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  #1  
Old 06-23-2012, 01:42 PM
gdpawel gdpawel is offline
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Default Personalized Medicine And Cancer Care

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

Findings presented at the 41st Annual Meeting of the European Society for Clinical Investigation in Uppsala, Sweden and the Annual Meeting of the American Assoication for Cancer Research (AACR) in San Diego, CA concluded that the functional cytometric profiling platform is relevant for the study of both "conventional" and "targeted" anti-neoplastic drug agents (anti-tumor and anti-angiogenic activity) in primary cultures of "fresh" human tumors.

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

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

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

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

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

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

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

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

Literature Citation:

Functional profiling with cell culture-based assays for kinase and anti-angiogenic agents Eur J Clin Invest 37 (suppl. 1):60, 2007
Functional Profiling of Human Tumors in Primary Culture: A Platform for Drug Discovery and Therapy Selection (AACR: Apr 2008-AB-1546)
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Last edited by gdpawel : 05-10-2013 at 01:04 AM. Reason: post full article
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  #2  
Old 06-23-2012, 01:58 PM
gdpawel gdpawel is offline
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Default DNA is not the whole story

Pharmacogenomics can be defined as the study of how a person's genetic makeup determines response to a drug. Whether a medicine works well for you or whether it causes serious side effects, depends, to a certain extent, on your genes.

A challenge facing pharmacogenomic profiling in cancer cell lines is the number and complexity of interactions a drug has with biological molecules in the body. Variations in many different molecules may influence how someone responds to a medicine. Teasing out the genetic patterns associated with particular drug responses involves some intricate and time-consuming scientific detective work.

DNA is not the whole story. Genomics has provided sophisticated target therapies, but cellular pathways contain redundancies that can be activated in response to inhibition of one or another pathway, thus promoting emergence of resistant cells and clinical relapse.

Cancer cells utilize cross-talk and redundancy to circumvent targeted therapies. They back up, zig-zag and move in reverse, regardless of what the sign posts say. Using genomic signatures to predict response is like saying the Dr. Seuss and Shakespeare are truly the same because they use the same words.

The building blocks of human biology are carefully construed into the complexities that we recognize as human beings. However, appealing genotyping analysis may appear to those engaged in this field, it will be years before these profiles can approximate the vagaries of human cancer.

The endpoints genotyping analysis are gene expression, examining a single process (pathway) within the cell or a relatively small number of processes (pathways) to test for "theoretical" candidates for targeted therapy.

The endpoints of phenotyping analysis are expression of cell-death, both tumor cell-death and tumor associated endothelial (capillary) cell-death (tumor and vascular death), and examines not only for the presence of the molecular profile, but also for its functionality, the interaction with other genes, proteins and other processes occurring within the cell, and for its "actual" response to anti-cancer drugs (not theoretical susceptibility).

Phenotyping analysis measures biological signals rather than DNA indicators, provides clinically validated information and plays an important role in cancer drug selection. The data that support phenotyping analysis is demonstrably greater and more compelling than any data currently generated from genotyping analysis.

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

We don't know how to handle one gene, never mind 20,000 genes. To put this in context, two percent of the human genome that codes for known proteins (the part that everyone currently studies) represents only 1/20 of the whole story.

It's not just PCR and the microarrays, 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 why 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 do different than a beautiful computer technology - it's not worth much without some very good applications ("apps") and we will confront one targeted drug after another.

A more highly productive direction would be to investigate the targeting agents in each individual patient's tissue culture, alone and in combination with other drugs, to guage the likelihood that the targeting will favorably influence each patient's outcome.

The need for phenotyping analysis has never been greater. As systems biologists point out, complexity is the hallmark of biological existence. Any attempts to oversimplify phenomena that cannot be simplified, have, and will continue to lead us in the wrong direction.

Systems Biology Is The Future Of Medical Research

[url]http://cancerfocus.org/forum/showthread.php?t=3473
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Old 08-13-2012, 12:20 AM
gdpawel gdpawel is offline
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Default Has the Era of Genomics Come and Gone?

Robert Nagourney, M.D., PhD., one of the pioneers of cell culture assays, 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 turn toward the incomprehensible 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 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 percent of the human genome that codes for known proteins (the part that everyone currently studies) represents only 1/20 of the whole story. One of the most important cancer related genes (PTEN), is under the regulation of 250 separate, unrelated genes. Thus, PTEN, KRAS and 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 thinkers who have attempted to draw 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 functional cytometric profiling performed at laboratories like Rational Therapeutics, Inc. and Weisenthal Cancer Group, has never been greater. As the 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.

Dr. Larry Weisenthal, one of the pioneers of functional cytometric profiling analysis, has described the use of RT-PCR and DNA microarrays in personalized oncology as analogous to the introduction of the personal computer. Dazzling hardware in search of a killer application. This was wonderful technology and the geekiest of people bought them and played with them, but they really didn’t start to do anything for a mass market until the introduction of the first killer application, which was a spreadsheet program called Visicalc.

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 dazzling technology to look for patterns of gene expression which correlate with and predict for the activity of anticancer drugs. Hundreds of millions of dollars have been spent on this effort. Objectively speaking, it’s like the emperor’s new clothes. So far, a qualified failure.

Academics are besides themselves over the promise of the new technology. It seems so cool that it simply must be good for something. How about in the area of identifying drugs which will work in individual patients? It has been a major bust by whatever standard you choose to apply. Objectively, if you compare and contrast the peer-reviewed medical literature supporting the use of functional cytometric profiling for personalizing drug selection versus the correspond literature supporting molecular profiling, the literature supporting functional profiling wins.

Literature Citation: 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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Last edited by gdpawel : 09-18-2012 at 01:16 PM. Reason: additional info
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Old 09-21-2012, 06:44 PM
gdpawel gdpawel is offline
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Default Which Personalized Chemotherapy Testing Methods Are More Direct? Part I

Whole Organism Testing

The most direct way to see if a chemotherapy drug will work is to administer it to the patient and see what happens. This is how most drugs are administered. Each patient, in effect, becomes his/her own experiment. If the drug(s) does not work, the patient needlessly suffers harmful side-effects, valuable treatment time is wasted, costs are incurred and the surviving tumor cells may become more resistant to all chemotherapy drugs, including drugs which the patient has not received. This is what is called clinically-acquired multi-drug resistance. Since patients cannot endure exposure to all of the available chemotherapy drugs, many potentially effective drugs will go untested. Also, since chemotherapy drugs commonly are administered in combination, there is no way to know which drug or drugs in a particular combination may have been more effective and which were less effective or not effective at all.

Cytometric Cancer Testing (Functional Profiling)

It pinpoints the ability of each drug to kill each patient's actual cancer cells. It accurately assesses the combined effect of the fullest possible range of genetic, chemical and mechanical interactions which govern tumor cell susceptibility to drug treatment. Factors include the presence and functionality of proteins and how those proteins interact with all other proteins and with other intracellular and intercellular processes. It accounts for cellular drug uptake, exclusion, expulsion, DNA repair and other resistance mechanisms.

Protein Testing

Proteins are chemicals which govern cell behaviors, such as susceptibility or resistance to specific chemotherapy drugs. They are manufactured within the cell's cytoplasm from blueprints which are carried from the nucleus in the form of messenger RNA. Protein testing is more direct than RNA testing because it reveals whether or not a protein which theorectially was encoded for by DNA actually was produced. However, not all proteins which are involved in response to treatment have been identified, only a small number of known proteins are tested and without additional types of testing, there is no way to tell if a protein which is present actually is functional or how it interacts with other proteins of known and unknown function.

Messenger RNA Testing

RNA acts as a messenger, splitting off from the DNA helix in the cell nucleus and carrying the blueprint for production of proteinis out of the nucleus and into the cytoplasm, essentially the 'factory floor' where proteins are manufactured. Proteins ultimately govern the behaviors of both normal cells and tumor cells. Tests which can detect the presence of specific types of RNA are a more direct method than testing the DNA because it shows that certain genetic information stored in the DNA actually is producing messenger RNA. However, the presence of RNA only implies but does not prove that proteins were produced. The importance of all proteins is not fully understood and so the tests look for only certain RNA sequences. Also, not fully understood is how the various proteins interact to support or interfere with drug sensitivity and resistance.

DNA Testing (Molecular Profiling)

Located in the cell nucleus, DNA contains genetic information which causes cells to behave as they do. DNA encodes for RNA, which encodes for production of proteins. DNA is the farthest upstream factor predisposing a theoretical even occurring at the other end of a highly complex process. Even if all genetic factors were understood, which they are not, the mere presence of a DNA sequence does not mean that the downstream even will occur. If a specific drug targets only a specific DNA sequence, the absence of that sequence might preclude the use of that drug. However, even if the sequence is present, it is still impossible to know if the drug will work. No DNA test can pinpoint specific drugs in the same class or detect synergy in drug combinastions. DNA tests involve tiny fragments of cells. In DNA tests, patients' tumor cells are never exposed to any anti-cancer drugs.

Source: Larry Weisenthal, M.D., PhD., Medical and Laboratory Director, Weisenthal Cancer Group, Huntington Beach, California
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Old 09-21-2012, 06:46 PM
gdpawel gdpawel is offline
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Default Which Personalized Chemotherapy Testing Methods Are More Direct? Part II

Located in the cell nucleus, DNA contains genetic information which causes cells to behave as they do. DNA encodes for RNA, which encodes for production of proteins. DNA is the farthest upstream factor predisposing a theoretical event occurring at the other end of a highly complex process. This is the least direct testing method (DNA testing or molecular profiling).

Even if all genetic factors were understood, the mere presence of a DNA sequence does not mean that the downstream even will occur. If a specific drug targets only a specific DNA sequence, the absence of that sequence might preclude the use of that drug.

However, even if the sequence is present, it is still impossible to know if the drug will work. No DNA test can pinpoint specific drugs in the same class or detect synergy in drug combinastions. DNA tests involve tiny fragments of cells. In DNA tests, patients' tumor cells are never exposed to any anti-cancer drugs.

RNA acts as a messenger, splitting off from the DNA helix in the cell nucleus and carrying the blueprint for production of proteinis out of the nucleus and into the cytoplasm, essentially the 'factory floor' where proteins are manufactured.

Proteins ultimately govern the behaviors of both normal cells and tumor cells. Tests which can detect the presence of specific types of RNA are a more direct method than testing the DNA because it shows that certain genetic information stored in the DNA actually is producing messenger RNA. This is a more direct testing method (RNA testing).

However, the presence of RNA only implies but does not prove that proteins were produced. The importance of all proteins is not fully understood and so the tests look for only certain RNA sequences. Also, not fully understood is how the various proteins interact to support or interfere with drug sensitivity and resistance.

Proteins are chemicals which govern cell behaviors, such as susceptibility or resistance to specific chemotherapy drugs. They are manufactured within the cell's cytoplasm from blueprints which are carried from the nucleus in the form of messenger RNA.

Protein testing (proteomic profiling) is more direct than RNA testing because it reveals whether or not a protein which theoretically was encoded for by DNA actually was produced.

However, not all proteins which are involved in response to treatment have been identified, only a small number of known proteins are tested and without additional types of testing, there is no way to tell if a protein which is present actually is functional or how it interacts with other proteins of known and unknown function.

Then there is the most direct testing method of whole cell testing (short of administering a drug to the patient and see what happens). The ability to pinpoint each drug to kill each patient's actual cancer cells (functional profiling). To accurately assesses the combined effect of the fullest possible range of genetic, chemical and mechanical interactions which govern tumor cell susceptibility to drug treatment.

Factors include the presence and functionality of proteins and how those proteins interact with all other proteins and with other intracellular and intercellular processes. It accounts for cellular drug uptake, exclusion, expulsion, DNA repair and other resistance mechanisms.

Source: Larry Weisenthal, M.D., PhD., Medical and Laboratory Director, Weisenthal Cancer Group, Huntington Beach, California
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Old 10-10-2012, 01:51 AM
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Default Cancer Patients Unaware of Personalized Medicine Choices?

(Medscape Oncology) Although the cancer field is marching on toward personalized medicine, with drugs being targeted to specific tumors, many patients are unaware that this revolution is taking place, a new survey shows.

"Clearly, there remains a need for patients to be better informed about personalized medicine, which is a shared responsibility amongst the multidisciplinary healthcare team, patient support groups, and the media," said Sabine Tejpar, MD, University Hospital of Leuven, Belgium. She was presenting the results of the survey here at the 2012 European Society for Medical Oncology (ESMO) Congress.

The survey was conducted by telephone and involved 811 patients from Argentina, China, France, Germany, Italy, Spain, and the United Kingdom. These patients had been diagnosed in the last 5 years with late-stage breast cancer (n = 164 patients), stage 3 or 4 non-small cell lung cancer (n = 157), or metastatic colorectal cancer (n = 490).

All of these cancer types have targeted therapies for certain patient subgroups: for instance, in breast cancer, there is trastuzumab (Herceptin, Genentech) for tumors that are HER2+ and hormonal therapy for breast cancer that is ER+; in NSCLC, there is erlotinib (Tarceva, Osi Pharmaceuticals) and gefitinib for tumors that are EGFRm+ and crizotinib (Xalkori, Pfizer) for tumors that have the ALK rearrangement. In colorectal cancer, there is cetuximab (Erbitux, Imclone) and panitumumab (Vectibix, Amgen), which is also for tumors of KRAS wild type.

For patients to benefit from these targeted therapies, a tumor sample must be sent for analysis, and this biomarker analysis can take 1 week or longer.

The survey revealed that most patients (74%) would be prepared to delay treatment for 2 weeks or longer in order to undergo additional tumor testing, in the hope that they may benefit from one of these targeted therapies. In addition, the majority of patients would allow hospitals to retain their tumor samples for future research, Dr. Tejpar reported.

"It was really striking that participants were willing to allow hospitals to retain their tumor samples even if this didn't directly relate to their own treatment. It shows that they want to advance research and help others with the disease," Dr. Tejpar said.

Of concern, however, was the finding that 32% of patients taking part in this survey were not aware that personalized medicine was available for their cancer. "There remains considerable scope for physicians and support groups to better inform patients that not all tumors are the same and that established and emerging tests may be able to determine which treatments may be the most effective for their particular tumor," the authors concluded.

Difficult Conversations

"I was not surprised by this finding," Dr. Tejpar commented. "This is a difficult conversation for a doctor to have with a patient," she said, and she suspects that many clinicians will hesitate before starting a discussion about personalized medicine. It involves asking the patient for a biopsy, but some of the biomarkers are rare, and patients have only a small chance of being suitable for a targeted treatment. It can be quite time consuming to explain all of this, and it can be disappointing for patients if it turns out that they do not have the biomarker that makes them eligible for the treatment.

However, she added, this is now evidence-based medicine, and "so I would urge clinicians to go ahead and have this conversation."

"It is a difficult conversation," agreed Jolanta Gore-Booth, founder and president of EuropaColon, a patient advocacy organization for colorectal cancer. Often there is a lot of hype surrounding a new targeted drug, and it can be difficult to explain to patients why they are not eligible. Another issue in European countries is that even if the patient is eligible and the drug is approved, costs may not be reimbursed, she said.

"Personalized medicine can be a really confusing concept for the public to get to grips with," Gore-Booth commented. "We need to improve public education and the way it is delivered."

"Cancer patients have a right to know about personalized medicine," she said, because "such knowledge ultimately has the power to influence their overall survival."

Speaking at a press conference ahead of a presentation at the ESMO patient seminar, Gore-Booth said that the promise of personalized medicine is to deliver "the right treatment for the right patient at the right time."

"But the reality is a little different," she said. "Between 2000 and 2009, there have been only 29 new cancer drugs and only 6 predictive markets in only 3 tumor types," said.

"Actually, this is good progress," commented Josef Tabernero, MD, head of medical oncology at Val d'Hebron Hospital, Barcelona, Spain, who was moderating the press conference.

Dr. Taberno is also chair of the ESMO 2012 Scientific Committee. Speaking to Medscape Medical News before the meeting, he said that the field is rapidly evolving and that the key message this year is that "personalized medicine is becoming a reality."

Data Protection Hampering Research

Also at the press briefing, medical oncologist Paulo Cassali, MD, Instituto Nazionale Tumori, Milan, Italy, raised the issue of how data protection is hampering research in this field of personalized medicine. At present, strict interpretation of European Union law requires that a patient giving informed consent for a tumor sample to be taken needs to be told exactly what the tissue will be tested for, he explained. But the field is evolving so rapidly, with new biomarkers emerging almost daily, that it is useful from a research point of view to test more widely than this — for several different biomarkers. It is also useful to analyze tissue retrospectively, even years after the tissue was obtained and stored. "So we want it to be a more global consent for donating tissue and agreeing to its use in research," he said.

"In some countries, some clinical trials are not approved, and some biobanks are not being populated with tissue because of these concerns about data protection," Dr. Cassali commented. An example is the Netherlands, where tissue could be banked only with a predefined scientific question, until a change in the law a few years ago that permits tissue to be donated for research, allowing the tissue to be used repeatedly in the future.

The survey was funded by Merck Serono, Germany.

2012 European Society for Medical Oncology (ESMO) Congress. Presented September 30, 2012: Abstract 1382.
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Old 10-21-2012, 02:24 PM
gdpawel gdpawel is offline
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Default Combining molecular analysis, chemosensitivity testing & therapy monitoring?

It was suggested in a paper by Dr. Katharina Pachmann that was presented at a recent ASCO trade show, about combining molecular analysis, chemo sensitivity testing in vitro, and therapy monitoring in vivo on disseminated tumor cells (CTC) in breast cancer patients.

Dr. Katharina Pachmann was the investigator who reported at an annual San Antonio Breast Cancer Symposium in 2004, using the CTC technique, German investigators showing that neoadjuvant chemotherapy with paclitaxel (taxol) causes a massive release of cells into the circulation, while at the same time reducing the size of the tumor. The finding helped to explain the fact that complete pathologic responses do not correlate well with improvements in survival (Oncol News Int'l, Vol 14, #5, May '05).

Two years before this, Dr. Christos Kosmas, published a study "Carcinomatous Meningits: Taxane-Induced" which found what is called "dissemination after taxane-based (taxol) chemotherapy. the study concluded that Carcinomatous Meningitis (a CNS metastasis) after a major response to front-line taxane-based regimens represents a grave disease manifestation and its incidence appears increased when compared retrospectivley to non-taxane-treated patients (American Journal Clinical Oncology 2002;63:6-15).

Monitoring CTCs could be utilized for confirmation after the patient is administered assay-directed most beneficial therapeutic agents.

Combining molecular analysis, chemosensitivity testing in vitro, and therapy monitoring in vivo on disseminated tumor cells in breast cancer patients.

Sub-category: Tumor/Cell Biology
Category: Tumor Biology

Meeting: 2010 ASCO Annual Meeting

Session Type and Session Title: This abstract has been published in conjunction with the meeting.

Abstract No: e21116

Citation: J Clin Oncol 28, 2010 (suppl; abstr e21116)

Author(s): K. Pachmann, O. Camara, T. Kroll, S. Carl, N. Rüdiger, C. Rabenstein, A. Plaschke-Schluetter; University of Jena, Jena, Germany; Transfusion Center Bayreuth, Bayreuth, Germany; MMI AG, Zurich, Switzerland

Abstract

Background:

Most breast cancer patients do not die of their primary tumor but from metastases developing sometimes years after the primary tumor has been removed. Cells from the tumor seem to be disseminated continuously during tumor growth and the first spread of tumor cells detectable with conventional methods is in the lymph nodes. Patients with lymph node positive disease have a poorer disease free survival than patients without affected lymph nodes. An increase in circulating epithelial tumor cell (CETC) numbers during adjuvant therapy is correlated with an 11 to 16-fold increase in hazard of relapse indicating increasing resistance to the applied drugs. Therefore, it would be desirable to better characterize these cells, test them for alternate drugs and monitor the actual response to the therapy decided on.

Methods:

For this purpose we have developed a test system comprising isolation of individual CETC from lymph nodes and blood from breast cancer patients for molecular characterization, chemo sensitivity testing of cells from the same sample defining the effectivity of the drugs as percentage of cells killed and measurement of the response of the CETC to the drugs in these patients treated according to guide lines.

Results:

The molecular characteristics and the sensitivity to the applied drugs of the tested cells and the response of the CETC were subsequently compared to clinical outcome.

Conclusions:

The response of CETC to therapy correlated highly with the previously tested chemo sensitivity and the molecular characteristics of these cells. Correlation to relapse or progression free survival is under investigation.

[url]http://meeting.ascopubs.org/cgi/content/abstract/28/15_suppl/e21116
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Old 05-28-2013, 01:46 PM
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Default Personalized Medicine vs Guideline-Based Medicine

Two philosophical approaches to the implementation of optimal health care are emerging, the use of evidence-based guidelines and the application of personalized medicine. Even though both approaches have important merits, they both also can present conflicting priorities that must be reconciled before they can be best leveraged.

Evidence-based guidelines are generated based on the body of clinical data available for a particular question. The highest level of evidence assigned in a guideline is based on multiple randomized controlled clinical trials. In general, randomized clinical trials have specific inclusion and exclusion criteria designed to represent a population broad enough and sufficiently enriched to attain a requisite number of end points and demonstrate a statistically and clinically significant difference in outcome. Subgroup analyses (both those that are prespecified and other post hoc analyses) are often performed to identify characteristics within the study population that are associated with greater benefit from the intervention, with no benefit, or even with harm. Yet these analyses are accompanied by warnings that findings should be cautiously interpreted (1).

Indeed, there is well-deserved skepticism regarding the utility and accuracy of subgroup analysis from clinical trials, and these analyses are therefore generally not used in the formulation of guidelines. Patients (including those enrolled in trials) have multiple characteristics, each of which may influence the behavior and significance of other characteristics. Analysis of a subgroup showing that a single characteristic influences outcome is of limited clinical significance unless multiple variables that may modify the importance of the single variable are considered. However, if well-conducted analyses from multiple sources demonstrate concordant findings, perhaps these subgroup analyses should be considered when guidelines are constructed and revised, given the impracticality of performing randomized clinical trials to answer the question of appropriateness for every possible subgroup.

In the end, the guidelines are usually established based on the inclusion criteria for the trial. The applicability of the guidelines may be questioned, or even suspect, when individual patients within the heterogeneous population to which the guidelines are applied in clinical practice differ in certain critical characteristics from those of the trial population on which the guideline recommendation is based. That is, the generalizability of trial results to clinical practice may be compromised by a number of factors involved in execution of the trial, such as where patients were recruited (e.g., inpatient vs outpatient venue, tertiary referral centers vs primary care centers).

The President's Council of Advisors on Science and Technology noted that personalized medicine refers to the tailoring of medical treatment to the individual characteristics of each patient. It does not literally mean the creation of drugs or medical devices that are unique to a patient, but rather the ability to classify individuals into subpopulations that differ in their susceptibility to a particular disease or their response to a specific treatment. Preventive or therapeutic interventions can then be concentrated on those who will benefit, sparing expense and side effects for those who will not (2). Although the increasing attention directed to personalized medicine has largely focused on the interaction of an individual's genome with specific treatments, any individual characteristics that affect treatment outcomes may be relevant to clinical decision making. If certain subpopulations within the total cohort of a clinical trial were considered unlikely to benefit from the intervention, based for example, on actual subgroup analysis, this hypothesis would need to be tested prospectively in a separate clinical trial to achieve a sufficient level of evidence about the value of the intervention in this patient subpopulation.

Although it is possible to make a case for equipoise in such a situation, once the guidelines include this subpopulation in the general group in which the intervention is recommended based on the results (or entry criteria) of clinical trials, it is difficult to overcome the multidimensional resistance to actually testing “not providing the intervention” when the guidelines recommend otherwise. Thus, the development of evidence-based guidelines based on a relatively broad set of enrollment criteria inhibits the subsequent development of personalized medicine within this “enrollment criteria” space.

The conflict between guideline-based medicine and personalized medicine predominantly occurs when considering withholding a therapy that is recommended or supported by the guidelines but that may not be beneficial for an individual patient. If a subpopulation may not benefit from the therapy, it is important to identify the subpopulation and verify this finding in an appropriate clinical trial. This presents a genuine opportunity to deliver better health care at lower costs by withholding the intervention.

Cultivating a health care culture poised to explore these opportunities is critical. This will entail more active participation from a range of stakeholders, including physicians who will need to embrace equipoise when the data support this position; insurers (including the Centers for Medicare & Medicaid Services) who have traditionally not been involved in the design, funding, and conduct of clinical trials; regulators who will need to develop policies to enable and support this type of patient-centered research; and health care organizations and quality-measurement groups who will need to develop more nuanced approaches to assessing quality of care and processes that monitor guideline implementation.

1. VanderWeele TJ, Knol MJ. Interpretation of subgroup analyses in randomized trials: heterogeneity versus secondary interventions. Ann Intern Med. 2011;154(10):680-683

2. President's Council of Advisors on Science and Technology. Priorities for Personalized Medicine. White House website. [url]http://www.whitehouse.gov/files/documents/ostp/PCAST/pcast_report_v2.pdf

Source: JAMA. 2013;():1-2. doi:10.1001/jama.2013.6629.
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Old 12-05-2013, 01:05 PM
gdpawel gdpawel is offline
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Default Oncology practices that should be stopped?

In ASCO's five more cancer practices that should stop, part of the Choosing Wisely campaign, an initiative of the American Board of Internal Medicine (ABIM) Foundation, the lead author Lowell Schnipper, M.D., from the Beth Israel Deaconess Medical Center in Boston says, "Do not use a targeted therapy unless a patient's tumor cells have a specific biomarker that predicts a favorable response to that therapy."

Targeted therapies are "phenomenally expensive medications," Dr. Schnipper told Medscape Oncology. The use of targeted therapy should be limited to patients who have an assay-verified tumor biomarker that provides a "red or green light" as to whether the tumor cells are susceptible to the therapy.

Specific cancers have genetic abnormalities that predict response to targeted therapies. For example, patients with non-small cell lung cancer (NSCLC) need to be tested for an EML4-ALK translocation before being treated with crizotinib, patients with metastatic NSCLC need to be tested for specific EGFR gene mutations before being treated with afatinib, and patients with melanoma need to be tested for BRAF V600E or V600K mutations before being treated with vemurafenib, dabrafenib, or trametinib.

Some of the list authors, including Dr. Schnipper, report financial relationships with industry, as detailed in the paper (J Clin Oncol. Published online October 29, 2013).

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.

Conflicted Confidence: Academic Oncologists’ Views on Multiplex Pharmacogenomic Testing

[url]http://jco.ascopubs.org/content/early/2014/03/18/JCO.2013.54.8016.full.pdf
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Last edited by gdpawel : 03-31-2014 at 09:33 PM. Reason: Additional info
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