gpawelski

The particular sequence of DNA that an organism possesses (genotype), or mutational assay, does not determine what bodily or behavioral form (phenotype), or cellular assay, 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. Until such time as cancer patients are selected for therapies predicted upon their own unique biology, we will confront one targeted drug after another. A better solution to this problem would be 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 (cellular assay) profiling these results in patients with a multitude type of cancers suggest this to be a highly productive direction. There is a ray of hope with immunotherapy, after the elements of the cancer industry had put it under a breadbox for over twenty years. Immunotherapy actually does work. However, researchers have no idea why it benefits some people but not others, because releasing the brake facilitates an all-out attack by the immune system, it can cause serious side effects - colitis, skin rashes, impaired pituitary function - that must be managed. The key is identifying the individual patients who stand to benefit (not average populations). Certainly new approaches to immunotherapy are both needed and welcome. It's not the answer to all of cancer, certainly, but when it works, it's helpful.

When they did comprehensive screening for gene mutations at MD Anderson, in a huge number of patients, they found an actionable target in 31%, but, of these 31%, only 10% responded to the targeted therapy. Overall, only 2.4% of all the patients receiving genomic profiling had a response. This is absolutely horrible. I think that genomic profiling is in general a scam, yet virtually everyone is doing it. I think that certain types of targeted genomic profiling is probably worthwhile -- e.g. EGFR mutations in lung cancer, but phenotype analysis can test for the same drugs using cell culture as a platform. San Francisco, CA—Neal J. Meropol, MD, of the University Hospitals Seidman Cancer Center, and Case Western Reserve University, Cleveland, OH, has long advocated against unnecessary treatment and testing of patients with cancer. At the 2015 Gastrointestinal Cancers Symposium, Dr Meropol outlined his reasons why clinicians should not bend to pressure to routinely test all tumors. “Here are my top 10 reasons why I believe we are not ready for routine molecular profiling of tumors,” he told the audience, listing the following reasons. 1. Assay Platform Limitations Variability in the sensitivity and specificity of the many platforms being promoted raises questions regarding analytic validation, said Dr Meropol, asking questions that raise concern. How are the genes selected for these panels? Does the platform look at the transcriptome or just the genome? Are we looking at epigenomic changes that may be relevant in selecting treatments? What is the turnaround time for the results? And what is the cost of these assays? 2. Tumors Are Heterogenous and Complex Mutations in a tumor may be different between sites. “Although they may look the same under a microscope, colon cancers and gastric cancers are extremely complex, and extremely heterogenous in terms of their molecular profiles,” Dr Meropol said. Nor will finding a single driver mutation guarantee that a single drug intervention will be effective, because of “cross talk” between pathways occurring downstream of a key mutation. “If we’re going to use a tumor biopsy for selecting treatment for an individual patient,” he said. “This biopsy should be done proximate to the time that we’re going to intervene with a new therapy.” 3. We Don’t Know the Drivers According to Dr Meropol, definitions used in the MATCH trial for identifying drivers to explore in a clinical trial are not yet good enough for routine care. “The reasons not to try it are that these are costly interventions, they may not work, they have side effects, and they provide false hope. This should not be our routine approach with patients,” he advised. 4. We Don’t Have the Evidence that Links Drugs to These Drivers The best level evidence is an FDA-approved dyad, but Dr Meropol stressed that this level of evidence is missing in nearly all drug cases. “Even if an agent meets a clinical end point, and there’s evidence of target inhibition, and there’s plausible evidence of a predictive or selection assay or analyte,” he said, “until it’s been proved in a prospective clinical trial, the evidence may be viewed as weak in terms of routine clinical practice.” Preclinical evidence is an even poorer prognosticator for patient outcomes. Dr Meropol iterated the need for incentivizing the development of biomarkers worldwide. 5. Investigational Drugs Are Not Widely Available There are limited clinical trial sites; patients have to seek studies and travel for them. “Not everybody lives in close proximity to a research center that has access to multiple clinical trials and new agents,” Dr Meropol said, “and getting compassionate access to a new drug in development is a logistically complicated process. It’s time-consuming and rather opaque.” 6. It Isn’t Practical to Screen Many to (Maybe) Help a Few The evidence is simply not there at this time, he said, highlighting a phase 1 study conducted at M.D. Anderson Cancer Center that intended to show the benefit of identifying clinical trials that might be appropriate for patients’ tumors. Of the 1283 patients assessed, 31% had at least 1 mutation, and among those who could be matched for treatment, approximately 10% had an antitumor response. But the overall response rate based on matching was only 2.4%. 7. There Is No Mechanism to Pay for Drugs for Off-Label Use Off-label use of expensive targeted agents is increasingly scrutinized by payers, and costs are falling on patients. “Recommending cancer drugs with high copays may not be ethical without strong evidence that it’s going to help that individual patient,” he said. 8. Drug Approval Based on Tumor Type, Not on Genotype The current (and old) paradigm is histology-based and requires large prospective phase 3 trials to provide the level of evidence that leads to a FDA and worldwide drug approval. But an emerging paradigm for drug approval is genome-based, using small studies looking for big effect to make decisions, “but we’re simply not there yet,” he said. 9. No Statistical Approach to Interpreting a Series of Anecdotes Dr Meropol asked: How much evidence is needed to conclude that a particular mutation should receive a particular therapy? How many patients are needed with outcome data across how many tissues of origin? And when looking at a major response, how can we distinguish between a fluke and an outcome that is real? The answers to these questions remain unknown. 10. Unintended Consequences for Patients Given the potential for confusion over interpretation, it is important to know who is interpreting the data and making the recommendations. “We don’t want to give our patients false hope,” said Dr Meropol. “We don’t want to subject them to the risks of needless biopsies, and we don’t want to subject them to the financial burden of therapies and procedures that are not destined to help them.” Source: Association for Value-Based Cancer Care (February 2015, Vol 6, No 1 - Personalized Medicine)

Therapies targeted at the specific genetics of a patient's lung cancer have proved harder to realize than expected. Ramaswamy Govindan vividly remembers the first time he treated his patients with the cancer drug gefitinib. It was the start of the millennium, and the outlook for patients with metastatic non-small-cell lung cancer (NSCLC) was dire: less than 40% survived a year after diagnosis. “The second patient I treated was about to go into hospice care,” recalls Govindan, a medical oncologist at Washington University School of Medicine in St Louis, Missouri. “But she went on to live three years before dying of a heart attack.” Gefitinib was approved by the US Food and Drug Administration (FDA) in 2003. Marketed as Iressa by AstraZeneca, its arrival was a watershed moment in the treatment of NSCLC, the most common type of lung cancer. The drug blocks a protein called epidermal growth factor receptor (EGFR), which transmits signals that help to control the division and migration of cancer cells. However, although some patients responded well to the treatment, many others did not. The same was true for another drug that targets EGFR: erlotinib (Tarceva), developed by Genentech and OSI Pharmaceuticals and approved by the FDA in 2004. The only apparent trend was that non-smokers were more likely than smokers to respond to erlotinib. “Back in the day, you would give Tarceva to somebody because they didn't smoke, but in the vast majority of those people it didn't help,” says Mark Kris, a thoracic oncologist at Memorial Sloan Kettering Cancer Center in New York City. In 2004, two research teams — one of which included Kris — discovered the secret1, 2. Both gefitinib and erlotinib were selectively active against lung cancers with hyperactive, mutated versions of the EGFR gene, but ineffective against tumours in which the gene was not mutated. Mutated EGFR is predom-inantly found in a type of NSCLC called adenocarcinoma, which accounts for 40% of lung cancers and is the most common form of the disease in people who have never smoked. The realization that specific genetic variants might help researchers to develop personalized lung-cancer treatments has launched a generation of targeted drugs that can deliver years of additional life to certain subgroups of patients. But some patients are still waiting to reap the medical benefits of the post-genomic era, and many doctors and clinical researchers fear that the low-hanging fruits of lung-cancer genetics may already have been picked. The cancer genome is a battered and scarred landscape of DNA-sequence changes as well as swapped, duplicated and deleted regions. The therapeutic focus is on the subset of these mutated genes — 'drivers' — that are essential for aggressive cell growth. The most useful drivers from a therapeutic perspective are oncogenes, which encode proteins that promote uncontrolled cell division and have the potential to convert a normally functioning cell into a cancer cell. Drugs that target mutant oncogenes might halt or reverse tumour growth. One major lung-cancer oncogene is EGFR. Mutations to the EGFR oncogene are detected in more than 40% of adenocarcinomas. Three drugs are commercially available for EGFR-mutant cancers, and more are in trials. In 2007, researchers uncovered a second driver oncogene that is present in 5–7% of adenocarcinomas. Called ALK, this gene encodes a poorly understood signalling protein and occasionally undergoes a genomic rearrangement that leaves the resulting protein permanently turned on. In 2011, the FDA approved crizotinib (marketed by Pfizer as Xalkori) for NSCLC patients whose tumours exhibit such rearrangements. Phase III trial data presented by Pfizer at the 2014 annual meeting of the American Society for Clinical Oncology (ASCO) indicate that crizotinib can extend the life of patients whose tumours have mutations in ALK. However, the benefits of these targeted drugs are only temporary — after about a year of remission, most tumours acquire resistance. For example, more than half of the tumours treated with EGFR inhibitors acquire a mutation called T790M in the EGFR gene3. This blocks the drug without interfering with the mutant protein's signalling. Tumours often contain genetically distinct cell populations, and many researchers believe that cancer recurrence may represent the evolutionary victory of an already-resistant minority. “Once we start to kill off cells that have the sensitizing mutation, the intrinsically resistant cells start to grow,” says Tony Mok, a clinical oncologist at the Chinese University of Hong Kong. Presentations at this year's ASCO meeting revealed promising clinical-trial data on drugs being developed by Clovis Oncology and AstraZeneca that inhibit the T790M mutant receptor. One molecule induced tumour shrinkage in almost two-thirds of patients. Patients with crizotinib-resistant tumours also received hopeful news this year. Such resistance often arises in the absence of a detectable mutation, which suggests that other mechanisms increase ALK activity to overwhelm crizotinib's modest capacity for inhibition. In April 2014, the FDA moved with unprecedented speed to approve the drug ceritinib (marketed by Novartis as Zykadia) based purely on a phase I trial4 showing a strong clinical response in resistant patients. Subsequent data suggest that ceritinib works equally well in both previously untreated and crizotinib-resistant patients. Ceritinib is 5 to 20 times more potent than crizotinib as an ALK inhibitor, and it is also more selective, says Alice Shaw, an oncologist at Massachusetts General Hospital in Boston, whose team led the phase I trial. At least nine other ALK drugs are in development. Targeted treatments benefit only a minority of lung-cancer patients. For the rest, the hunt continues for drivers that might prove vulnerable to therapy. Most progress has been seen in people diagnosed with adenocarcinoma and who do not smoke, many of whom have cancers that have arisen through one primary driver mutation (see page S12). By contrast, the mutational load in a smoker's tumour can be overwhelming, making it a challenge to separate the signals of likely driver mutations from the noise generated by large numbers of 'passenger' mutations that make a minimal contribution to tumour growth. But even targeting the genetic culprit in a single driver mutation can be tricky. Take the example of the oncogene KRAS, which encodes a signalling protein involved in cell proliferation. KRAS mutations appear in as many as one-quarter of adenocarcinomas, but attempts at targeted therapy have so far failed. A study reported at the 2014 ASCO meeting suggests that a subset of patients with KRAS-mutant NSCLC may benefit from a combination of drugs that target several proteins in the same biological pathway as KRAS. So far, only 10–15% of KRAS-mutant tumours respond to combination treatment, says Vassiliki Papadimitrakopoulou, a medical oncologist at the MD Anderson Cancer Center in Houston, Texas, who helped to coordinate the study. “We would like to see more than that.” For patients with non-adenocarcinoma lung cancers, targeted options are limited. Very few patients with squamous cell carcinoma (SCC) — the second most common form of lung cancer — have EGFR or ALK driver mutations. Most SCC tumours occur in smokers, and are plagued by the same extensive genomic mutation that is confounding efforts to apply targeted treatment to smokers' adenocarcinomas. This may be about to change, thanks to the work of Govindan and his colleagues at the Cancer Genome Atlas (TCGA), which in 2012 published a detailed assessment of the SCC genomic landscape derived from tissue samples from 178 SCC tumours5. The results suggested a number of avenues for potential intervention. A mutation in the gene CDKN2A, for example, is found in 70% of SCC tumours and could be a target. The urgent need for progress in lung-cancer treatment has inspired Papadimitrakopoulou, who is collaborating with other US investigators on the Lung Cancer Master Protocol. Launched in June, this multi-arm, multi-institutional clinical trial will use sequencing to match SCC patients with targeted drug candidates. It will also accumulate a lot of cancer genomic data. “We will be characterizing the largest set of SCCs across the United States,” says Papadimitrakopoulou. Govindan and his colleagues are also working on large-scale genomic analysis. After a genomic survey of mutations in 230 adenocarcinoma tumours6, published in July 2014, he and fellow TCGA coordinators Louis Staudt and Matthew Meyerson are working on plans to study a larger number of tumour samples in the hope of detecting additional targetable drivers. The robust performance of drugs that target ALK and EGFR has made testing for mutations in these genes routine. But as the cost of sequencing plummets, some clinicians believe that it makes more sense to survey hundreds of cancer-related genes rather than just those two to provide a larger set of potential targets. Kris is among the evangelists for extensive clinical sequencing. “If you have lung cancer in 2014, the first thing we do is a biopsy that includes a comprehensive genetic test for all potential drivers,” he says. Companies are also providing the tools to do this. Foundation Medicine, a company in Cambridge, Massachusetts, co-founded by TCGA scientists, generates oncology diagnostic reports for clinicians based on sequencing data from 236 cancer-associated genes. The company expects to do 25,000 tests in 2014, up from 9,000 in 2013. In June, the Memorial Sloan Kettering Cancer Center forged a partnership with Quest Diagnostics of Madison, New Jersey, to broaden clinician access to the centre's in-house genetic test, which also surveys numerous oncogenes in parallel. Genetic analyses could help to identify patients with mutations that are rare in lung cancer but are common in other tumour types. For example, a subset of adenocarcinoma patients with mutations affecting the RET gene might benefit from cabozantinib, a drug that targets this alteration in thyroid cancer7. And with much of the pharmaceutical industry's oncology efforts focused on developing targeted drugs, data from sequencing the genes of lung-cancer patients can also help to direct those patients to clinical trials. To assess the impact of sequencing on lung-cancer care, Kris and other scientists — who formed a group called the Lung Cancer Mutation Consortium — sequenced as many as 10 known oncogenes in more than 1,000 patients. Kris reports that 28% of the people tested were matched to clinical trials they might not otherwise have known about8. As with KRAS, many oncogenes are informative scientifically but are not medically useful, leading some researchers to question the short-term benefits of routine, large-scale tumour sequencing in patients — a practice Mok says is unlikely to improve lung-cancer care significantly until the next EGFR comes along. Still, he believes that genetic analysis must be embedded into the diagnostic process so that drugs can be matched to a patient as quickly as possible — he holds out hope that new drivers will soon join ALK and EGFR. As would everyone struggling to find new weapons against this lethal disease. With such resources at hand, more doctors might look forward to experiencing the sweet satisfaction Govindan encountered on providing his patient with just the treatment she needed to buy years of additional life. http://www.nature.com/nature/journal/v5 ... 13S8a.html

Employing multi-dimensional analyses of both genomic and phenotypic platforms Robert A. Nagourney, M.D. Oncologists confront numerous hurdles as they attempt to apply the new cancer prognostic and predictive tests. Among them are the complexities of gene arrays that introduce practicing physicians to an entirely new lexicon of terms like “splice variant, gene-rearrangement, amplification and SNP.” Although these phrases may roll of the tongue of the average molecular biologists (mostly PhDs), they are foreign and opaque to the average oncologist (mostly MDs). To address this communication shortfall laboratory service providers provide written addenda (some quite verbose) to clarify and illuminate the material. Some institutions have taken to convening “molecular tumor boards” where physicians most adept at genomics serve as “translators.” Increasingly, organizations like ASCO offer symposia on modern gene science to the rank and file, a sort of Cancer Genomics for Dummies. If we continue down this path, oncologists may soon know more but understand less than any other medical sub-specialists. However well intended these educational efforts may be, none of them are prepared to address the more fundamental question: How well do genomic profiles actually predict response? This broader issue lays bare our tendency to confuse data with results and big data with big results. To wit, we must remember that our DNA, originally provided to each of us in the form of a single cell (the fertilized ovum) carries all of the genetic information that makes us, us. From the hair follicles on our heads to the acid secreting cells in our stomach, every cell in our body carries exactly the same genetic data neatly scripted onto our nuclear hard-drives. What makes this all work, however, isn’t the DNA on the hard drive, but instead the software that judiciously extracts exactly what it needs, exactly when it needs it. It’s this next level of complexity that makes us who we are. While it is true that you can’t grow hair or secrete stomach acid without the requisite DNA, simply having that DNA does not mean you will grow hair or make acid. Our growing reliance upon informatics has created a “forest for the trees” scenario, focusing our gaze upon nearby details at the expense of larger trends and insights. What is desperately needed is a better approximation of the next level of complexity. In biology that moves us from the genotype (informatics) to the phenotype (function). To achieve this, our group now regularly combines genomic, transcriptomic or proteomic information with functional analyses. This enables us to interrogate whether the presence or absence of a gene, transcript or protein will actually confer that behavior or response at the system level. I firmly believe that the future of cancer therapeutics will combine genomic, transcriptomic and/or proteomic analyses with functional (phenotypic) analyses. Recent experiences come to mind. A charming patient in her 50s underwent a genomic analysis that identified a PI3K mutation. She sought an opinion. We conducted an EVA-PCD assay on biopsied tissue that confirmed sensitivity to the drugs that target PI3K. Armed with this information, we administered Everolimus at a fraction of the normal dose. The response was prompt and dramatic with resolution of liver function abnormalities, normalization of her performance status and a quick return to normal activities. A related case occurred in a young man with metastatic colorectal cancer. He had received conventional chemotherapies but at approximately two years out, his disease again began to progress. A biopsy revealed that despite prior exposure to Cetuximab (the antibody against EGFR) there was persistent activity for the small molecule inhibitor, Erlotinib. Consistent with prior work that we had reported years earlier, we combined Cetuximab with Erlotinib, and the patient responded immediately. Each of these patients reflects the intelligent application of available technologies. Rather than treat individuals based on the presence of a target, we can now treat based on the presence of a response. The identification of targets and confirmation of response has the potential to achieve ever higher levels of clinical benefit. It may ultimately be possible to find effective treatments for every patient if we employ multi-dimensional analyses that incorporate the results of both genomic and phenotypic platforms.

Mark Pegram, M.D. The use of cutting-edge technology and bioinformatics to inform clinical decision-making in oncology is still a ways off, according to Mark Pegram, MD, the Susy Yuan-Huey Hung Professor of Oncology and Director of the Stanford Breast Oncology Program, Stanford University, Palo Alto, California. At the 9th Annual New Orleans Summer Cancer Meeting, Dr. Pegram said the “lofty goal” of targeted therapeutic “cocktails”—which will be needed to address the molecular diversity of tumors—is proving hard to achieve. Circulating Tumor Cells Circulating tumor cells as an alternative to serial biopsies of metastatic lesions has great appeal, but the uptake of this technology has been somewhat anemic. One problem is obtaining a consistent definition of a circulating tumor cell. The cell must be positive for cytokeratin, must have a nucleus, must have a negative control, must be negative for leukocyte cytoplasm (white cell markers), and the nucleus must fit inside the cytoplasm. “These are the things measured using a huge variety of different approaches for defining and capturing [circulating tumor cells],” he said. The most clinically advanced is the CellSearch System, which uses an antibody/ferrofluid combination to attach specifically to circulating tumor cells, and magnets to draw those cells out of the blood sample to be stained and identified. The test enumerates the number of circulating tumor cells in a patient with metastatic disease, and this is correlated with overall survival. “The problem with this assay is that it is not sensitive enough to capture [circulating tumor cells] in early stages of disease. While enumeration of [circulating tumor cells] is prognostic, let’s be honest: that’s not what we are interested in,” Dr. Pegram said. “We are interested in predicting response to treatment.” He has observed that while some clinicians are “enamored” of this technology and do use it, others realize that it holds little value over routine restaging with radiographic studies. The assay also reveals little as to what is happening in these cells, and the small number of circulating tumor cells captured—five or so—is insufficient for fully deciphering the tumor, he said. Capturing more cells could help, and that is what microfluidics-based cell separation does. This new, simpler technology passes blood through a membrane, separating larger tumor cells from other blood elements and yielding thousands of cells upon which clinically relevant tests can be performed. “The approaches that have much higher yields will be more useful because they will be informative as to what cells are doing at a molecular level,” he predicted. Even more sophisticated blood-based technology will someday be better able to capture the genetic heterogeneity of advanced solid tumors at a gene-expression level so they can be compared with the primary tumor. This, however, will present other challenges. “In one blood sample there are multiple populations of [circulating tumor cells] that are different from another. This will pose a diagnostic challenge and a treatment challenge, as well, if we find unique targets within the same patient at the same time,” he said. “Until we can come to terms with the complexity of solid tumor malignancies, we can’t make informed decisions.” At this point, guideline committees “have not latched on to [circulating tumor cells] as a ‘must’ in clinical practice,” he indicated, calling circulating tumor cell determination a “consideration,” but one lacking in great value until emerging technologies can interrogate circulating tumor cells at a molecular level. Genomics and Drug Development The promise of genomics was to identify mutations within a tumor and thus allow the clinician to concoct a tailored therapeutic cocktail. In reality, however, the scenario is infinitely complex. Within a single MCF-7 human breast cancer cell, for instance, 157 chromosomal break points have been found. “We have rich genomic information in a tumor cell, but this does not tell the doctor how to treat the patient,” he said. The Cancer Genome Atlas (TCGA) Network, in its examination of its first 507 breast cancer samples, revealed only four frequently mutated genes out of 50 that were identified: PIK3CA, TP53, MAP3K1, and GATA3. “This was a stunning observation,” commented Dr. Pegram. “We thought we would discover multiple new therapeutic targets in breast cancer and therefore have home runs in drug development, but we found only four, and all four were already known to be common mutations.” Drugs are already targeting PI3K, the other three frequent mutations are not druggable, and the rest of the 50 genes are low-frequency mutations (affecting about 2% of breast cancers) for which pharmaceutical companies are unlikely to invest. “This will pose a challenge because our current models of drug development will not survive this reality,” he predicted. Furthermore, according to Dr. Pegram, deep sequencing identifies even more heterogeneity, revealing individual clones with different mutational profiles within the same tumor. The current next-generation diagnostics are not performing deep sequencing and therefore are not demonstrating the molecular heterogeneity that is critical for selecting the best targeted agent, he said. Even “more sobering,” he continued, is that this complexity is present at the time of diagnosis, with further alterations piled on due to drug resistance. Cancer and genomes are not static; they are a moving target, he reiterated. While the situation is clinically frustrating now, there is the potential to tease apart the molecular evolution of cancers with future sequencing technology, and this “extraordinary” achievement could give insights into prevention strategies. Adding Proteomic Data Even more complex than genomics is proteomics, the large-scale analysis of protein-expression profiles through mass spectrometry. Proteomic information on post-translational modifications in the tumor (ie, phosphorylation, glycolisation, etc) could be a useful adjunct to genomic information, producing a more “holistic view” of pathway regulation. “The hope is that mixing proteomic work along with genomic work will facilitate our understanding of what is going on in the dynamic tumor cell,” Dr. Pegram said. “But the problem with proteomics is size: the proteome is much larger than the genome, due to alternative splicing and protein modification.” The information desired from proteomics includes all protein-to-protein interactions, protein functions and their regulation, protein modifications, subcellular location, and protein concentrations. Current approaches do not provide all this information. While polymerase chain reaction (PCR) testing determines gene amplification, there is no PCR equivalent for proteomics. Sequencing tools are robust in genomics, but mass spectrometry is still emerging in proteomics. Furthermore, proteomic data is “big data,” and huge servers are needed just to store the data. Novel approaches are currently being pioneered to address these issues, he said. In summary, Dr. Pegram said, “Mutational events in cancer can yield complex and deranged pathways, but they are still highly functional and they can take the lives of our patients. We need to understand them.” Disclosure: Dr. Pegram reported no potential conflicts of interest. The ASCO Post, September 1, 2014, Volume 5, Issue 14 http://www.ascopost.com/issues/septembe ... locks.aspx

United States vs Caris Life Sciences, Caris Diagnostics, Miraca Life Sciences It is familiar and makes me somewhat feel slightly ill, but it was refreshing to see that action is being taken. Just a note, however, that the fraud was not discovered by CMS but instead the case derived its impetus from the persistence of two (justifiably) disgruntled former employees. I suspect that many companies are just one disgruntled employee away from facing a similar experience. In this case, except for the monumental stupidity that these complainants' superiors evinced in ineptly dealing with their employees, the violations likely would never have been detected by CMS. http://pathologyblawg.com/wp-content/up ... plaint.pdf Wild West of Molecular Testing? Lawsuit Alleges Caris Engaged in Aggressive Marketing http://www.cancerletter.com/articles/20140808_1 http://www.cancerletter.com/articles/20140808_3 Note: Foundation Medicine is not any different than Caris Diagnostics in Phoenix (now Miraca Life Sciences), beyond testing for standard pathology "targets" such as ER, PR, Her2, EGFR mutations, KRAS, BRAF. They aren't worth much for the sorts of chemotherapy which is used in 95% of all cancers and useless with respect to drug combinations. While fresh tissue is very dear and hard to come by, function trumps structure, in terms of potency and robustness of information provided than using archival paraffin blocks. Batch Processing of tumor biopsies for cell markers viewtopic.php?f=8&t=50687

Published Studies Often Conflict With Results Reported to ClinicalTrials.gov Joseph S. Ross, M.D., MHS. Yale University School of Medicine Study results published in major medical journals often conflict with the data its authors have submitted to ClinicalTrials.gov, according to an analysis published in JAMA March 11, 2014. The ClinicalTrials.gov registry, maintained by the National Library of Medicine, was created to help improve transparency in the medical literature by ensuring that all results of clinical trials, whether published or not, are archived in a single repository. A 2007 law mandated that researchers post results of studies on all products regulated by the US Food and Drug Administration (FDA) within 12 months. Many journals have also pledged to require their authors to report their findings in the registry. But numerous problems with the registry have been documented since its creation, including a failure of many researchers to report their results and sloppy data entry by investigators. A new analysis by Joseph S. Ross, MD, MHS, an assistant professor of medicine at Yale University School of Medicine, and his colleagues raise questions about the accuracy of what is reported in the registry and in the medical literature. The team compared the results of 96 trials published in top-tier medical journals, including JAMA, the New England Journal of Medicine, and the Lancet, with the results of those trials reported in ClinicalTrials.gov. They found at least 1 discrepency in the results reported for 93 of the trials. Results matched in both the registry and journal article in only about half the cases. Ross discussed the findings with news@JAMA. news@JAMA: Why did you choose to do this study? Dr Ross: Our research group is interested in thinking of ways to improve the quality of clinical research. When the Food and Drug Administration amendments were passed requiring results reporting [to the ClinicalTrials.gov registry], we were interested in how that would play out. There have been studies about how compliant researchers are with this requirement. We wanted to look at how accurate the reported findings are. By comparing the reported results to published trials, we wanted to see how well it was working. What we found was a surprise. news@JAMA: Why were the results surprising? Dr Ross: We found important discrepancies between the results reported in ClinicalTrials.gov and the published results. We don’t know which is right. There were lots of end points reported in 1 source that weren’t reported in the other. news@JAMA: Can you give an example? Dr Ross: We started by looking at the primary end points published in high-impact journals and what end points were reported in ClinicalTrials.gov. Of 90-some-odd trials, there were 150 to 160 primary end points; 85% were described in both sources, 9% only in ClinicalTrials.gov and 6% only in the publications. For the more than 2000 secondary end points, 20% were reported only in ClinicalTrials.gov and 50% only in publications. Only 30% were described in both sources. You see that only part of the information is available in 1 source. We need to make the sources as complete as possible. The publications need to link back to ClinicalTrials.gov because they often don’t include all the end points. news@JAMA:Why might there be such a difference? Dr Ross: There are a lot of potential explanations. More end points were reported in the published papers than in ClinicalTrials.gov. This suggests authors are reporting end points in the paper that make the results look better that weren’t predetermined. That can skew the literature. news@JAMA: Could edits made by the journals, such as requests for more information or new analyses, or typographical errors account for some discrepancies? Dr Ross: It could be editing. An authorship team submits the results and these are publications that have strong editorial staffs. There could be slightly different approaches in analysis submitted to the 2 sources. Some are typographical errors. For example, 1 study reported a hazard ratio of 4 in ClinicalTrials.gov instead of the hazard ratio of 2 in the study [the hazard ratio and standard deviation were transposed]. That perverts the study result. news@JAMA: What can be done to improve the accuracy results in reporting? Dr Ross: These results are increasingly being used by researchers and in meta-analyses; we want them to be accurate. The journals pay a large staff of full-time editors to make sure these studies don’t have errors, but ClinicalTrials.gov has a relatively small staff. We may need a larger endeavor than what the National Library of Medicine originally envisioned. A third of the discordant results led to a different interpretation of the trial. This a problem we need to be attending to. We studied the highest-tier journals, so this is likely the best-case scenario. These are likely the highest-achieving researchers. Who knows what’s happening with lower-tier journals? http://newsatjama.jama.com/2014/03/11/a ... rials-gov/ Note: Different results from the same study reported in different publications. This is sort of mind boggling. It shows that a whole lot of the time medical research authors are massaging and/or cherry picking their own data and they can't even keep their own stories straight!

Personalized Chemotherapy: Understanding Clinical Trials - the Kaplan Meier Graph In this video of Personalized Cancer Chemotherapy, Dr. Larry M. Weisenthal explains the Kaplan-Meier graph. The graph is often used in clinical trials to compare survival times among patients with the same type of cancer who received different chemotherapy treatments. Understanding the graph is easy and also very useful as it will enable you to cut through the clutter in published clinical trial manuscripts and see at glance if any chemotherapy regimen provided a superior survival benefit. Big Data Meets Cancer: Neil Hunt at TEDxBeaconStreet The consistent and specific cure or control of cancer will require multiple drugs administered in combination targeted to abnormal patterns of normal cellular machinery that effect or reflect malignant behavior, according to Dr. Arnold Glazier, former Oncology Fellow at Johns Hopkins. It is finding the patterns of malignant cells and developing a set of 5 to 10 drugs in order to cure or control cancer that classical clinical trials are not going to solve. In clinical research, studies are deemed reportable when they achieve statistical significance. The so-called power analysis is the purview of the biostatistician who examines the desired outcome and explores the number of patients (subjects) required to achieve significance. The term “N” is this number. The most famous clinical trials are those large, cooperative group studies that, when successful, are considered practice-changing. That is, a new paradigm for a disease is described. To achieve this level of significance it is generally necessary to accrue hundreds, even thousands of patients. This is the “N” that satisfies the power analysis and fulfills the investigators expectations. So what about Trials of N=1? This disrupts every tenet of cancer research, upends every power analysis and completely rewrites the book of developmental therapeutics, according to Laboratory Oncologist Dr. Robert A. Nagourney. Every patient is his or her own control. Their good outcome reflects the success or failure of "the trial." There is no power analysis. It is an "N" of 1. This “breakthrough” concept however, has been the underpinning of the work of investigators like Drs. Larry Weisenthal, Andrew Bosanquet, Ian Cree, Robert Nagourney and all the other dedicated researchers who pioneered the concept of advancing cancer outcomes one patient at a time. These intrepid scientists described the use of each patient’s tissue to guide therapy selection. They wrote papers, conducted trials and reported their successful results in the peer-reviewed literature. These results have provided statistically significant improvements in clinical responses, times to progression, even survival. By incorporating the contribution of the cellular milieu into clinical response prediction, these functional platforms have consistently outperformed their genomic counterparts in therapy selection. With Cancer, Don’t Ask the Experts http://robertanagourney.wordpress.com/2 ... e-experts/

Robert A. Nagourney, M.D. The New York Yankees catcher Yogi Berra famous quote, “Déjà vu all over again,” reminds me of the growing focus on the concept of “N- of-1.” For those of you unfamiliar with the catchphrase, it refers to a clinical trial of one subject. In clinical research, studies are deemed reportable when they achieve statistical significance. The so-called power analysis is the purview of the biostatistician who examines the desired outcome and explores the number of patients (subjects) required to achieve significance. The term “N” is this number. The most famous clinical trials are those large, cooperative group studies that, when successful, are considered practice-changing. That is, a new paradigm for a disease is described. To achieve this level of significance it is generally necessary to accrue hundreds, even thousands of patients. This is the “N” that satisfies the power analysis and fulfills the investigators expectations. So what about an N-of-1? This disrupts every tenet of cancer research, upends every power analysis, and completely rewrites the book of developmental therapeutics. Every patient is his or her own control. Their good outcome reflects the success or failure of “the trial.” There is no power analysis. It is an “N” of 1. This “breakthrough” concept however, has been the underpinning of the work of investigators like Drs. Larry Weisenthal, Andrew Bosanquet, Ian Cree, myself and all the other dedicated researchers who pioneered the concept of advancing cancer outcomes one patient at a time. These intrepid scientists described the use of each patient’s tissue to guide therapy selection. They wrote papers, conducted trials and reported their successful results in the peer-reviewed literature. These results I might add have provided statistically significant improvements in clinical responses, times to progression, even survival. By incorporating the contribution of the cellular milieu into clinical response prediction, these functional platforms have consistently outperformed their genomic counterparts in therapy selection So why, one might ask, have the efforts of these dedicated investigators fallen on deaf ears? I think that the explanation lies in the fact that we live in a technocracy. In this environment, science has replaced religion and medical doctors have abdicated control of clinical development to the basic scientists and basic scientists love genomics. It is no longer enough to have good results; you have to get the results the right way. And so, meaningful advances in therapeutics based on functional platforms have been passed over in favor of marginal advances based on genomic platforms. There is nothing new about N-of-1. It has been the subject of these investigators compelling observations for more than two decades. Though functional platforms (such as our EVA-PCD) are not perfect, they provide a 2.04 (1.62 to 2.57, P < 0.001) fold improvement in clinical response for virtually all forms of cancer – as we will be reporting (Apfel C, et al Proc ASCO, 2013). It seems that in the field of cancer therapeutics “perfect is the enemy of good.” By this reasoning, good tests should not be used until perfect tests are available. Unfortunately, for the thousands of Americans who confront cancer each day there are no perfect tests. Perhaps we should be more willing to use good ones while we await the arrival of perfect ones. After all, it was Yogi Berra who said, “If the world was perfect, it wouldn’t be.”

An illustrated executive summary to explain what MCED is all about. They made another discovery, a refinement to the elusive mechanism of arterial inflammation, which is in turn the triggering event in atherosclerosis. It's not simply massive calcium accumulation death (MCAD), but massively calcified endosomal death (MCED). It's not simply generalized increased calcium uptake; it's formation of massively calcified endosomes, which are extruded as massively calcified exosomes, which phagocytic immune cells try to ingest and around which lymphocytes form rosettes. In his most recent research, Dr. Weisenthal has drilled-down even deeper into the mechanism that causes blood vessels to become inflamed and blocked. Previously, Dr. Weisenthal’s understood the newly-discovered process of endothelial cell death somehow involved a massive accumulation of calcium. However, Dr. Weisenthal has discovered that the calcium focuses on tiny structures called endosomes and exosomes - and he now understands how that produces the inflammation. MCED Discovery http://www.vasocell.com/MCED_Discovery.html A two minute animated video that explains the new finding. http://vimeo.com/100928488

The 16th International Symposium on Anti-Angiogenic Therapy: Recent Advances and Future Directions in Basic and Clinical Cancer Research. Date:February 6-8, 2014 Location:San Diego, California 92122, United States Description: The field of anti-angiogenic therapy is quite complicated with various results with individual agents in different disease types. In fact, the efficacy of such agents in the advanced setting is different from that of an early stage in the adjuvant setting. In addition to learning more about the efficacy and appropriate use of these agents, it is also important for health care providers to understand new toxicities that have been recognized in association with the use of anti-angiogenic agents. This symposium will provide a comprehensive overview of the appropriate use of anti-angiogenic therapy in patients with solid malignancies. In addition, this symposium will review the appropriate use of anti-angiogenic agents and allow the learner to recognize toxicity and potential biomarkers. The main area of feedback focused on biomarkers and the appropriate use of therapy. This is an inherent challenge as we do not have any biomarkers that are validated. However we will continue to scan the literature and seek speakers who can address the issue of biomarkers and patient selection. We will also seek speakers and discuss resistance pathways, which overlap with the above issues. One Laboratory Oncologist has the answer; will they listen? Poster Presentation: Massive calcium accumulation death (MCAD) of endothelial cells as a putative mechanism for Avastin (bevacizumab) anti-angiogenesis and acquired resistance to bevacizumab. Larry Weisenthal, Summer Williamson, Cindy Brunschweiler, and Constance Rueff-Weiesnthal We have discovered that human endothelial cells undergo two forms of cell death. 1. A non-specific form of cell death, similar to that of other normal and neoplastic cells. 2. A unique form of cell death, seen only in endothelial cells, associated with massive accumulation of calcium. We call this massive calcium accumulation death or MCAD. MCAD may be identified by cytochemical staining with: a. Fast Green alone b. Fast Green/Hematozylin c. Fast Green/Wright-Giemsa d. Alizarin red S (most advantageous) Sera from different patients is variably inhibitory of MCAD; circulating pro-angiogenic factors may be the mechanism of bevacizumab failure and a test called AngioRx assay may identify sera with such factors. Here is what's new this year: We have discovered that MCAD occurs when endothelial cells deprived of VEGF begin to form massively calcified endosomes, which result in a unique form of cell death, specific to endothelial cells, and triggered only by pharmaceuticals known to have anti-angiogenic effects. It is not triggered by traditional cytotoxic agents. When many calcified endosomes are formed, the cells die and release massively calcified exosomes into the cellular millieu. We isolated calcified exosomes produced by incubating circulating endothelial cells from a normal blood donor for 3 days in the presence of bevacizumab. We then incubated freshly drawn buffy coat leukocytes from the same normal donor and found that (1) neutrophils, monocytes, and lymphocytes clustered around these calcified exosomes and appeared to interact with them and (2) this resulted in the release of TNF into the culture medium. Besides being an inflammatory mediator, TNF has been shown to promote retinal vasculogenesis in various occular models and TNF inhibition has been shown to inhibit retinal vasculogenesis, in a manner similar to VEGF depletion by bevacizumab. We think that this provides a mechanism for bevacizumab resistance, to wit: VEGF depletion --> MCAD, with formation of massively calcified endosomes and exosomes --> provoke phagocytosis and other direct interactions with inflammatory cells which result in the release of TNF (and probably other pro-angiogenic mediators; studies in progress) --> rescue of microcapillaries from the vasculotoxic effect of VEGF depletion.

Endothelial Massive Calcium Accumulation Death (MCAD): Mechanism, Target, and Predictive Biomarker for Anti-Angiogenic Therapy Presented at the 13th international symposium on anti-angiogenic therapy: recent advances and future directions in basic and clinical cancer research. LaJolla, CA. Sponsor: MD Anderson Cancer Center; planning committee Robert S. Kerbel, Lee M Ellis, et al., 03 February 2011 Weisenthal Cancer Group Abstract We cultured human umbilical vein endothelial cells with bevacizumab, with tyrosine kinase inhibitors known to be AA, and with traditional cytotoxic drugs. The images below show that, in the presence of physiological saline and non-favorable culture conditions, the vast majority of the endothelial cells undergo a “non-specific” type of cell death (NSCD), not associated with calcium accumulation, but with loss of cell membrane integrity, allowing uptake of the Fast Green dye, staining these dead dells a pale blue green. In the presence of known AA agents (e.g. bevacizumab, some TK inhibitors) a large percentage of the endothelial cells undergo death associated with massive calcium accumulation (MCAD), with these cells staining hyperchromatic, refractile, blue-black, precisely as reported in http://www.ncbi.nlm.nih.gov/pubmed/18793333 and http://meeting.ascopubs.org/cgi/content ... ppl/e13617 and http://tinyurl.com/weisenthal-breast-lapatinib MCAD is strikingly demonstrated by Fast Green/Alizarin staining as reported in http://precedings.nature.com/documents/4499/version/1 Traditional cytotoxic drugs (e.g. cisplatin) produce only NSCD and inhibit MCAD. We propose that MCAD is a cell death mechanism unique to endothelial cells and provides a practical biomarker to predict for AA activity in clinical oncology and drug development, as well as a potential drug target. http://precedings.nature.com/documents/ ... 6647-1.pdf Nature Precedings doi:10.1038/npre.2011.6647.1

MCED: A newly-discovered mechanism of endothelial cell death Using a patented laboratory test, we have discovered a new cell death pathway in endothelial cells which we refer to as Massively Calcified Endosomal Death (MCED). Exploitation of this pathway may afford an effective approach to the treatment of cancer and to the prevention and treatment of atherosclerotic vascular disease, heart attack, and stroke. MCED in Coronary and Vascular Disease “Cholesterol levels might not matter. The most important cause of heart attack, stroke, and arterial blockage might be the presence or absence of circulating MCED factors.” The underlying mechanisms of atherosclerotic vascular disease are not well-understood by scientists. It is not known, for example, precisely how pathogenic lipids trigger an inflammatory response in arterial walls. Neither is it well-established how atherosclerotic arteries become calcified. Likewise, the mechanisms underlying the cause of calcific cardiac valvular disease (e.g. mitral and aortic stenosis) remain largely unknown. And why are cholesterol and other lipid levels only imperfect predictors of coronary artery disease? We have discovered a previously unknown biological mechanism that explains much of what is not understood about arterial blockage and heart disease. Understanding the mechanism will allow for development of drugs that control it. We postulate that massively calcified endosomal death is the triggering event for both vascular inflammation and vascular calcium accumulation. Interruption of the MCED pathway, using MCED-targeted drugs, may offer the most potent and specific approach to the prevention and treatment of coronary vascular disease. MCED in Cancer The highly-promising treatment paradigm of anti-angiogenic therapy has so far achieved only moderate success. Anti-angiogenic research is severely hindered by the inadequacy of disease models and predictive biomarkers. Acquired resistance to anti-angiogenic agents is poorly understood, as is the mechanism through which treatment with bevacizumab (Avastin) increases the risk of cardiovascular disease MCED induction - precisely the opposite of the goal in heart disease - may be effective in treating cancer. “Activation of the MCED pathway may enhance effectiveness of anticancer drugs that work by destroying blood vessels necessary to feed the growth of the cancer.” http://mcadvasocell.com/MCED_Home.html

"These measures are 'the most important aims of treatment' in these patients because improvements in overall and progression-free survival (OS and PFS) have hit a ceiling in trial after trial of chemotherapies," I personally think this is scandalous. What they are saying is that they are coming up with any drugs which are any better than the drugs that they have been using all along. So big Pharma has no new drugs to sell. So they change the goal line. Or, more accurately, they lower the bar. Progression free survival and overall survival are hard objective endpoints. Quality of life is totally squishy and unobjective. So future clinical trials in cancer are going to be designed and scored by psychologists. Patients should never ever let them get away with this. Their feet should be held close to the fire. Shame on them.

Quality of life (QoL) and symptom benefit should be accepted by clinicians and regulators as additional coprimary endpoints in clinical trials of chemotherapies for platinum-resistant and refractory ovarian cancer, according to a group of experts. These measures are "the most important aims of treatment" in these patients because improvements in overall and progression-free survival (OS and PFS) have hit a ceiling in trial after trial of chemotherapies, say Michael Friedlander, MD, and colleagues from the Prince of Wales Hospital, in New South Wales, Australia. The group published a letter on May 13 in the Journal of Clinical Oncology. The conventions of OS and PFS should remain in place in trials but be supplemented by these "other meaningful ways to measure treatment benefit," they say. The letter writers are responding to a recent study and accompanying editorial published in the journal that related to 2 chemotherapies being compared in a phase 3 trial in this patient population (J Clin Oncol. 2013;30:3841-3847). In the trial, patupilone and liposomal doxorubicin produce the same PFS (3.7 months median) and a comparable OS (13.2 vs 12.7 months). In short, Dr. Friedlander and his colleagues believe that palliative chemotherapy should be also evaluated for improvement in quality of life and symptoms and that those measures should count in the drug approval process. There needs to more than one "route to registration of new agents," they say about the need for regulatory changes. Agreed, said David Spriggs, MD, of Memorial Sloan-Kettering Cancer Center, in New York City. He served as the editorialist on the study of patupilone vs liposomal doxorubicin and, in turn, responded to the Australian letter about his essay and the trial. "It is essential," Dr. Spriggs writes, that "comfort, function and quality of life have a place in the commercialization pathway." Both he and the Australians believe that "today's development process seems excessively focused on duration of life." Patients with recurrent ovarian cancer…are incurable with today's therapies. "Patients with recurrent ovarian cancer (platinum-sensitive or resistant) are incurable with today's therapies," he writes, adding that life expectancy is 12 to 18 months. The problem of poor prognosis is not limited to ovarian cancer, adds Dr. Spriggs. "In these settings…a patient's goal is to enjoy a comfortable and highly enjoyable life for as long as possible," he says. But accommodating QoL as a primary endpoint in a drug approval trial "has historically been quite difficult," Dr. Spriggs adds. "This is a reflection of the fact that QoL can be slippery when reduced to practice." Dr. Friedlander and colleagues report that there is a major clinical trial under way (Gynecologic Cancer Intergroup Symptom Benefit Trial) that is seeking to "validate an instrument to measure symptom benefit that can be applied to clinical trials." The trial is also seeking to identify subsets of patients who are most likely to benefit from palliative chemotherapy. The authors have disclosed no relevant financial relationships. Citation: New Endpoints Proposed for Chemotherapy in Ovarian Cancer. Medscape. Jun 18, 2013.

Robert A. Nagourney, M.D. When asked to define what constituted xxxography in his 1964 Supreme Court decision (Jacobellis versus Ohio 1964) Justice Potter Stewart stated, “I know it when I see it.” When I reviewed an article on the changing landscape of clinical trials in non-small cell lung cancer (NSCLC) (Shifting patterns in the interpretation of phase 3 clinical trial outcomes in advanced non-small cell lung cancer: The bar is dropping, Sacher A. G. et al, J Clin Oncol May 10, 2014), Justice Stewart came to mind. The authors selected 203 NSCLC trials from a total of 245 studies conducted between 1980 and 2010. They compared how often the studies met their endpoints with how often the study authors’ called the results “positive.” Among the findings, it seems that earlier studies (before the year 2000) were geared for overall survival, while later studies (after 2000) overwhelmingly favored progression free survival. Although patient survivals changed little, the number of trials reported as successful increased dramatically. Progression-free survival measures how long it takes for a patient to fail treatment. That is, for the disease to worsen on therapy. Its use increased after 2000 when Docetaxel, for the first time, provided a survival advantage in recurrent disease. The FDA’s willingness to accept progression-free survival for drug approval was originally based on their expectation that the benefit would be “substantial and robust” but they did not define the term. One group has suggested that improvements should be of the magnitude of 50 percent. Another went even further suggesting a doubling of the survival advantage. Unfortunately, the trend has been just the opposite. Trials from the 1980s on average gave a 3.9 month improvement, which fell to a meager 0.9 months after 2000. What are patients and their physicians to make of these trends? First, the large clinical trials, that are so common today, are much more likely to achieve significance. The troubling corollary is that statistical significance is not the same as clinical relevance. The “publish or perish” climate, combined with the skyrocketing cost of drug development has placed inordinate demands upon investigators and their sponsors to achieve “positive results.” Fearing failure, many pharmaceutical companies sponsor “safe” trials that provide incremental advances but few breakthroughs. Meaningful advances in oncology are generally quite evident. The first use of Interferon alpha for the treatment of hairy cell leukemia provided a response rate of 100 percent and earned a lead article in the New England Journal of Medicine (NEJM) with only seven patients! Similarly the 57 percent response rate for Crizotinib in ALK positive lung cancer required only 82 patients for a place in the NEJM. Unfortunately, the failure of contemporary investigators to identify more “paradigm changing therapies” has forced many to lower the bar. The clear solution to the problem is the better selection of candidates for therapy. Despite advances in molecular biopsy a paucity of truly effective companion diagnostics exist. Outside of EGFR, ALK, and ROS-1, it is anybody’s guess how to manage the vast majority of non-small cell lung cancer patients. While we expand our armamentarium and develop better companion diagnostics, today we can apply measures of cellular response (as found in functional cytometric assays) that capture all of operative mechanisms of sensitivity for all classes of drugs. While it is not always possible to know why a patient will respond, it is possible to know that they will respond. In the words of Judge Stewart, when it comes to a responsive lung cancer patient “I know it when I see it.” Are the reports on Nivolumab as treatment for NSLC cause for near term hope or to be viewed with restraint. The drug appears to have been fast tracked, but reports have gone from relatively optimistic to less so in the last year or so. Bristol-Myers Squibb statistical data: http://web1.pharmiweb.com/PressReleases ... 4f9rBtOUc8 Positive report in BusinessWeek Oct 2013: http://www.businessweek.com/ap/2013-10- ... ancer-drug More restrained report in Business Week May 15, 2014: http://www.businessweek.com/ap/2014-05- ... study-data

Shifting Patterns in the Interpretation of Phase III Clinical Trial Outcomes in Advanced Non–Small-Cell Lung Cancer: The Bar Is Dropping Adrian G. Sacher, Lisa W. Le and Natasha B. Leighl Princess Margaret Cancer Centre/University Health Network, University of Toronto, Toronto, Ontario, Canada. Corresponding author: Natasha B. Leighl, MD, MMSc, Department of Biostatistics, Division of Medical Oncology/Hematology, Princess Margaret Cancer Centre/University Health Network, University of Toronto, 610 University Ave, 5-105, Toronto, Ontario, Canada M5G 2M9; e-mail: Natasha.Leighl@uhn.ca Abstract Purpose: Despite multiple trials of new agents in advanced non–small-cell lung cancer (NSCLC), outcomes remain poor. This study explores how the design and interpretation of randomized trials in advanced NSCLC has changed over time. Methods: Phase III randomized controlled trials of systemic therapy for advanced NSCLC between 1980 and 2010 were identified, and their primary end point, outcome, statistical significance, and conclusions were recorded. Results: Of 245 trials identified, 203 were eligible for study inclusion. Although overall survival remains the most common primary end point of phase III trials, more trials from the last decade have used progression-free survival instead (none in 1980 to 1990, 13% in 2001 to 2010; P = .002). The percentage of trials meeting their primary statistical end points remained stable over time; however, the percentage of trials reporting a positive outcome without meeting that end point increased (30% in 1980 to 1990, 53% in 2001 to 2010; P < .001). A trend toward decreasing magnitude of survival gain in positive trials was seen over time (3.9 months in 1980 to 1990, 2.5 months in 2001 to 2010; P = .11), with a concomitant increase in the sample size of clinical trials over the same time period (median: 152 patients in 1980 to 1990, 413 in 2001 to 2010; P < .001). Only studies predating 1990 reported negative results as a result of insufficient magnitude of survival benefit despite statistical significance. Conclusion: A significant shift has occurred over the past three decades in the design and interpretation of phase III trials in advanced NSCLC. The use of survival as the primary measure of benefit is declining, as is the magnitude of benefit deemed clinically relevant. J Clin Oncol 32. http://jco.ascopubs.org/content/early/2 ... l.pdf+html Progression-Free Survival: Meaningful or Simply Measurable? http://m.jco.ascopubs.org/content/30/10/1030.full

Those on Xalkori (crizotinib) but their NSCLC worsened or cannot tolerate taking it? Zykadia (ceritinib) is a new FDA-approved prescription medicine that is used to treat people with non-small cell lung cancer (NSCLC) that: * Is caused by a defect in a gene called anaplastic lymphoma kinase (ALK), and * Has spread to other parts of the body, and * Who have taken the medicine crizotinib, but their NSCLC worsened or they cannot tolerate taking crizotinib The effectiveness of Zykadia (ceritinib) is based on response rate and duration of response. There are no data demonstrating an improvement in patient reported outcomes or survival with Zykadia (ceritinib). If you or a loved one has been diagnosed with ALK+ NSCLC and have already received an ALK inhibitor, ask your doctor if Zykadia (ceritinib) may be right for you. Make an appointment to talk to your doctor today. IMPORTANT INFORMATION AND INDICATION FOR ZYKADIA (ceritinib) CAPSULES What is the most important information I should know about ZYKADIA? Zykadia (ceritinib) may cause serious side effects, including: *Stomach and intestinal problems. Zykadia (ceritinib) causes stomach and intestinal problems in most people, including diarrhea, nausea, vomiting, and stomach-area pain. These problems can sometimes be severe. Follow your health care provider's instructions about taking medicines to help these symptoms. Call your health care provider for advice if your symptoms are severe or do not go away. * Liver problems. Zykadia (ceritinib) may cause liver injury. Your health care provider should do blood tests at least every month to check your liver while you are taking Zykadia. Tell your health care provider right away if you get any of the following: you feel tired have itchy skin your skin or the whites of your eyes turn yellow you have nausea or vomiting you have a decreased appetite you have pain on the right side of your stomach-area your urine turns dark or brown (tea color) you bleed or bruise more easily than normal * Lung problems (pneumonitis). Zykadia may cause severe or life-threatening swelling (inflammation) of the lungs during treatment that can lead to death. Symptoms may be similar to those symptoms from lung cancer. Tell your health care provider right away if you have any new or worsening symptoms, including: trouble breathing or shortness of breath cough with or without mucous fever chest pain * Heart problems. Zykadia may cause very slow, very fast, or abnormal heartbeats. Your health care provider may check your heart during treatment with Zykadia. Tell your health care provider right away if you feel new chest pain or discomfort, dizziness or lightheadedness, faint, or have abnormal heartbeats. Tell your health care provider if you start to take or have any changes in heart or blood pressure medicines. See "What are possible side effects of Zykadia?" for more information about side effects. What is Zykadia? Zykadia is a prescription medicine that is used to treat people with non-small cell lung cancer (NSCLC) that: is caused by a defect in a gene called anaplastic lymphoma kinase (ALK), and has spread to other parts of the body, and who have taken the medicine Xalkori (crizotinib), but their NSCLC worsened or they cannot tolerate taking Xalkori (crizotinib) It is not known if Zykadia is safe and effective in children. What should I tell my health care provider before taking Zykadia? Before you take Zykadia, tell your health care provider about all of your medical conditions, including if you: have liver problems have diabetes or high blood sugar have heart problems, including a condition called long QT syndrome are pregnant or plan to become pregnant. Zykadia may harm your unborn baby. Women that are able to become pregnant should use an effective method of birth control during treatment with Zykadia and for up to 2 weeks after stopping Zykadia. Talk to your health care provider about birth control methods that may be right for you are breastfeeding or plan to breastfeed. It is not known if Zykadia passes into your breast milk. You should not breastfeed if you take Zykadia Tell your health care provider about the medicines you take, including prescription medicines, over-the-counter medicines, vitamins, and herbal supplements. How should I take Zykadia? Take Zykadia exactly as your health care provider tells you. Do not change your dose or stop taking unless your health care provider tells you to Take Zykadia 1 time each day Take Zykadia on an empty stomach, do not eat for 2 hours before and do not eat for 2 hours after taking Zykadia If you miss a dose of Zykadia, take it as soon as you remember. If your next dose is due within 12 hours, then skip the missed dose. Just take the next dose at your regular time What should I avoid while taking Zykadia? You should not drink grapefruit juice or eat grapefruit during treatment with Zykadia. It may make the amount of Zykadia in your blood increase to a harmful level What are the possible side effects of Zykadia? Zykadia may cause serious side effects, including: See "What is the most important information I should know about Zykadia?" High blood sugar (hyperglycemia). People who have diabetes or glucose intolerance, or who take a corticosteroid medicine have an increased risk of high blood sugar with Zykadia. Follow your health care provider's instructions about monitoring your blood sugar. Call your health care provider right away if you have any symptoms of high blood sugar, including: increased thirst increased hunger headaches trouble thinking or concentrating urinating often blurred vision tiredness your breath smells like fruit The most common side effects of Zykadia include: stomach and intestinal problems. See "What is the most important information I should know about Zykadia?" tiredness, decreased appetite, and constipation These are not all of the possible side effects of Zykadia. For more information, ask your health care provider or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. General information about the safe and effective use of Zykadia Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use Zykadia for a condition for which it was not prescribed. Do not give it to other people, even if they have the same symptoms you have. It may harm them. You can ask your health care provider or pharmacist for more information about Zykadia. Click here for full Prescribing Information. http://www.pharma.us.novartis.com/produ ... irmasrc=NA Sincerely, The Zykadia Team Novartis Pharmaceuticals Corporation Now that it's FDA approved, phenotype assayists are ordering some and building up a database, to give it to the right patients. There is entirely too much trial-and-error giving so much side effects to the wrong patients.

The problem with ALK-rearranged NSCLC targeted drug Zykadia (ceritinib) Zykadia (ceritinib) being approved is a good thing as it is yet another drug that may provide good benefit for some or even possibly many people. The real question is whether it is right for a specific patient with a specific cancer. The answer to that is they don't know because they don't even bother to test for it. They simply test whether the mutation or gene structure exists in the cancer patient for which this drug might be of use. Without any other compelling testing or data on actual use and effect of the drug on that specific cancer patient the odds will always be 50/50, as it is pointed out in how we perform trial and error medicine. The problem here isn't whether Zykadia is an effective drug or not, it's the same problem they still refuse to deal with and that is whether it is an effective drug or not for each specific patient, the whole purpose of targeted therapy. The assumption is that because you have the mutation (the specific focus) which a drug is related too, it should have some effect and does not account for anything else of which there are and has already been pointed out, seemingly limitless factors. It costs entirely too much to study and determine all of these things, they just want what they need to get approved. It is so much more complex than that and is why Zykadia has great effect in one and little to none in another even though the tests they currently use say it should work simply because they assume it will as they have the same mutation. Truth is, without proper whole cell live assay testing done on a proper sample, the only way to know if it will work or not is trial and error, the very way they do treatment today, take the drug over a period of time and see if it is working or not. Mutation testing to find targeted drugs is good but it is only a piece to the puzzle and does not really indicate whether it will work for one patient over another with the same mutation. If it did, every single patient with the mutation would benefit exactly the same with the same drug, it simply just doesn't work like that even though that is the basis of the primary treatment assumption for all cancers and all treatments. So, besides not approaching drug selection and treatment properly to begin with the other big factor is of course cost which many governments and insurance providers are becoming more and more unwilling to justify. Nobody is looking for a cure, it gets thrown around a lot because that's what they all wish for. Truth is every cancer and every patient is unique so there is likely no cure-all, at least not with the knowledge they have today. We have treatments and a good focus for treatment is to turn cancer into a cronic condition which can be maintained and controlled until natural death occurs. Very slowly the focus in the US is switching to that but it will probably take some time. Disease stability is something that can be achieved if they focus on it properly and both PFS, OS and QOL are all part of the equation. PFS and OS can be definitive, QOS is subjective so very difficult to quantify properly. The Downside To Clinical Trials viewtopic.php?f=28&t=51167

FDA Approves Zykadia (Ceritinib) for ALK-Positive Lung Cancer A second drug that specifically targets non-small cell lung cancer (NSCLC) that is positive for the ALK gene rearrangement has been approved by the US Food and Drug Administration (FDA). The new drug, ceritinib (Zykadia, Novartis), in indicated for patients with ALK-positive NSCLC who have previously been treated with crizotinib (Xalkori, Pfizer), the first targeted agent for this patient population. This is an accelerated approval, and comes 4 months ahead of schedule. ALK gene rearrangement is found in about 2% to 7% of patients with NSCLC, which makes up about 85% of all lung cancer, according to the FDA announcement. Since its launch in 2011, crizotinib has become a standard of care in this small patient population, with data showing that it doubles progression-free survival when compared with chemotherapy. However, some patients become resistant to crizotinib, and until now, there has been no other targeted therapy to offer these patients. Zykadia (ceritinib now fills that role. "Ceritinib represents an important treatment option for ALK-positive NSCLC patients who relapse after starting initial therapy with crizotinib," said lead investigator Alice Shaw, MD, PhD, from the Massachusetts General Hospital Cancer Center in Boston. "This approval will affect the way we manage and monitor patients with this type of lung cancer, as we will now be able to offer them the opportunity for continued treatment response with a new ALK inhibitor," she said in a statement. The drug went through the FDA Accelerated Approval Program, which allows approval of a drug to treat a serious or life-threatening disease based on clinical data showing the drug has an effect on a surrogate end point reasonably likely to predict clinical benefit to patients. This program provides earlier patient access to promising new drugs while the company conducts confirmatory clinical trials, the agency said. The accelerated approval was based on a clinical trial of 163 patients with metastatic ALK-positive NSCLC, who progressed on or were intolerant to treatment with crizotinib. The most common sites of metastases in the patient population studied were brain (60%), liver (42%), and bone (42%) Results showed that about half of the participants had their tumors shrink, and this effect lasted an average of about 7.0 months, the agency noted. The overall response rate was 54.6% (95% confidence interval [CI], 47% - 62%), and the median duration of response was of 7.4 months (95% CI, 5.4 - 10.1), the company added in its press release. Common adverse effects of Zykadia (ceritinib) include gastrointestinal symptoms, such as diarrhea, nausea, vomiting, and abdominal pain. Laboratory abnormalities, such as increased liver enzymes, pancreatic enzymes, and increased glucose levels, were also observed. It was approved 4 months ahead of the product's prescription drug user fee goal date of August 24, the date the agency was scheduled to complete review of the drug application. The FDA also granted Zykadia (ceritinib) Breakthrough Therapy Designation, priority review, and Orphan Product Designation. The manufacturer has demonstrated through preliminary clinical evidence that the drug may offer a substantial improvement over available therapies, the agency said. It had the potential, at the time the application was submitted, to be a significant improvement in safety or effectiveness in the treatment of a serious condition. Also, the drug is intended to treat a rare disease, it noted. Citation: FDA Approves Ceritinib for ALK-Positive Lung Cancer. Medscape. Apr 29, 2014. Approval After Phase I: Ceritinib Runs the Three-Minute Mile http://theoncologist.alphamedpress.org/ ... teMile.pdf

Those on Xalkori (crizotinib) but their NSCLC worsened or cannot tolerate taking it? Zykadia (ceritinib) is a new FDA-approved prescription medicine that is used to treat people with non-small cell lung cancer (NSCLC) that: * Is caused by a defect in a gene called anaplastic lymphoma kinase (ALK), and * Has spread to other parts of the body, and * Who have taken the medicine crizotinib, but their NSCLC worsened or they cannot tolerate taking crizotinib The effectiveness of Zykadia (ceritinib) is based on response rate and duration of response. There are no data demonstrating an improvement in patient reported outcomes or survival with Zykadia (ceritinib). If you or a loved one has been diagnosed with ALK+ NSCLC and have already received an ALK inhibitor, ask your doctor if Zykadia (ceritinib) may be right for you. Make an appointment to talk to your doctor today. IMPORTANT INFORMATION AND INDICATION FOR ZYKADIA (ceritinib) CAPSULES What is the most important information I should know about ZYKADIA? Zykadia (ceritinib) may cause serious side effects, including: *Stomach and intestinal problems. Zykadia (ceritinib) causes stomach and intestinal problems in most people, including diarrhea, nausea, vomiting, and stomach-area pain. These problems can sometimes be severe. Follow your health care provider's instructions about taking medicines to help these symptoms. Call your health care provider for advice if your symptoms are severe or do not go away. * Liver problems. Zykadia (ceritinib) may cause liver injury. Your health care provider should do blood tests at least every month to check your liver while you are taking Zykadia. Tell your health care provider right away if you get any of the following: > you feel tired > have itchy skin > your skin or the whites of your eyes turn yellow > you have nausea or vomiting > you have a decreased appetite > you have pain on the right side of your stomach-area > your urine turns dark or brown (tea color) > you bleed or bruise more easily than normal * Lung problems (pneumonitis). Zykadia may cause severe or life-threatening swelling (inflammation) of the lungs during treatment that can lead to death. Symptoms may be similar to those symptoms from lung cancer. Tell your health care provider right away if you have any new or worsening symptoms, including: > trouble breathing or shortness of breath > cough with or without mucous > fever > chest pain * Heart problems. Zykadia may cause very slow, very fast, or abnormal heartbeats. Your health care provider may check your heart during treatment with Zykadia. Tell your health care provider right away if you feel new chest pain or discomfort, dizziness or lightheadedness, faint, or have abnormal heartbeats. Tell your health care provider if you start to take or have any changes in heart or blood pressure medicines. See "What are possible side effects of Zykadia?" for more information about side effects. What is Zykadia? Zykadia is a prescription medicine that is used to treat people with non-small cell lung cancer (NSCLC) that: > is caused by a defect in a gene called anaplastic lymphoma kinase (ALK), and > has spread to other parts of the body, and > who have taken the medicine Xalkori (crizotinib), but their NSCLC worsened or they cannot tolerate taking Xalkori (crizotinib) It is not known if Zykadia is safe and effective in children. What should I tell my health care provider before taking Zykadia? Before you take Zykadia, tell your health care provider about all of your medical conditions, including if you: > have liver problems > have diabetes or high blood sugar > have heart problems, including a condition called long QT syndrome > are pregnant or plan to become pregnant. Zykadia may harm your unborn baby. Women that are able to become pregnant should use an effective method of birth control during treatment with Zykadia and for up to 2 weeks after stopping Zykadia. Talk to your health care provider about birth control methods that may be right for you > are breastfeeding or plan to breastfeed. It is not known if Zykadia passes into your breast milk. You should not breastfeed if you take Zykadia Tell your health care provider about the medicines you take, including prescription medicines, over-the-counter medicines, vitamins, and herbal supplements. How should I take Zykadia? >Take Zykadia exactly as your health care provider tells you. Do not change your dose or stop taking unless your health care provider tells you to > Take Zykadia 1 time each day > Take Zykadia on an empty stomach, do not eat for 2 hours before and do not eat for 2 hours after taking Zykadia > If you miss a dose of Zykadia, take it as soon as you remember. If your next dose is due within 12 hours, then skip the missed dose. Just take the next dose at your regular time What should I avoid while taking Zykadia? > You should not drink grapefruit juice or eat grapefruit during treatment with Zykadia. It may make the amount of Zykadia in your blood increase to a harmful level What are the possible side effects of Zykadia? Zykadia may cause serious side effects, including: > See "What is the most important information I should know about Zykadia?" > High blood sugar (hyperglycemia). People who have diabetes or glucose intolerance, or who take a corticosteroid medicine have an increased risk of high blood sugar with Zykadia. Follow your health care provider's instructions about monitoring your blood sugar. Call your health care provider right away if you have any symptoms of high blood sugar, including: > increased thirst > increased hunger > headaches > trouble thinking or concentrating > urinating often > blurred vision > tiredness > your breath smells like fruit The most common side effects of Zykadia include: > stomach and intestinal problems. See "What is the most important information I should know about Zykadia?" >tiredness, decreased appetite, and constipation These are not all of the possible side effects of Zykadia. For more information, ask your health care provider or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. General information about the safe and effective use of Zykadia Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use Zykadia for a condition for which it was not prescribed. Do not give it to other people, even if they have the same symptoms you have. It may harm them. You can ask your health care provider or pharmacist for more information about Zykadia. Click here for full Prescribing Information. http://www.pharma.us.novartis.com/produ ... irmasrc=NA Sincerely, The Zykadia Team Novartis Pharmaceuticals Corporation Now that it's FDA approved, phenotype assayists are ordering some and building up a database, to give it to the right patients. There is entirely too much trial-and-error giving so much side effects to the wrong patients.

Zykadia (ceritinib) being approved is a good thing as it is yet another drug that may provide good benefit for some or even possibly many people. The real question is whether it is right for a specific patient with a specific cancer. The answer to that is they don't know because they don't even bother to test for it. They simply test whether the mutation or gene structure exists in the cancer patient for which this drug might be of use. Without any other compelling testing or data on actual use and effect of the drug on that specific cancer patient the odds will always be 50/50, as it is pointed out in how we perform trial and error medicine. The problem here isn't whether Zykadia is an effective drug or not, it's the same problem they still refuse to deal with and that is whether it is an effective drug or not for each specific patient, the whole purpose of targeted therapy. The assumption is that because you have the mutation (the specific focus) which a drug is related too, it should have some effect and does not account for anything else of which there are and has already been pointed out, seemingly limitless factors. It costs entirely too much to study and determine all of these things, they just want what they need to get approved. It is so much more complex than that and is why Zykadia has great effect in one and little to none in another even though the tests they currently use say it should work simply because they assume it will as they have the same mutation. Truth is, without proper whole cell live assay testing done on a proper sample, the only way to know if it will work or not is trial and error, the very way they do treatment today, take the drug over a period of time and see if it is working or not. Mutation testing to find targeted drugs is good but it is only a piece to the puzzle and does not really indicate whether it will work for one patient over another with the same mutation. If it did, every single patient with the mutation would benefit exactly the same with the same drug, it simply just doesn't work like that even though that is the basis of the primary treatment assumption for all cancers and all treatments. So, besides not approaching drug selection and treatment properly to begin with the other big factor is of course cost which many governments and insurance providers are becoming more and more unwilling to justify. Nobody is looking for a cure, it gets thrown around a lot because that's what they all wish for. Truth is every cancer and every patient is unique so there is likely no cure-all, at least not with the knowledge they have today. We have treatments and a good focus for treatment is to turn cancer into a cronic condition which can be maintained and controlled until natural death occurs. Very slowly the focus in the US is switching to that but it will probably take some time. Disease stability is something that can be achieved if they focus on it properly and both PFS, OS and QOL are all part of the equation. PFS and OS can be definitive, QOS is subjective so very difficult to quantify properly. The Downside To Clinical Trials viewtopic.php?f=28&t=51167

A second drug that specifically targets non-small cell lung cancer (NSCLC) that is positive for the ALK gene rearrangement has been approved by the US Food and Drug Administration (FDA). The new drug, ceritinib (Zykadia, Novartis), in indicated for patients with ALK-positive NSCLC who have previously been treated with crizotinib (Xalkori, Pfizer), the first targeted agent for this patient population. This is an accelerated approval, and comes 4 months ahead of schedule. ALK gene rearrangement is found in about 2% to 7% of patients with NSCLC, which makes up about 85% of all lung cancer, according to the FDA announcement. Since its launch in 2011, crizotinib has become a standard of care in this small patient population, with data showing that it doubles progression-free survival when compared with chemotherapy. However, some patients become resistant to crizotinib, and until now, there has been no other targeted therapy to offer these patients. Zykadia (ceritinib now fills that role. "Ceritinib represents an important treatment option for ALK-positive NSCLC patients who relapse after starting initial therapy with crizotinib," said lead investigator Alice Shaw, MD, PhD, from the Massachusetts General Hospital Cancer Center in Boston. "This approval will affect the way we manage and monitor patients with this type of lung cancer, as we will now be able to offer them the opportunity for continued treatment response with a new ALK inhibitor," she said in a statement. The drug went through the FDA Accelerated Approval Program, which allows approval of a drug to treat a serious or life-threatening disease based on clinical data showing the drug has an effect on a surrogate end point reasonably likely to predict clinical benefit to patients. This program provides earlier patient access to promising new drugs while the company conducts confirmatory clinical trials, the agency said. The accelerated approval was based on a clinical trial of 163 patients with metastatic ALK-positive NSCLC, who progressed on or were intolerant to treatment with crizotinib. The most common sites of metastases in the patient population studied were brain (60%), liver (42%), and bone (42%) Results showed that about half of the participants had their tumors shrink, and this effect lasted an average of about 7.0 months, the agency noted. The overall response rate was 54.6% (95% confidence interval [CI], 47% - 62%), and the median duration of response was of 7.4 months (95% CI, 5.4 - 10.1), the company added in its press release. Common adverse effects of Zykadia (ceritinib) include gastrointestinal symptoms, such as diarrhea, nausea, vomiting, and abdominal pain. Laboratory abnormalities, such as increased liver enzymes, pancreatic enzymes, and increased glucose levels, were also observed. It was approved 4 months ahead of the product's prescription drug user fee goal date of August 24, the date the agency was scheduled to complete review of the drug application. The FDA also granted Zykadia (ceritinib) Breakthrough Therapy Designation, priority review, and Orphan Product Designation. The manufacturer has demonstrated through preliminary clinical evidence that the drug may offer a substantial improvement over available therapies, the agency said. It had the potential, at the time the application was submitted, to be a significant improvement in safety or effectiveness in the treatment of a serious condition. Also, the drug is intended to treat a rare disease, it noted. Citation: FDA Approves Ceritinib for ALK-Positive Lung Cancer. Medscape. Apr 29, 2014. Approval After Phase I: Ceritinib Runs the Three-Minute Mile http://theoncologist.alphamedpress.org/ ... teMile.pdf

In targeted gene therapy - the targeted gene or "driver" oncogene - doctors use a therapy that works on just one gene, then it's possible for tumors to shrink. Unfortunately, those tumors will eventually find a way to subvert that gene. There is some twelve main gene signaling pathways in cancer. Gene signaling is part of a complex system of communication that governs cellular activity and coordinates cell action. In order for gene therapy to work, doctors must influence not only single genes, but their entire pathways, which are also comprised of numerous genes. They also must get rid of the malignant stem cells, which multiply and produce new cancer cells. Further complicating matters is the fact that these malignant stem cells are practically immortal. 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. 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.

JAMA papers raise questions about FDA drug and device approval Gary Schwitzer HealthNewsReview.org An important series of papers was published in the Journal of the American Medical Association this week. “Clinical Trial Evidence Supporting FDA Approval of Novel Therapeutic Agents, 2005-2012,” by Dr. Joseph Ross and colleagues, concluded that the quality of clinical trial evidence used by the FDA as the basis of approving new drugs varies widely. A couple of interesting data points: - in the seven-year period of analysis, 37% of drugs were approved on the basis of a single pivotal trial. - trials using surrogate end points as their primary outcome formed the exclusive basis of approval for 45% of drugs approved. http://jama.jamanetwork.com/article.asp ... id=1817794 In an opinion piece, “Opening the FDA Black Box,” Drs. Steven Goodman and Rita Redberg said the study: “…raises a host of questions needing further exploration. Despite the FDA requirement for evidence from a minimum of 2 randomized clinical trials supporting an effect on health outcomes, 37% of product approvals were based on only 1 trial, 53% of cancer trials were nonrandomized, and an active comparator was used in only 27% of non–infectious disease trials. Surrogate end points were used in almost all approvals via the accelerated approval process and in 44% of nonaccelerated approvals. Trials were comparatively short, with most lasting less than 6 months, even those assessing chronic treatments for chronic diseases. Cancer drugs, perhaps predictably, were more often approved via the accelerated process and with weaker designs.” http://jama.jamanetwork.com/article.asp ... id=1817770 Another paper looked at the reasons that FDA marketing approval for new drugs was delayed or denied. http://jama.jamanetwork.com/article.asp ... id=1817795 And a fourth paper looked at FDA regulation of medical devices, “a process that has received relatively little attention,” according to Goodman and Redberg, who continued: “There are 2 different pathways of devices to market. The most rigorous is the premarket approval (PMA) route, which requires some evidence of clinical effectiveness and safety data, although only 14% of high-risk devices have been assessed in even 1 randomized controlled trial, usually unblinded. As a result of the 2004 Medical Devices User Fee Act, which requires the FDA to require the “least burdensome route” to approval, less than 1% of medical devices are approved through this most rigorous pathway.For moderate- and low-risk devices, the other route is the 510(k) pathway, which allows devices to be marketed if they show “substantial equivalence” to existing devices.A 2010 Institute of Medicine committee strongly recommended elimination of this path. (That paper also describes) an underexamined third way for a device to reach the market via the “supplement” process, used for modifications of devices originally approved through a PMA. Focusing on cardiac implantable electronic devices in the period from 1979-2012, Rome et al found that there were 5825 supplemental PMA applications for 77 original devices—a median of 50 supplements per device, of which about half were for design changes. It is not surprising that many of the devices are, according to the authors, “much different from the original.” Rome et al report that supplemental PMA applications are commonly approved without clinical testing, based on reviewer judgments, suggesting that “in some cases, preclinical testing may be superior to clinical testing in assessing changes.” The main role of preclinical testing is to identify devices that demonstrate problems in the laboratory setting and thus avoid clinical testing of that device change. However, the absence of problems in the laboratory setting might not reliably predict the long-term fate of the device in the human body, where environmental and physiologic forces impossible to replicate in the laboratory setting work in combination. The malfunction of implantable cardioverter-defibrillator leads, which resulted in a widespread recall,and the hazards posed by particles shed from metal-on-metal hip replacements were not predictable based on engineering insights or in vitro studies. More empirical work is needed to assess the validity of reviewer judgments about whether clinical data are needed prior to certain types of device approval. Moreover, if the approval process depends on subsequent clinical trials, a less obvious consequence of constant design modification is that it could be difficult to know what device versions were used in the trials and whether results are generalizable to other versions of the device.” http://jama.jamanetwork.com/article.asp ... id=1817796 In USA Today, Liz Szabo wrote a good summary of the JAMA papers under the headline, “Not all FDA-approved drugs get same level of testing: Evidence behind FDA-approved drugs and devices often has major limitations.” http://www.usatoday.com/story/news/nati ... g/4713621/