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Default The False Economy of Genomic Analyses

Targeted therapies, named for their capacity to target specific tumor related features, are being developed and marketed at a rapid pace. Yet with an objective response rate of 10 percent (Von Hoff et al JCO, Nov 2011) reported for a gene array/IHC platform that attempted to select drugs for individual patients that have a long way to go before these tests will have meaningful clinical applications.

Dr. Robert Nagourney is medical and laboratory director at Rational Therapeutics, Inc., in Long Beach, California, and an instructor of Pharmacology at the University of California, Irvine School of Medicine. He is board-certified in Internal Medicine, Medical Oncology and Hematology. He did an analysis of using the ALK gene test vs a cell-based functional profiling test for Xalkori (crizotinib).

"Let’s examine the more established, accurate and validated methodologies currently in use for patients with advanced non-small cell lung cancer. I speak of patients with EGFR mutations for which erlotinib (Tarceva) is an approved therapy and those with ALK gene rearrangements for which the drug crizotinib (Xalkori) has recently been approved.

The incidence of ALK gene rearrangement within patients with non-small cell lung cancer is in the range of 2–4 percent, while EGFR mutations are found in approximately 15 percent. These are largely mutually exclusive events. So, let’s do a “back of the napkin” analysis and cost out these tests in a real life scenario.

One hundred patients are diagnosed with non-small cell lung cancer.
• Their physicians order ALK gene rearrangement $1,500
• And EGFR mutation analysis $1,900
• The costs associated $1,500 + $1,900 x 100 people = $340,000
Remember, that only 4 percent will be positive for ALK and 15 percent positive for EGFR. And that about 80 percent of the ALK positive patients respond to crizotinib and about 70 percent of the EGFR positive patients respond to erlotinib.

So, let’s do the math.

We get three crizotinib responses and 11 erlotinib responses: 3 + 11 = 14 responders.
Resulting in a cost per correctly identified patient = $24,285

Now, let’s compare this with an ex-vivo analysis of programmed cell death.

Remember, the Rational Therapeutics panel of 16+ drugs and combinations tests both cytotoxic drugs and targeted therapies. In our soon to be published lung cancer study, the overall response rate was 65 percent. So what does the EVA/PCD approach cost?

Again one hundred patients are diagnosed with non-small cell lung cancer.
• Their physicians order an EVA-PCD analysis $4,000
• The costs associated: $4,000 x 100 people = $400,000
• With 65 percent of patients responding, this
constitutes a cost per correctly identified patient = $6,154

Thus, we are one quarter the cost and capable of testing eight times as many options. More to the point, this analysis, however crude, reflects only the costs of selecting drugs and not the costs of administering drugs. While, each of those patients selected for therapy using the molecular profiles will receive an extraordinarily expensive drug, many of the patients who enjoy prolonged benefit using EVA/PCD receive comparatively inexpensive chemotherapeutics.

Furthermore, those patients who test negative for ALK and EGFR are left to the same guesswork that, to date has provided responses in the range of 30 percent and survivals in the range of 12 months.

While the logic of this argument seems to have escaped many, it is interesting to note how quickly organizations like ASCO have embraced the expensive and comparatively inefficient tests. Yet ASCO has continued to argue against our more cost-effective and broad-based techniques."

[url]http://robertanagourney.wordpress.com/2011/09/11/the-false-economy-of-genomic-analyses/#comments
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Old 04-26-2012, 02:09 PM
gdpawel gdpawel is offline
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Default Implications of a New Target in NSCLC

The incidence of ALK gene rearrangement in patients with NSCLC is in the range of 2-4 percent, while EGFR mutations are found in approximately 15 percent. These are largely mutually exclusive events. And now we have the ROS1 rearrangement in patients in the range of 1-2 percent, with another report of ALK rearrangement in the range of 1-2 percent (Bergethon, et al, J Clin Oncol. 2012; 30:863-870).

Dr. Howard (Jack) West told Medscape Oncology that “with a growing battery of extremely uncommon but potentially highly relevant markers in NSCLC, what is needed is a multiplex platform to test a broad range of targets simultaneously, using a limited amount of tissue, and for a reasonable price. If such testing capability is not readily available, we will soon reach a breaking point where it is not feasible to seek a series of separate $1500 mutation tests from multiple laboratories in search of patient subgroups totaling 1%-3% of the larger patient population.”

[url]http://www.medscape.com/viewarticle/761569

Yet with an objective response rate of 10 percent (Von Hoff, et al JCO, Nov 2011) reported for a gene array/IHC platform that attempted to select drugs for individual patients, it doesn’t seem to be a very accurate or validated methodology to use in patients with advanced NSCLC.

And those patients who do test negative for ALK and EGFR are left to the same guesswork that has provided responses in the range of 30 percent and survivals in the range of 12 months. It’s interesting to note how quickly organizations like ASCO have embraced the expensive and comparatively inefficient molecular testing.

If you don’t have the mutant gene, why would you want the same treatment? It’s like saying, a friend had a son who was not doing well in math and got a math tutor who greatly improved her son’s grades. My son does not have a problem with math, but would like to do better in basketball, can I get the same tutor?

There are lots of things which determine if drugs work, beyond the existence of a given target (like ALK). Does the drug even get into the cancer cell? Does it get pumped out of the cell? Does the cell have ways of escaping drug effects? Can cells repair damage caused by the drug? Do combinations of drugs work in ways which can't be predicted on the basis of static gene expression patterns?

Tumor biology is a lot more complex than we'd like it to be. Cancer is more complex than its gene signature. Many common forms of cancer present as a host of mutated cells, each with a host of mutations. And they're genetically unstable, constantly changing. That's why so many cancers relapse after initially successful treatment. You kill off the tumor cells that can be killed off, but that may just give the ones that are left a free reign. While a "target" test tells you whether or not to give "one" drug, a "functional" pre-test can find other compounds and combinations and can recommend them, all from the one test.
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