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Old 04-28-2012, 10:43 AM
gdpawel gdpawel is offline
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Default Matching Targeted Therapies To Tumor's Specific Gene Mutations

Matching Targeted Therapies To Tumor's Specific Gene Mutations May Be Key To Personalized Cancer Treatment

Customizing targeted therapies to each tumor's molecular characteristics, instead of a one-size-fits-all approach by tumor type, may be more effective for some types of cancer, according to research conducted by The University of Texas MD Anderson Cancer Center.

MD Anderson's Phase I findings were presented on the opening press program of the 47th Annual Meeting of the American Society of Clinical Oncology. Apostolia-Maria Tsimberidou, M.D., Ph.D., associate professor in MD Anderson's Department of Investigational Cancer Therapeutics, and the study's principal investigator, presented the data.

Marking the largest scale on which this approach has been examined to date, the study analyzed the results of matching targeted therapies with specific gene mutations in patients. The data indicated that this strategy was associated with higher rates of response, survival and failure-free survival than observed in non-matched patients.

Pairing Patient and Treatment

"This preliminary study strongly suggests that molecular analysis is needed to use the right drug for the right patient. Up to this point, we have treated tumor types, but this study shows we cannot treat all patients with a tumor type the same way. We need to take into consideration a number of factors, and this study suggests that a personalized approach is needed to improve clinical outcomes for patients with cancer," said Tsimberidou.

The identification of pathways involved in carcinogenesis, metastasis and drug resistance; new technologies enabling tumor molecular analysis; and the discovery of targeted therapies have stimulated research focusing on the use of targeted agents as part of a personalized medicine approach, she said.

"Over the past decades, a personalized medicine approach using Gleevec has changed the way we treat chronic myeloid leukemia, as well as survival rates," said Razelle Kurzrock, M.D., professor and chair of MD Anderson's Department of Investigational Cancer Therapeutics. "We wanted to apply a similar approach to solid tumors."

Research Methods and Results

In the initial analysis, Tsimberidou analyzed 1,144 patients with metastatic or inoperable cancer underwent testing for molecular aberrations at MD Anderson. Their median age was 58, and the median number of prior treatments was four. Of these patients, 460 had one or more gene aberration, including:

-- 10 percent with a PIK3CA mutation

-- 18 percent with a KRAS mutation

-- 8 percent with a NRAS mutation

-- 17 percent with a BRAF mutation

-- 3 percent with an EGFR mutation

-- 2 percent with a CKIT mutation

-- 21 percent PTEN loss

-- 37 percent a p53 mutation

Patients with gene aberrations were treated on clinical trials with matched targeted agents, when available. Regimens included one or more therapies targeting PIK3CA, mTOR, BRAF, MEK, multikinases, KIT or EGFR. Outcomes of patients with gene aberrations treated with matched therapy were compared with those patients with gene aberrations who were not treated with matched therapy

because of issues such as: eligibility, study availability; insurance coverage and/or logistical problems with the study calendar. For the 175 patients with one aberration, the response rate was 27 percent with matched targeted therapy. The response rate was 5 percent in 116 patients when treated with non-matched therapy.

Patients who received matched targeted therapy had median survival of 13.4 months, while median survival for patients treated with unmatched targeted therapy was nine months. Median failure-free survival in patients who received matched targeted therapy was 5.2 months, compared to 2.2 months for patients who received unmatched targeted therapy.

Further Research Needed

These preliminary results merit further investigation and confirmatory, prospective studies are needed, especially because the study was not a randomized study and therefore biases could influence the results.

"MD Anderson's goal is to better understand the biology involved in each patient's carcinogenesis by testing each tumor for genetic abnormalities driving tumor growth to guide treatment selection. This strategy will lead to the optimization of personalized therapy," Tsimberidou said.

Another goal is to match targeted therapies to patients earlier in treatment.

"When Gleevec was first introduced, it was tested in patients in blast crisis and the response rate was about 15 percent. In contrast, when tested in the front line setting, and with the introduction of similar but increasingly potent second- and third-generation drugs, patients' response rate was close to 100 percent, and now their expected survival is 25 years and counting," said Kurzrock. "Ultimately, to best match treatments to patients and offer the most therapeutic benefit, assessing a patient's molecular markers has to become the standard at diagnosis."

About the Phase I Program The Time is Now

MD Anderson's Phase I program is the largest of its kind and accounts for the majority but not all of the institution's earliest clinical studies. In 2010, of the 11,000 patients who participated in MD Anderson clinical trials, more than 1,150 were enrolled in one of the 120 Phase I trials in the program.

Currently, tumors are tested up for up to 12 molecular aberrations, but at the rate technology is rapidly advancing, Kurzrock expects that number to climb to more than 100 in the near future.

Patients treated in the Phase I Program are typically very ill and all other approved therapies have failed them. Yet they are 'fighters' who are willing to try anything, including studies not specific to their diagnosis to test the effectiveness of a new drug, drug combination or delivery method, said Kurzrock.

"This study affirms what we in the cancer community have been talking about for a decade matching drugs to patients," said Kurzrock. "The time is now. The drugs are here. The technology is here, and with our program at MD Anderson we can bring the two together in hopes to offer the most personalized care for our patients."

In addition to Tsimberidou and Kurzrock, other authors on the all-MD Anderson study included N. G. Iskander, David S. Hong, M.D., Jennifer J. Wheler, M.D., Siqing Fu, M.D., Ph.D., Sarina A. Piha-Paul, M.D., Aung Naing, M.D., Gerald Falchook, Filip Janku, M.D., Ph.D., all assistant professors of the Department of Investigational Cancer Therapeutics; Raja Luthra, Ph.D., professor, Department of Hematopathology, Research and Sijin Wen, Ph.D., Division of Quantitative Sciences.

Source: University of Texas M. D. Anderson Cancer Center
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Old 04-28-2012, 10:44 AM
gdpawel gdpawel is offline
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Default Molecular profiling is still waiting for its first killer app.

What has changed a lot, since the turn of the century, has been the increasing acceptance of the concept that cancer is a very heterogenous disease and that it would be a good thing to personalize cancer treatment.

This is quite a change when oncologists simply accepted the concept of one-size-fits-all treatment. It's a good thing that oncologists are increasingly open to the concept of personalized therapy.

It has become routine to test breast cancer patients for the mutation conferring sensitivity to Herceptin. It is becoming routine to test lung cancer patients for the mutation conferring sensitivity to Iressa and Tarceva. There is the KRAS test in colon cancer.

This, of course, leaves out the three dozen other drugs (and myriad drug combinations) which may often be even more effective in each of these diseases, and it leaves out virtually all of the other forms of cancer.

Then there are the new technologies for measuring the expression (biological activity) of literally hundreds to thousands of genes as part of a single test. There are two main technologies involved: RT-PCR (reverse transcription polymerase chain reaction) and DNA microarray.

So what research scientists in universities and cancer centers have been doing for the past ten years is to try and figure out a way to use this technology to look for patterns of gene expression which correlate with and predict for the activity of anticancer drugs.

There are lots of things which determine if drugs work, beyond the existence of a given "target." 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?

I think it's a very good idea to continue to develop molecular tests: they have utility in specific situations; it's just that it's absolutely crazy to be putting 99% of resources into tests which have 1% of the current potential utility. What we need is a balanced approach to developing, applying, and improving tests based on both molecular profiling and functional profiling.

The whole concept of using molecular "signatures" of any kind to do anything beyond the most straightforward of cases (i.e. single gene mutations, etc.) is so flawed that everyone should have seen the problems at the beginning.

The reason no one seemingly sees it now can be explained by the facts that the technology itself is so elegant and beautiful. But a beautiful biological technology is no different than a beautiful computer technology - it's not worth much without some very good applications ("apps"), and personalized molecular medicine is still waiting for its first killer app.

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 nice, 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

Human beings are demonstrably more than the sum of their genes. Cancer biology and the study of cancer therapy are many things, but simple is not one of them. Complex problems require solutions that incorporate all of their complexities, however uncomfortable this may be for genomic investigators.

Gene signatures test for theoretical candidates for targeted therapy. Genomic predictions are based 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 a refinement of statistical data, like conventional treatment is based on previous randomized clinical trials (population studies).

The substance of cancer, its responsiveness to therapeutics and its ultimate cure, require a more definitive analysis. By studying human cellular behavior within the context of vascular, stromal and inflammatory elements, the functional profiling platform provides the closest approximation of human biology possible.

The original Human Genome Project (the world's most expensive telephone book*) dealt with a homogeneous population of normal diploid cells. This is different from primary tumors, which are heterogeneous and have a genomic signature unique to each and every patient. Functional profiling is a biomarker of heterogeneous cancer cells and genomic signatures unique to every individual patient.

* The sequencing of the entire human genome gave us the address and the next door neighbors of every human gene, yet we don't know what they do, how they do it, why they do it, or who they do it with. - Dr. Robert A. Nagourney
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Last edited by gdpawel : 04-06-2013 at 03:44 PM. Reason: additional info
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Old 04-28-2012, 10:45 AM
gdpawel gdpawel is offline
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Default Is it the Gene or the Epigene?

Because there is technology to look at the gene, the focus has become the gene. Many markers, genetic amplifications, point mutations, etc. have been found that supposedly delineate hard-coded genotypic changes that lead to cancer for specific organs and tissues. And the list continues to grow.

However, many of these so-called mutations may be found in healthy cells. The question becomes whether genetic changes are the real molecular cause of cancer? Research over the past few years suggests that they are not. Newer insights into the cancer epigenome could point the way to more effective treatments.

Epigenetics may have important implications for the treatment of disease, most notably cancer. Epigenetics is the study of molecular modifications which sit on top of the DNA in our cells, in effect switching our genes on and off, telling our cells how they should behave.

Research scientists from places like Edinburgh University, McGill University, MD Anderson and Johns Hopkins are now realizing that if those epigenetic markings are disrupted, causing a gene to become incorrectly active or silent, a healthy cell could become diseased. They are beginning to uncover the mechanisms behind these switches and the circumstances under which changes occure.

Without cell function analysis though, gene therapy would be beyond imagination. Tissue culture methods have made gene therapy possible. The ability to trasfect cultured cells with DNA gene sequences has allowed scientists to assign functions to different genes and understand the mechanisms that activate or redress their function. The interaction between cell biology and genetics gave birth to molecular biology.

The set of all malignant cells that could evolve must apply to "all" pathways of tumor cell evolution and "all" combinations of genetic and epigenetic alterations. It must be independent of any particular pathway of tumor cell evolution. The normal cellular machinery that potentially can carry out malignant behavior is encoded within the normal human genome, essentially the same for all types of cancer.

Cell culture assays with cell-death endpoints have allowed the identification of clinically relevant gene expression patterns which correlate with clinical drug resistance and sensitivity for different drugs in specific diseases. There is no single gene whose expression accurately predicts therapy outcome, emphasizing that cancer is a complex disease and needs to be attacked on many fronts.

Functional tumor cell profiling assesses the activity of a drug upon combined effect of all cellular processes (cell "population" level rather than at the "single" cell level), using combined metabolic (cell metabolism) and morphologic (structure) endpoints.

Molecular tests, such as those which identify DNA or RNA sequences or expression of individual proteins often examine only one component of a much larger, interactive process. Drug resistance and sensitivity is multifactorial. Functional tumor cell profiling can show this at the cell population level, measuring the interaction of the entire genome.

Functional tumor cell profiling visualizes directly the drug effect upon cancer cells. Photomicrographs of actual tumor cells show the condition of cells as they are received and enriched in the lab, and also the conditions of control cells post-culture.

In this visualization, the microscopic slides sometime show that the exact same identical individual culture well, shows some clusters have taken up vast amounts of the molecular drug, while right next door, clusters of the same size, same appearance, same everything haven't taken up any of the drug.

Not only is this an important predictive test but it is also a unique tool that can help to identify newer and better drugs, evaluate promising drug combinations, and serve as a "gold standard" correlative model with which to develop new DNA, RNA, and protein-based tests that better predict for drug activity.

The cell-based profiling platform has the capacity to measure genetic and epigenetic events as a functional, real-time adjunct to static genomic and proteomic platforms.

Epigenetic Factors: [url]http://cancerfocus.org/forum/showthread.php?t=455
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Old 04-28-2012, 10:49 AM
gdpawel gdpawel is offline
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Default Molecular vs Functional (Cytometric) Profiling

There are lots of things which determine if drugs work, beyond the existence of a given "target." 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?

We can currently test virtually all classes of drugs: traditional cytotoxic drugs, which remain the workhorses of cancer chemotherapy. Targeted drugs, such as the kinase inhibitors. Drugs which target the blood supply of the tumor. Drugs which activate the immune system to kill cancer. Combinations of drugs.

"Molecular" tests have 1% of the current capabilities of the tests which we have today. It's a very good idea to continue to develop molecular tests: they have utility in specific situations; it's just that it's absolutely crazy to be putting 99.99% of resources into tests which have 1% of the current potential utility. What we need is a balanced approach to developing, applying, and improving tests based on both molecular profiling and functional profiling.

With regard to the British NHS, British NHS bases drug approval and drug use not only on effectiveness (American, FDA criterion) but also on cost-effectiveness (something which the FDA and health insurance companies are currently not permitted to use as a criterion). As a result, the number of cancer drugs used in the UK is less than in the USA and the amount of money spent on cancer chemotherapy is much, much less.

But the British NHS is constantly pressured by the public to approve new cancer treatments. New cancer drugs are horrendously expensive (thousands of dollars per month), and the British NHS is looking for politically-palatable ways of continuing to control the use of anticancer drugs.

This is the key quote from a Newsweek story about the British NHS:

"Importantly," Mr. Peach added, "tests can also predict whether certain drugs won't work - sparing patients potentially unnecessary treatment and making things more cost-effective."

I'm quite certain that the British NHS would be completely uninterested in the cell-based assay testing approach. Trying to identify drugs and drug combinations which have the best chance of working and putting them together in complex combinations, when appropriate, as opposed to
using KRAS and EGFR testing to avoid the use of specific expensive drugs, in specific situations.

With respect to the circulating tumor cell approach; the yield of tumor cells from peripheral blood is much too low for cell-based assay testing. Additionally, there are major advantages in studying tumors in native, three dimensional conformation (there is a phenomenon known as "multicellular resistance" which cannot be tested or observed in single cells).

However, there is a lot of promise in using circulating tumor cells for "molecular" testing. The problem is simply the very limited utility of "molecular" tests. There have been reports of companies reporting out results on circulating tumor cells. Frankly, they are not found to be credible (or particularly useful), and there hasn't been any published data to support this, at present.

Personalized Cancer Cytometrics More Accurate than Molecular Gene Testing

[url]http://cancerfocus.org/forum/showthread.php?t=3490
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Old 04-28-2012, 10:53 AM
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Default Tarceva (Erlotinib) in Lung Cancer — Molecular and Clinical Predictors of Outcome

A subsequent study from another laboratory did not show correlations between gene mutations and patient survival.

Tarceva (Erlotinib) in Lung Cancer — Molecular and Clinical Predictors of Outcome

Ming-Sound Tsao, M.D., Akira Sakurada, M.D., Ph.D., Jean-Claude Cutz, M.D., Chang-Qi Zhu, M.D., Ph.D., Suzanne Kamel-Reid, Ph.D., Jeremy Squire, Ph.D., Ian Lorimer, Ph.D., Tong Zhang, M.D., Ni Liu, M.Sc., Manijeh Daneshmand, M.D., Paula Marrano, M.Sc., Gilda da Cunha Santos, M.D., Ph.D., Alain Lagarde, Ph.D., Frank Richardson, D.V.M., Ph.D., Lesley Seymour, M.D., Ph.D., Marlo Whitehead, M.Sc., Keyue Ding, Ph.D., Joseph Pater, M.D., and Frances A. Shepherd, M.D.

Background:

A clinical trial that compared erlotinib with a placebo for non–small-cell lung cancer demonstrated a survival benefit for erlotinib. We used tumor-biopsy samples from participants in this trial to investigate whether responsiveness to erlotinib and its impact on survival were associated with expression by the tumor of epidermal growth factor receptor (EGFR) and EGFR gene amplification and mutations.

Methods:

EGFR expression was evaluated immunohistochemically in non–small-cell lung cancer specimens from 325 of 731 patients in the trial; 197 samples were analyzed for EGFR mutations; and 221 samples were analyzed for the number of EGFR genes.

Results:

In univariate analyses, survival was longer in the erlotinib group than in the placebo group when EGFR was expressed (hazard ratio for death, 0.68; P=0.02) or there was a high number of copies of EGFR (hazard ratio, 0.44; P=0.008). In multivariate analyses, adenocarcinoma (P=0.01), never having smoked (P<0.001), and expression of EGFR (P=0.03) were associated with an objective response. In multivariate analysis, survival after treatment with erlotinib was not influenced by the status of EGFR expression, the number of EGFR copies, or EGFR mutation.

Conclusions:

Among patients with non–small-cell lung cancer who receive erlotinib, the presence of an EGFR mutation may increase responsiveness to the agent, but it is not indicative of a survival benefit.

Source: N Engl J Med 2005; 353:133-144July 14, 2005

[url]http://www.nejm.org/doi/full/10.1056/NEJMoa050736
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Old 04-28-2012, 10:55 AM
gdpawel gdpawel is offline
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Default Genotype does not equal Phenotype

This genotying assay is interesting because the realization is that genotype does not equal phenotype. 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. The 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.

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 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.

Until such time as cancer patients are selected for therapies predicated upon their own unique biology, we will confront one targeted drug after another.

A better solution to this problem is to investigate the targeting agents in each individual patient’s tissue culture, alone and in combination with other drugs, to gauge the likelihood that the targeting will favorably influence each patient’s outcome.

Functionally (cytometric) profiling these results to date in patients with a multitude type of cancers suggest this to be a highly productive direction.

Multiple mutations and cancer

[url]http://www.ncbi.nlm.nih.gov/pmc/articles/PMC298677/
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Old 05-01-2012, 06:55 PM
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Default The Unfulfilled Promise of Genomic Analysis

Dr. Robert Nagourney
Medical and Laboratory Director
Rational Therapeutics, Inc.
Long Beach, California

In the March 8 issue of the New England Journal of Medicine, investigators from London, England, reported disturbing news regarding the predictive validity and clinical applicability of human tumor genomic analysis for the selection of chemotherapeutic agents.

As part of an ongoing clinical trial in patients with metastatic renal cell carcinoma (the E-PREDICT) these investigators had the opportunity to conduct biopsies upon metastatic lesions and then compare their genomic profiles with those of the primary tumors. Their findings are highly instructive, though not terribly unexpected. Using exon-capture they identified numerous mutations, insertions and deletions. Sanger sequencing was used to validate mutations. When they compared biopsy specimens taken from the kidney they found significant heterogeneity from one region to the next.

Similar degrees of heterogeneity were observed when they compared these primary lesions with the metastatic sites of spread. The investigators inferred a branched evolution where tumors evolved into clones, some spreading to distant sites, while others manifested different features within the primary tumor themselves. Interestingly, when primary sites were matched with metastases that arose from that site, there was greater consanguinity between the primary and met than between one primary site and another primary site in the same kidney. Another way of looking at this is that your grandchildren look more like you, than your neighbor.

Tracking additional mutations, these investigators found unexpected changes that involved histone methyltransferase, histone d-methyltransferase and the phosphatase and tensin homolog (PTEN). These findings were perhaps among the most interesting of the entire paper for they support the principal of phenotypic convergence, whereby similar genomic changes arise by Darwinian selection. This, despite the observed phenotypes arising from precursors with different genomic heritages. This fundamental observation suggests that cancers do not arise from genetic mutation, but instead select advantageous mutations for their survival and success.

The accompanying editorial by Dr. Dan Longo makes several points worth noting. First he states that “DNA is not the whole story.” This should be familiar to those who follow my blogs, as I have said the same on many occasions. In his discussion, Dr Longo then references Albert Einstein, who said “Things should be made as simple as possible, but not simpler.” Touché.

I appreciate and applaud Dr. Longo’s comments for they echo our sentiments completely. This article is only the most recent example of a growing litany of observations that call into question molecular biologist’s preternatural fixation on genomic analyses. Human biology is not simple and malignantly transformed cells more complex still. Investigators who insist upon using genomic platforms to force disorderly cells into artificially ordered sub-categories, have once again been forced to admit that these oversimplifications fail to provide the needed insights for the advancement of cancer therapeutics. Those laboratories and corporations that offer “high price” genomic analyses for the selection of chemotherapy drugs should read this and related articles carefully as these reports portend a troubling future for their current business model.

All laboratory platforms are subject to “sampling errors”. That is, the tissue procured may not be reflective of the overall biology of the disease. This however is compounded by laboratory platforms that use FNA’s to measure genes or other “analytes” that are not functional parameters of the disease process, in all its complexity. These are instead mere reflections of the disease process, as it were, a veneer of information gleaned from the most superficial surface.

To address smapling errors, we prefer large specimens which are assessed in their native state, not propagated or sub=cultured (thereby avoiding addtional artifacts). These are preferably obtained from metastatic sites, which often reflect greater degeees of resistance over the tumor primaries, giving us the best “shot” at both. We know from extensive clinical experience that many (most) patients that have responses to systemic therapy, have overall improvement with only a minority having true “mixed” responses. We also know that the tumors and their metastatic lesions share biologic similarities that provide useful insights into the tumor’s relative sensitivity to drugs. Even still, the subsequent re-growth of tumors, may reflect clonal expansion resulting from the elimination of the more sensitive tumors and emergence of a new dominant clone. To address this, we will often re-biopsy and re-dedicate our efforts to controlling the second or subsequent clones.

All of these theoretical issues are hurdles to be overcome. They contribute to the fact that, although our lab analyses consistently double objective response rates, they are not perfect predictors. It is extremely important to remember that all the medical oncologists in practice today confront all of these same issues (heterogeneity, clonal divergence, differeing biology from primary to met, etc) yet they select drugs and combinations with absolutely no guidance whatsover!

[url]http://robertanagourney.wordpress.com/2012/03/12/the-unfulfilled-promise-of-genomic-analysis/#respond
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Old 05-18-2012, 06:44 PM
gdpawel gdpawel is offline
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Default G719X and the Novel Mutations and Response to Targeted Therapies

The exon 18 mutation known as a G719X can respond to Tarceva, even though a patient made be EGFR negative. Fortunately, some physicians don't follow the so-called rules of chasing gene mutations. If you have the EGFR mutation, give it out. If you don't have the EGFR mutation, don't give it out.

When it comes to "drug selection" though, the molecular investigator can only measure those analytes in paraffin wax that they know to measure. If you are not aware of and capable of measuring a biologically relevant event, you cannot seek to detect it. If you don't know about the G719X, you don't know what to look for, and you aren't going to find it. The same goes for all the other loads of mutations clinicians don't know about, ABC, XYZ, you name it.

Originally, Xalkori was developed for patients who carried the CMET mutation. However, they later found a responding subpopulation that was actually carrying an unrecognized ALK gene rearrangement. Nexavar was originally evaluated for the treatment of BRAF mutation positive patients. Yet it was the drug's cross reactivity with the VEFG tyrosine kinases that lead to broader clinical applications.

The point is, each of these phenomena represents accidental successes. The lessons learned from this is that cancer biology is complex. Actually, it doesn't matter why Tarceva worked, so long as it did. I understand that there is reason to believe that the more potent irreversible EGFR/HER2 dual inhibitor Neratinib (HKI-272) may be even more selective for this point mutation.

The premise of the functional (cytometric) profiling platform is that the observation of a biological signal identifies a candidate for therapy whether we understand or recognize the target. Were it not for the clinical observation of response in patients, investigators would been unlikely to make the discoveries that provide such good clinical responses.

When cell function analysis first identified lung cancer as a target for Iressa, and began to administer the closely related Tarceva to lung cancer patients, neither Lynch nor Paez had identified the sensitizing EGFR mutations. That had absolutely no impact upon the excellent responses that were observed with cell function analysis.

It didn't matter why it worked, but that it worked. Might we not use functional analytical platforms (functional cytometric profiling) to gain insights into the next, and the next, and the next generation of drugs and therapies that target pathways like MEK, ERK, SHH, FGFR, PI3K, etc.?

Source: Cell Function Analysis

Response to second-line Tarceva (erlotinib) in an EGFR mutation-negative patient with non-small-cell lung cancer

[url]http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3267591/
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Last edited by gdpawel : 06-26-2013 at 12:05 PM. Reason: additional info
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Old 03-29-2013, 01:45 PM
gdpawel gdpawel is offline
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Default Targeted Cancer Therapies Doomed to Fail?

By Michael Smith, MedPage Today
Reviewed by Dori F. Zaleznik, MD; Associate Clinical Professor of Medicine, Harvard Medical School, Boston

Studies from two separate groups found that KRAS mutations, both preexisting and acquired, explained resistance to EGFR that emerges during therapy for colorectal cancer with single-drug targeted treatment.

Note that the KRAS mutations were detectable in blood samples well before treatment failure was observed.

Resistance to targeted cancer therapies may be almost inevitable, at least if they are used alone, two groups of researchers reported online in Nature.

Mathematical modeling, based on genetic testing of colorectal cancer patients, suggests that resistance already exists even before targeted therapy begins, according to Luis Diaz, MD, of Johns Hopkins Kimmel Cancer Center, and colleagues.

One effect of single-agent targeted therapy, they noted, is to allow tumor cells containing resistance mutations to grow and prosper, leading to disease progression.

A second group, led by Alberto Bardelli, PhD, of the Institute for Cancer Research and Treatment in Turin, Italy, found some evidence of preexisting resistance, but added that resistance could also emerge as a result of single-agent targeted treatment.

The solution, both groups argued, may be to use combination therapies to delay or prevent progression.

Molecules that block the epidermal growth factor receptor (EGFR) often have a dramatic initial effect on cancers driven by the receptor, Diaz and colleagues noted.

But resistance almost always arises within a few months of starting therapy, leading to relapse, although the exact mechanisms of the resistance have been unclear.

To help clarify the situation, they studied 28 patients with metastatic colorectal cancer, a disease in which patients whose tumors have a wild-type KRAS gene are often sensitive to EGFR blockade.

Four of the patients already had KRAS mutations at the start of monotherapy with panitumumab (Vectibix), a monoclonal antibody aimed at EGFR. But nine of the remaining 24 with normal KRAS developed mutations about 5 or 6 months after starting treatment.

Mathematical modeling, Diaz and colleagues wrote, showed that the parent cells of those with KRAS mutations must have been present before the panitumumab treatment started.

“These resistance mutations develop by chance as cancer cells divide so that tumors always contain thousands of resistance cells,” Diaz said in a statement, adding that the findings likely apply to any targeted cancer therapy.

Co-author Bert Vogelstein, MD, also of Johns Hopkins, added that the finding means that “long-term remissions of advanced cancers will be nearly impossible with single targeted agents.”

The research team also noted that their method – testing tumor DNA found in the blood – is noninvasive and was able to detect changes in KRAS long before those changes translated into renewed tumor growth.

That should allow physicians the opportunity to alter the treatment, perhaps by adding agents to the regimen.

“The good news is that there is a limited number of pathways that go awry in cancer, so it should be possible to develop a small number of agents that can be used in a large number of patients,” Vogelstein said in a statement.

Bardelli and colleagues reached similar conclusions after studying colorectal tumor cell lines and a group of 10 patients with metastatic disease who were being treated with cetuximab (Erbitux), a chimeric antibody aimed at EGFR.

They found that preexisting KRAS mutations were amplified in one patient and emerged after treatment in six others.

The resistance mutations were detectable in blood samples as early as 10 months before radiological assessment confirmed that the disease had progressed, Bardelli and colleagues said.

“Our results suggest that blood-based noninvasive monitoring of patients undergoing treatment with anti-EGFR therapies … could allow for the early initiation of combination therapies that may delay or prevent disease progression,” they concluded.

The study by Diaz and colleagues was supported by The Virginia and D. K. Ludwig Fund for Cancer Research, the National Colorectal Cancer Research Alliance, the NIH, the National Cancer Institute, the European Research Council, the Austrian Science Fund, and the John Templeton Foundation.

The authors declared competing financial interests, including affiliations with Personal Genome Diagnostics and Inostics.

The study by Bardelli and colleagues had support from the European Union Seventh Framework Programme, the Associazione Italiana per la Ricerca sul Cancro, the Regione Piemonte, the Fondazione Piemontese per la Ricerca sul Cancro, Oncologia Ca’ Granda ONLUS, Mr William H. Goodwin and Mrs Alice Goodwin and the Commonwealth Foundation for Cancer Research, the Experimental Therapeutics Center of Memorial Sloan-Kettering Cancer Center, the Society of MSKCC, the NIH, the Beene Foundation, and the Regione Lombardia and Ministerio Salute.

The authors declared they had no competing financial interests

[url]http://www.nature.com/nature/journal/vaop/ncurrent/full/nature11219.html

[url]http://www.nature.com/nature/journal/vaop/ncurrent/full/nature11156.html
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