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  #11  
Old 12-18-2013, 10:35 PM
gdpawel gdpawel is offline
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Pharmacogenomics can be defined as the study of how a person’s genetic makeup determines response to a drug. Although any number of labs and techniques can detect mutant genes, this area of pharmacogenomics was ripe for proprietary tests, invented alongside the drug and owned by the drug developer and/or a partner in the diagnostics field.

This business opportunity evolved as more drugs were approved with companion diagnostics. Unfortunately, the introduction of these new drugs has not been accompanied by specific predictive tests allowing for a rational and economical use of the drugs.

Companion diagnostics and their companion therapies are what's being pushed as "personalized medicine" as they enable the identification of likely responders to therapies that work in patients with a specific molecular profile. However, companion diagnostics tend to only answer a targeted drug-specific question and may not address other important clinical decision needs.

These companion diagnostics are being used to predict responsiveness and determine candidacy for a particular therapy often included in drug labels as either required or recommended testing prior to therapy initiation. I certainly would not want to be "denied" treatment because of gene testing. Gene testing is not a clear predictor of a lack of benefit from particular targeted therapies.

Anyone familiar with cellular biology knows that having the genetic sequence of a known gene (genotype) does not equate to having the disease state (phenotype) represented by that gene. It requires specific cellular triggers and specialized cellular mechanisms to literally translate the code into the work horse of the cellular world - proteins.
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  #12  
Old 02-21-2014, 01:33 PM
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Default Scientists challenge the genetic interpretation of biology

A proposal for reformulating the foundations of biology, based on the 2nd law of thermodynamics and which is in sharp contrast to the prevailing genetic view, is published in the Journal of the Royal Society Interface under the title "Genes without prominence: a reappraisal of the foundations of biology". The authors, Arto Annila, Professor of physics at Helsinki University and Keith Baverstock, Docent and former professor at the University of Eastern Finland, assert that the prominent emphasis currently given to the gene in biology is based on a flawed interpretation of experimental genetics and should be replaced by more fundamental considerations of how the cell utilises energy. There are far-reaching implications, both in research and for the current strategy in many countries to develop personalised medicine based on genome-wide sequencing.

Is it in your genes?

By "it" we mean intelligence, sexual orientation, increased risk of cancer, stroke or heart attack, criminal behaviour, political preference and religious beliefs, etcetera. Genes have been implicated in influencing, wholly or partly, all these aspects of our lives by researchers. Genes cannot cause any of these features, although geneticists have found associations between specific genes and all of these features, many of which are entirely spurious and a few are fortuitous.

How can we be so sure?

When a gene, a string of bases on the DNA molecule, is deployed, it is first transcribed and then translated into a peptide - a string of amino acids. To give rise to biological properties it needs to "fold" into a protein.

This process consumes energy and is therefore governed by the 2nd law, but also by the environment in which the folding takes place. These two factors mean that there is no causal relationship between the original gene coding sequence and the biological activity of the protein.

Is there any empirical evidence to support this?

Yes, a Nordic study of twins conducted in 2000 showed there was no evidence that cancer was a "genetic" disease - that is - that genes play no role in the causation of cancer. A wider international study involving 50,000 identical twin pairs published in 2012, showed that this conclusion applied to other common disease as well. Since the sequencing of the human genome was completed in 2001 it has not proved possible to relate abnormal gene sequences to common diseases giving rise to the problem of the "missing heritability".

What is the essence of the reformulation?

At the most fundamental level organisms are energy-consuming systems and the appropriate foundation in physics is that of complex dissipative systems. As energy flows in and out and within, the complex molecular system called the cell, fundamental physical considerations, dictated by the 2nd law of thermodynamics, demand that these flows, called actions, are maximally efficient (follow the path of least resistance) in space and time. Energy exchanges can give rise to new emergent properties that modify the actions and give rise to more new emergent properties and so on. The result is evolution from simpler to more complex and diverse organisms in both form and function, without the need to invoke genes. This model is supported by earlier computer simulations to create a virtual ecosystem by Mauno Rönkkö of the University of Eastern Finland.

What implications does this have in practice?

There are many, but two are urgent.

1. to assume that genes are unavoidable influences on our health and behaviour will distract attention from the real causes of disease, many of which arise from our environment;

2. the current strategy towards basing healthcare on genome-wide sequencing, so called "personalised healthcare", will prove costly and ineffective.

What is personalised health care?

This is the idea that it will be possible to predict at birth, by determining the total DNA sequence (genome-wide sequence), health outcomes in the future and take preventive measures. Most European countries have research programmes in this and in the UK a pilot study with 100,000 participants is underway.

Reference: University of Eastern Finland

Citation: "Scientists challenge the genetic interpretation of biology." Medical News Today. MediLexicon, Intl., 21 Feb. 2014.
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  #13  
Old 03-27-2014, 10:21 PM
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Default Is It Ethical to Deny Cancer Patients Functional Analyses?

Robert A. Nagourney, M.D.

The ethical standards that govern human experimentation have become an important topic of discussion. Clinical trials are conducted to resolve medical questions while protecting the rights and well-being of the participants. Human subject committees known as Institutional Review Boards (IRB’s) not only confront questions of protocol design and patient protection but also the appropriateness of the questions to be answered. The Belmont Report (1979) defined three fundamental principles i) respect for persons, ii) beneficence and iii) justice. These have been incorporated into regulatory guidelines codified in the code of federal regulations like 45 CFR 46.111. One historical experience offers an interesting perspective upon contemporary oncologic practice.

[url]http://www.hhs.gov/ohrp/humansubjects/guidance/belmont.html

With advances in cardiac surgery in the1970s and 1980s, in both valvular and coronary artery bypass, an alarming amount of post-operative bleeding was being observed. To address this complication an enzyme inhibitor named Aprotinin was developed by Bayer pharmaceuticals. The drug works by preventing the body from breaking down blood clots (thrombolysis). This is critical for the prevention of postoperative bleeding. Concerns regarding its safety led to Aprotinin’s temporary withdrawal from the market, but those have been resolved and the drug is again available.

After Aprotinin’s introduction, clinical trials were conducted to test its efficacy. Initial results were highly favorable as the drug consistently reduced post-op bleeding. By December 1991, 455 patients had been evaluated providing strong statistical evidence that Aprotinin reduced bleeding by more than 70 percent. Despite this, trialists continued to accrue patients to Aprotinin versus “no treatment” studies. By December 1992, more than 2,000 patients had been accrued and by October of 1994, the number had increased to more than 3,800 patients. Yet the 75 percent risk reduction remained entirely unchanged. Thus, 3,400 patients at untold cost and hardship were subjected to the risk of bleeding to address a question that had long since been resolved.

In a 2005 analysis, Dean Fergusson et al, decried that it should have been evident to anyone who cared to review the literature that Aprotinin’s efficacy had been established. Further accrual to clinical trials beyond 1991 only exposed patients to unwarranted risk of bleeding, and had no possible chance of further establishing the clinical utility of the intervention. This stands as a striking lack of consideration for patient well-being. Fergusson’s review raises further questions about the ethics of conducting studies to prove already proven points. With this as a backdrop, it is instructive to examine functional profiling for the prediction of response to chemotherapy.

Beginning in 1997, a cumulative meta-analysis of 34 clinical trials (1,280 patients), which correlated drug response with clinical outcome was reported. Drug sensitive patients had a significantly higher objective response rate of 81 percent over the response rate of 13 percent for those found drug resistant (P < 0.0000001).

[url]http://htaj.com/current.pdf

This was met by the ASCO/Blue Cross-Blue Shield Technology Assessment published in Journal of Clinical Oncology (Schrag, D et al J Clin Oncol, 2004) that cried for further clinical trials. A subsequent meta-analysis correlated the outcome of 1929 patients with leukemia and lymphoma against laboratory results and again showed significantly superior outcomes for assay directed therapy (P <0.001) (Bosanquet AG, Proc. Amer Soc Hematology, 2007).

[url]http://jco.ascopubs.org/content/22/17/3631.full

In response, a second ASCO Guideline paper was published in 2011. (Burstein H et al J Clin Oncol, 2011) Although the authors were forced to concede the importance of the field, they concluded that “participation in clinical trials evaluating these technologies remains a priority.”

[urlhttp://jco.ascopubs.org/content/early/2011/07/18/JCO.2011.36.0354.full.pdf

Most recently we conducted a cumulative meta-analysis of 2581 treated patients that established that patients who receive laboratory “sensitive” drugs are 2.04 fold more likely to respond (p < 0.001) and 1.4 fold more likely to survive one year or more (p <0.02) (Apfel C. Proc Am Soc Clin Oncol 2013).

[url]http://meetinglibrary.asco.org/content/118466-132

Each successive meta-analysis has concluded, beyond a shadow of a doubt, that human tumor functional analyses (e.g. EVA-PCD) identify effective drugs and eliminate ineffective drugs better than any other tool at the disposal of cancer physicians today. Not unlike those investigators who continued to accrue patients to trials testing Aprotinin, long after the result were in, oncologists today continue to clamor for trials to prove something which, to the dispassionate observer, is already patently obvious. If we now pose the question “Is it ethical to deny patients functional analyses to select chemotherapy?” the answer is a resounding No!
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  #14  
Old 12-16-2016, 05:15 PM
gdpawel gdpawel is offline
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Default When Genetic Tests Disagree About Best Option For Cancer Treatment

Two widely used tests to analyze the genetics of tumors often don't come to the same conclusions, according to head-to-head analyses.

Authors of two recent studies comparing these tests say doctors need to be careful not to assume that these tests are providing a complete picture of a tumor's genetic variants, when using them to select treatments for cancer patients.

Dr. C. Anthony "Tony" Blau and colleagues at the University of Washington School of Medicine in Seattle compared results from two commonly used tests that are used to identify mutations in tumors. The FoundationOne test is used on tissue samples extracted from tumors. Guardant360 gathers traces of tumor DNA from blood samples.

Blau started out with a small sample of just nine patients, as he reported Thursday in JAMA Oncology. One had no mutations at all recognized by either test. Of the remaining eight, the two tests provided remarkably different results. Only 22 percent of the time (in 10 out of 45 instances) did both tests identify the same mutation.

[url]http://jamanetwork.com/journals/jamaoncology/article-abstract/2593039

That's not to say the tests themselves are technically flawed, Blau told Shots. But each test has its limitations, and so the results vary.

Tests of tumor tissue don't sample the entire tumor. And tumor cells aren't all the same, so a sample doesn't give a complete picture of tumor genetics.

Blood tests sample free-floating cells that break loose from tumors. That's a useful technology if a tumor is hard to sample directly, but again it provides an incomplete snapshot of the cancer's genetic mutations. "They're looking for a needle in a haystack," Blau says.

Blood samples drawn at different times can produce different results, because different cells may be in the blood. And tumors evolve over time, so some of the difference could reflect that as well.

"The mutations you are looking for that might guide you to a particular drug can present in most or only a tiny fraction of cells," Blau said. So either test can fail to detect a clinically important mutation.

These blood tests often include a list of cancer drugs for doctors to consider, based on the mutations detected. The recommendations also varied, because the tests often found different mutations. Only 25 percent of the time (in 9 of 36 cases) did these two tests recommend the same drug among the eight patients in the study.

These observations build on similar results of a somewhat larger study, published in August in the journal Oncotarget. In a sample of 28 patients, researchers found consistent results only about 17 percent of the time.

[url]https://www.ncbi.nlm.nih.gov/pubmed/?term=chae+oncotarget+concordance

"It all boils down to a question of tumor biology," says lead author of that study, Young Kwang Chae, an oncologist and a co-director of the Developmental Therapeutics Program of the Division of Hematology and Oncology at Northwestern University's Feinberg School of Medicine.

"You can never say one test is the gold standard, or that one is better than the other," he said. Because they are looking at different samples, it's not surprising their results vary.

Many of the results from these tests are hard to interpret in the first place. In many instances, the presence of a particular mutation doesn't tell a doctor exactly what form of therapy would work best.

But Chae says when he finds an "actionable genetic alteration" from either test, he uses that that to guide a patient's therapy.

"Both tests are right," argues Dr. Rick Lanman, chief medical officer at Guardant Health, which produces the blood-based Guardant360 test. If either test detects a particular mutation, there is high confidence that the particular mutation exists. And doctors can confidently base therapy on that positive detection, he says.

Doctors could get more complete results if they ran both tests on everybody, "but that's not cost effective," Lanman says.

His counterpart at Foundation Medicine, which makes the FoundationOne test, isn't convinced that both tests are equally reliable. Dr. Vincent Miller says the blood tests can miss a lot more than tests run on tumor tissue.

He points to a recent study of pancreatic cancer. Gene variants very frequently found in pancreatic cancer were detected in 87 percent of tumor samples. But blood tests only found the mutations about 25 percent of the time.

[url]https://www.ncbi.nlm.nih.gov/pubmed/27833075

Miller says his company has a blood test as well as the test for solid tumors, and they're in the process of running a direct comparison, using the same genetic information. That could help clarify how much trust to put in blood tests, he says. "The technology may have gotten a little ahead of the clinical practice and the science," he says.

Doctors may be lulled into thinking that these tests are providing definitive results, but they're not. And that's the overarching message for Blau at the University of Washington.

"You really have to be thoughtful about how you apply these to clinical decision making," he says. "If you don't understand these limitations, if you just treat the reports at face value, that could be leading to instances where oncologists use drugs that are unlikely to be effective."

Citation: When Genetic Tests Disagree About Best Option For Cancer Treatment NPR Health News December 16, 2016
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  #15  
Old 09-15-2017, 01:31 PM
gdpawel gdpawel is offline
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Default Is Cytometric Profiling The Same As Genomic Testing?

Larry M. Weisenthal, M.D., Ph.D.
Laboratory Oncologist

Is Cytometric Profiling the same as Genomic Testing?

No. If you research personalized cancer treatment approaches you will also find information relating to “genomic testing.” This is also known as “molecular testing,” “target profiling,” "gene testing," or by other names. Lately, it's proponents have begun calling it "precision oncology." It is far from precise.

Here is an excerpt from an article appearing in the January 25, 2017 edition of the ASCO Post (ASCO stands for American Society of Clinical Oncology).

"The practical case against precision oncology [genomic testing] is that it is unlikely to benefit most people with cancer. Data from next-generation sequencing of persons with advanced cancers indicate fewer than 10% have actionable mutations.

The only randomized trial of precision medicine, the SHIVA trial, tested whether genetic analyses and pathway-directed therapy produce better outcomes than investigator choice and found no progression-free survival difference between these strategies...

...The biologic case against precision oncology is that it contrasts with our modern understanding of cancer."

[url]http://www.ascopost.com/issues/january-25-2017/what-precisely-is-precision-oncology-and-will-it-work/
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