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Old 01-04-2011, 10:03 AM
gdpawel gdpawel is offline
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Default New Blood Test That Counts Circulating Tumor Cells To Be Developed

By Catharine Paddock, PhD

Using next-generation Circulating Tumor Cell (CTC) technology to capture, count and characterize circulating tumor cells in patients' blood, Johnson and Johnson and Massachusetts General Hospital hope to equip doctors with a more advanced non-invasive way to find out from a few cells how much a cancer has spread, personalize treatment for patients, and monitor their progress.

Circulating tumor cells (CTCs) are cells that have come away from a primary tumor, are circulating in the bloodstream, and have the potential to seed secondary tumors in another part of the body.

On Monday, Veridex, a Johnson and Johnson company, announced the new partnership will also involve Ortho Biotech Oncology Research & Development (ORD), a unit of Johnson & Johnson Pharmaceutical Research & Development that has expertise in oncology therapeutics, biomarkers and companion diagnostics.

Veridex already markets the first FDA-approved CTC test, the CellSearch blood test, launched in 2004.

The company says that "CTCs are proven to be an independent predictor of Overall Survival (OS) and Progression Free Survival (PFS)", and that "... monitoring of CTCs can indicate a significant change in prognosis as early as after the first treatment cycle and at each step of the way".

By partnering with Massachusetts General Hospital (MGH), who bring expertise in new CTC technologies, Veridex hope the collaboration will be able to exploit the latest technological, biological and clinical innovations to produce a more advanced diagnostic tool that oncologists can use for personalizing patient care, and a more advanced investigative tool that researchers and developers can use to speed up and improve the discovery and development of new drugs.

The result will be a "bench-top system" that will "specifically isolate and explore the biology of rare cells at the protein, RNA and DNA levels", said the Veridex statement.

Dr Mehmet Toner, director of the BioMicroElectroMechanical Systems Resource Center in the MGH Center for Engineering in Medicine, said:

"We have developed and continue to develop a broad range of technologies that are evolving what we know about cancer and cancer care."

"This collaboration is an opportunity to apply our past learning to the advancement of a platform that will ultimately benefit patients with cancer," he added.

Veridex's Head of Technology Innovation and Strategy, Robert McCormack, told the press that:

"This new technology has the potential to facilitate an easy-to-administer, non-invasive blood test that would allow us to count tumor cells, and to characterize the biology of the cells."

"Harnessing the information contained in these cells in an in vitro clinical setting could enable tools to help select treatment and monitor how patients are responding," he added.

Nicholas Dracopoli, ORD's Vice President for Biomarkers, said new technologies that "allow us to use CTCs for the first time as templates for novel DNA, RNA and protein biomarkers" are giving CTCs a bigger role in drug discovery and development.

"Given the demand for actionable data to guide personalized medicine for patients with cancer, there is a rapidly growing need for advanced, automated non-invasive technologies that can aid in selection of treatment and monitor response throughout the course of their disease," he explained.

Sources: Johnson & Johnson, Veridex.

American Cancer Society's Dr. J. Leonard Lichtenfeld has put this in proper perspective. He reminds us on his cancer blog, "there is always a caution that comes along with these types of announcements."

First, and perhaps the most obvious, is the fact that this is an announcement of a research deal. Nothing more, nothing less. It is not a new breakthrough. It is not something that has been proven effective in improving cancer detection and treatment.

Not that it is anything less than stunning to develop and demonstrate that this technology works, but as with all research it is a giant step to go successfully from the laboratory phase of development to the clinical phase of making a real difference in patients' lives.

Researchers have signed a contract with a company to further develop this research and determine whether in fact it can be applied successfully to large numbers of patients in a more efficient and less expensive manner.

He reiterated that it is also important to remember that there are many researchers who have been working on other techniques to accomplish the same goal, some for many years.
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Last edited by gdpawel : 11-16-2011 at 10:58 AM. Reason: post full article
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Old 01-04-2011, 10:06 AM
gdpawel gdpawel is offline
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Default Circulating Tumor Cells in Blood

It would be important to develop a method of in vivo labelling of tumor cells in the circulation and to monitor their trafficking and homing to other sites. If these cells are viable and therefore able to disseminate, I think the most robust test to this end is to document their ability to metastasize.

What I know of CTC technology is that is has great potential - for drug selection - ten or twenty years down the road, and they should continue to try and make strides. However, in drug selection, there is a problem with growing or manipulating tumor cells in any way. When looking for cell-death-related events, which mirror the effect of drugs on living tumors, cells are generally not grown or amplified in any way. The object is occurrence of programmed cell death in cells that come into contact with therapeutic agents.

How do you aggregate a sufficient number of cancer cells to make accurate determinations? Detectable tumor cells in the peripheral blood are present only in extremely small numbers. This precludes allowing a sufficient number of cells to incubate for a few days in the presence of chemotherapeutic agents. Analysis of a relatively small number of isolated cancer cells cannot yield the same quality information as subjecting living cells to chemotherapeutic agents, begging the question of whether or not it can accurately predict which drugs will work and which will not.

CTCs are free-floating cancer cells that can remain in isolation from a tumor for over twenty years. What is the relationship of such long-lasting cells to the tumor cells that need to be attacked through tested substances?

Then there is the question of heterogeneity. The original Immunicon research team really became known for their ability to track and isolate circulating tumor, endothelial, immune and other disease associated circulating cell populations and then using every tool available to further characterize them. The problem they know is the heterogeneity of all these cell populations is greater than any one thought thus defining and characterizing them is more difficult as is finding them - also finding vital ones - as many if not most are dead or dying - this is one of the reasons why the metastatic process is so inefficient.

Tumors in the body are genetically variable. What is the relationship between CTCs and primary tumors or their already established metastases? It has already been established that the gene expression profile of a metastatic lesion can be different compared to that of the primary. The status of the marker Her2/neu in CTCs sometimes differs from that of the original primary tumor, which would point to different prescriptions for Herceptin.

The number of cells discovered in the CTC technique has turned out to be a good prognosticator of how well empiric treatments are working, but less certain in the ability to use it for drug selection. The "problem" is in isolating and analyzing single cancer cells. The supposition is that common cancers can be detected and cured through analysis at a genetic level of a small number of cells or even a single wayward cell.

Genetic or IHC testing examines dead tissue that is preserved in paraffin or formalin. How is that going to be predictive to the behavior of living cells in spontaneously formed colonies or microspheres? Can it describe the complex behavior of living cancer cells in response to the injury they receive from different forms of chemotherapy? There is a big difference between living and dead tissue.

Some molecular tests do utilize living cells, but generally of individual cancer cells in suspension, sometimes derived from tumors and sometimes derived from CTCs. Don't forget, this was tried with the human clonogenic assay, which had been discredited long ago.

Again, this has been a very promising field of research, however, it's turning out to be much more complex as we learn more. More research is needed and no one really has figured out how it all fits. Although they're getting closer and closer.

There was a symposium in Washington DC in September of 2009, devoted entirely to the circulating tumor cells (CTC) technology. Although it's a monitoring system to determine if therapy is working, it is not of value in selecting therapy (drug selection).

Circulating tumor cells (CTCs) are cancer cells that have detached from solid tumors and entered the blood stream. This can begin the process of metastasis. To metastasize, or spread cancer to other sites in the body, CTCs travel through the blood and can take root in another tissue or organ.

In stem cell research, anti-cancer treatments often effectively shrink the size of tumors, but some might have the opposite effect, actually expanding the small population of cancer stem cells that then are capable of metastasizing.

The technique requires only a simple blood draw from a patient, but its sensitivity and specificity allow physicians to observe true changes in CTCs that are greater than or less than the 5 CTC cutoff. This information may help physicians predict progression-free and overall survival in individual patients both before and following a single cycle of therapy.

The cutoff is 5 tumor cells. Less than 5 means that things are going well. More than 5 means that things are going poorly. But you can see the difference between 4 and 6 is not all that great. What they found out from that symposium was that it's perhaps useful as an adjunct to traditional methods for following tumor response, such as x-rays, blood tests, CTs, MRIs, history, physical exam, etc.
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Last edited by gdpawel : 10-22-2011 at 11:36 AM. Reason: additional info
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Old 01-07-2011, 10:40 AM
gdpawel gdpawel is offline
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Default Circulating Cells: Helpful for Cancer Patients or Just Interesting?

Emile E. E. Voest
Department of Medical Oncology
UMC Utrecht, the Netherlands

Background:

In the era of targeted therapy a multitude of new agents to treat cancer is developed. Unfortunately only 5% of these agents will ultimately be approved for clinical use. One of the reasons for this high failure rate is our inability to select patients for the appropriate therapy. The potential recurrence rate of an individual tumor is relatively well defined by prognostic factors, however, our tools to predict response to therapy are very limited. Developing predictive markers to assess which patients will benefit from treatment are therefore highly needed. This educational session will be devoted to circulating biomarkers. In this presentation I will focus on circulating cells as potential markers for treatment response. Several circulating cell types currently under investigation: circulating tumor cells; circulating (endothelial) progenitor cells (C(E)PC); and circulating endothelial cells (CTC), the value of measuring these cells will be discussed in detail below.

Discussion:

Circulating Tumor Cells

Of all surrogate tumor tissues, CTCs have probably received the greatest attention the last years (1–8). It is becoming increasingly clear that the number, and change in number, of CTCs is prognostic for several types of cancer, including breast, colorectal- and prostate cancer (4–7) In the NIH clinical trials database, currently 298 trials are listed that measure CTC and correlate these measurements with treatment outcome. Few of these trials prospectively uses CTC to make treatment decisions. Now that CTC detection techniques have significantly improved and proper logistics for CTCs have become implemented in trials, a feasible, new goal is to characterize CTCs and to study specific molecular targets on CTCs (8). However, several limitations should be taken into consideration. A substantial percentage of patients have no detectable CTCs. Furthermore, CTCs may serve as surrogate tissue but may not be representative for real tumor tissue. CTCs may represent a subset of tumor cells. Next to this, EpCAM-based CTC detection may cause a bias for cells that have a low or no EpCAM expression.

CTCs have a clear potential as pharmacodynamic biomarker in early oncology trials. Potential applications of measuring actual target modulation are, for example, to provide proof of mechanism of action of the drug and to study the biologically active dose range. With the availability of pharmacodynamic assays for growth hormone receptors on CTCs, opportunities arise in monitoring of activating- or resistance-conferring mutations and measuring change in activity of down-stream signaling molecules intracellularly that can indicate the level of inhibitory activity of the drug. The development of new techniques that improve CTC detection sensitivity allows for increasing sensitivity in subsequent characterization. These advanced techniques may enable further specified CTC analysis which could lead to a more personalized therapy for the patient in the future. In summary, there are many interesting and encouraging developments in the field of CTC detection and their characterization that may lead to further development and incorporation of CTCs as pharmacodynamic biomarker in early clinical trials of targeted anti-cancer therapy.

Circulating Endothelial (Progenitor) Cells

In addition to CTC, circulating normal cells may also predict tumor progression or host responses to treatment. The best studied cells are circulating endothelial cells (CEC) and circulating endothelial progenitor cells (EPC). The relevance of EPCs in cancer growth suggests that EPCs might be used as a surrogate marker for angiogenic activity (9–12). Both circulating mature endothelial cells (CECs) and endothelial progenitor cells (EPCs) are increased in the blood of cancer patients and correlate with angiogenesis and tumor volume. Therefore these cells might serve as a biomarker to determine prognosis, response to therapy and the optimal biological dose (OBD) of anti-angiogenic agents.

CEC levels correlate with progressive disease, as patients with growing tumors have higher CEC levels compared to patients with stable disease. Conversely, CEC levels return to normal after successful treatment. This suggests that CECs correlate with the presence and the activity of a tumor and indicates that CECs hold the potential to measure changes in disease activity and therefore response to therapy. Clinically this has been investigated in patients with metastatic breast cancer treated with low dose metronomic chemotherapy. In these patients the CEC count after 2 months of continuous therapy could predict both disease-free and overall-survival after a prolonged follow-up of more than 2 years. Others showed that high baseline levels of CECs predicted response to metronomic chemotherapy combined with bevacizumab. We showed that CEC and EPC were increased in the blood of cancer patients after treatment with various chemotherapeutic regimens. The increase in CEC and EPC is seemingly unrelated to the presence of a tumour since adjuvant chemotherapy showed similar kinetics. This suggests that EPC and CEC release after chemotherapy is part of a reactive host response independent of tumor type and chemotherapy regimen. This response may very well be an important factor in determining the outcome of patients, as EPC and CEC have been found to stimulate tumour growth, metastasis formation and limit chemotherapeutic efficacy by prevention of necrosis. The magnitude of the increase of CEC and EPC after chemotherapy was associated not only with response to chemotherapy after 3 cycles but also with PFS and OS. This correlation between CEC/EPC and prognosis of patients is supported by other studies (13, 14). There are several limitations to take into account. EPC and CEC detection techniques are labor intensive, time consuming, often require fresh samples and the number of circulating cells are commonly very low.

In summary, circulating EPC and CEC are biologically interesting but presently the detection techniques and inter- and intrapatient variability prohibit wide spread use of these cells in routine clinical care.

Future Directions: Can We Use Circulating Cells in Clinical Decision Making?

The above described studies have greatly contributed to our understanding of the biology of cancer. Measurement of these cells has clearly prognostic value. It furthermore indicates avenues to further refine specific assays to use circulating cells as biomarkers. However, the data are presently insufficient to consider circulating cells to predict outcome of treatment in such a manner that anti-cancer treatment can be started or even more important stopped. Given the response rates of current anti-cancer treatment and the willingness of patients to undergo treatment even for relatively low success percentages imposes high sensitivity and specificity requirements on potential predictive tests. Presently, none of these circulating cell assays fulfil these requirements but the enormous potential of these circulating cells as pharmacodynamic markers deserves prospective clinical trials to further assess their value.

References:

1. Stebbing J, Jiao LR. Circulating tumour cells as more than prognostic markers. Lancet Oncol 2009; 10: 1138–9.

2. Mostert B, Sleijfer S, Foekens JA, Gratama JW. Circulating tumor cells (CTCs): detection methods and their clinical relevance in breast cancer. Cancer Treat Rev 2009; 35: 463–74.

3. Dotan E, Cohen SJ, Alpaugh KR, Meropol NJ. Circulating tumor cells: evolving evidence and future challenges. Oncologist 2009; 14: 1070–82.

4. Cristofanilli M, Budd GT, Ellis MJ, et al. Circulating tumor cells, disease progression, and survival in metastatic breast cancer. N Engl J Med 2004; 351: 781–91.

5. Hayes DF, Cristofanilli M, Budd GT, et al. Circulating tumor cells at each follow-up time point during therapy of metastatic breast cancer patients predict progression-free and overall survival. Clin Cancer Res 2006; 12: 4218–24.

6. Cohen SJ, Punt CJ, Iannotti N, et al. Relationship of circulating tumor cells to tumor response, progression-free survival, and overall survival in patients with metastatic colorectal cancer. J Clin Oncol 2008; 26: 3213–21.

7. de Bono JS, Scher HI, Montgomery RB, et al. Circulating tumor cells predict survival benefit from treatment in metastatic castration-resistant prostate cancer. Clin Cancer Res 2008; 14: 6302–9.

8. Lianidou ES, Mavroudis D, Sotiropoulou G, Agelaki S, Pantel K. What's new on circulating tumor cells? A meeting report. Breast Cancer Res 2010; 12: 307.

9. Gao D, Nolan DJ, Mellick AS, Bambino K, McDonnell K, Mittal V. Endothelial progenitor cells control the angiogenic switch in mouse lung metastasis. Science 2008; 319: 195.

10. Kaplan RN, Riba RD, Zacharoulis S, et al. VEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche. Nature 2005; 438: 820.

11. Shaked Y, Ciarrocchi A, Franco M, et al. Therapy-induced acute recruitment of circulating endothelial progenitor cells to tumors. Science 2006; 313: 1785.

12. Shaked Y, Henke E, Roodhart JM, et al. Rapid chemotherapy-induced acute endothelial progenitor cell mobilization: implications for antiangiogenic drugs as chemosensitizing agents. Cancer Cell 2008; 14: 263.

13. Roodhart JM, Langenberg MH, Vermaat JS, et al. Late release of circulating endothelial cells and endothelial progenitor cells after chemotherapy predicts response and survival in cancer patients. Neoplasia 2010; 12: 87–94.

14. Roodhart JM, Langenberg MH, Daenen LG, Voest EE. Translating preclincal findings of (endothelial) progenitor cell mobilization into the clinic; from bedside to bench and back. BBA–Reviews on Cancer, 2009; 1796: 41–9.

[url]http://educationbook.aacrjournals.org/cgi/content/full/2011/1/23
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Last edited by gdpawel : 01-20-2013 at 11:31 PM. Reason: corrected url address
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Old 01-13-2011, 11:34 PM
gdpawel gdpawel is offline
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Default Heterogeneous populations of circulating tumor cells

The cells that slough off from a cancerous tumor into the bloodstream are a genetically diverse bunch, Stanford University School of Medicine researchers have found. Some have genes turned on that give them the potential to lodge themselves in new places, helping a cancer spread between organs. Others have completely different patterns of gene expression and might be more benign, or less likely to survive in a new tissue. Some cells may even express genes that could predict their response to a specific therapy. Even within one patient, the tumor cells that make it into circulating blood vary drastically.

The finding underscores how multiple types of treatment may be required to cure what appears outwardly as a single type of cancer, the researchers say. And it hints that the current cell-line models of human cancers, which showed patterns that differed from the tumor cells shed from human patients, need to be improved upon.

The new study, which was published online in PLoS ONE, is the first to look at so-called circulating tumor cells one by one, rather than taking the average of many of the cells. And it's the first to show the extent of the genetic differences between such cells.

"Within a single blood draw from a single patient, we're seeing heterogeneous populations of circulating tumor cells," said senior study author Stefanie Jeffrey, MD, professor of surgery and chief of surgical oncology research.

For over a century, scientists have known that circulating tumor cells, or CTCs, are shed from tumors and move through the bloodstreams of cancer patients. And over the past five years, there's been a growing sense among many cancer researchers that these cells - accessible by a quick blood draw - could be the key to tracking tumors non-invasively. But separating CTCs from blood cells is hard; there can be as few as one or two CTCs in every milliliter of a person's blood, mixed among billions of other blood cells.

To make their latest discovery, Jeffrey, along with an interdisciplinary team of engineers, quantitative biologists, genome scientists and clinicians, relied on a technology they developed in 2008. Called the MagSweeper, it's a device that lets them isolate live CTCs with very high purity from patient blood samples, based on the presence of a particular protein - EpCAM - that's on the surface of cancer cells but not healthy blood cells.

With the goal of studying CTCs from breast cancer patients, the team first tested whether they could accurately detect the expression levels of 95 different genes in single cells from seven different cell-line models of breast cancer - a proof of principle since they already knew the genetics of these tumors. These included four cell lines generally used by breast cancer researchers and pharmaceutical scientists worldwide and three cell lines specially generated from patients' primary tumors.

"Most researchers look at just a few genes or proteins at a time in CTCs, usually by adding fluorescent antibodies to their samples consisting of many cells," said Jeffrey. "We wanted to measure the expression of 95 genes at once and didn't want to pool our cells together, so that we could detect differences between individual tumor cells."

So once Jeffrey and her collaborators isolated CTCs using the MagSweeper, they turned to a different kind of technology: real-time PCR microfluidic chips, invented by a Stanford collaborator, Stephen Quake, PhD, professor of bioengineering. They purified genetic material from each CTC and used the high-throughput technology to measure the levels of all 95 genes at once. The results on the cell-line-derived cells were a success; the genes in the CTCs reflected the known properties of the mouse cell-line models. So the team moved on to testing the 95 genes in CTCs from 50 human breast cancer patients - 30 with cancer that had spread to other organs, 20 with only primary breast tumors.

"In the patients, we ended up with 32 of the genes that were most dominantly expressed," said Jeffrey. "And by looking at levels of those genes, we could see at least two distinct groups of circulating tumors cells." Depending on which genes they used to divide the CTCs into groups, there were as many as five groups, she said, each with different combinations of genes turned on and off. And if they'd chosen genes other than the 95 they'd picked, they likely would have seen different patterns of grouping. However, because the same individual CTCs tended to group together in multiple different analyses, these cells likely represent different types of spreading cancer cells.

The diversity, Jeffrey said, means that tumors may contain multiple types of cancer cells that may get into the bloodstream, and a single biopsy from a patient's tumor doesn't necessarily reflect all the molecular changes that are driving a cancer forward and helping it spread. Moreover, different cells may require different therapies. One breast cancer patient studied, for example, had some CTCs positive for the marker HER2 and others lacked the marker. When the patient was treated with a drug designed to target HER2-positive cancers, the CTCs lacking the molecule remained in her bloodstream.

When the team went on to compare the diverse genetic profiles of the breast cancer patients' CTCs with the cells they'd studied from the cell lines, they were in for another surprise: None of the human CTCs had the same gene patterns as any of the cell-line models.

"These models are what people are using for drug discovery and initial drug testing," said Jeffrey, "but our finding suggests that perhaps they're not that helpful as models of spreading cancers." While the human cell-line cells did show diversity between each of the seven cell lines, they didn't fall into any of the same genetic profiles as the CTCs from human blood samples.

These results don't have immediate impacts for cancer patients in the clinic because more work is needed to discover whether different types of CTCs respond to different therapies and whether that will be clinically useful for guiding treatment decisions. But the finding is a step forward in understanding the basic science behind the bits of tumors that circulate in the blood. It's the first time that scientists have used high-throughput gene analysis to study individual CTCs, and opens the door for future experiments that delve even more into the cell diversity. The Stanford team is now working on different methods of using CTCs for drug testing as well as studying the relationship between CTC genetic profiles and cancer treatment outcomes. They've also expanded their work to include primary lung and pancreatic cancers as well as breast tumors.

Source: Stanford University Medical Center

[url]http://www.medscape.com/viewarticle/782543

Note: There is not a single validation of a molecular marker in CTCs (Liquid Biopsy) that provides prognostic information or predicts response to cancer therapies.

According to laboratory oncologist Dr. Robert A. Nagourney, liquid biopsy can mean several different things. On the one hand it can be a multiplexed biochemical, proteomic, circulating DNA types of analyses on serum. On the other, it can be circulating tumor cell (CTC) extraction mostly for genomics. The CTC approach is offered commercially and has use in target identification, when distinct driver mutations are found, but it does not capture the cellular microenvironment (e.g. stroma, vasculature, cytokines) critical to accurate response prediction of many classes of drugs. This is why cell function analysis exclusively uses fresh tissue explants.
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Last edited by gdpawel : 08-06-2014 at 12:46 AM. Reason: additional info
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Old 01-19-2011, 03:26 PM
gdpawel gdpawel is offline
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Default It's not that unusual for healthy people to have an occasional cancer cell in blood

In an Opinion column on CNN, Dr. H. Gilbert Welch, M.P.H., a professor of medicine at the Dartmouth Institute of Health Policy & Clinical Practice and the author of Overdiagnosed: Making People Sick in the Pursuit of Health" (Beacon Press 2011), raises questions about this simple new blood test that is able to detect minute quantities of cancer cells that might be circulating in your bloodstream.

“The conventional wisdom is people either have a disease or they do not. But, in fact, there are a lot of people somewhere in between. . . I don't know whether this test will help some patients. It might, but it will take years to figure that out... Ironically, what this test might actually teach us is that it's not that unusual for healthy people to have an occasional cancer cell in their blood.”

[url]http://www.cnn.com/2011/OPINION/01/11/welch.overdiagnosed.cancer/index.html?npt=NP1

Dr. Elaine Schattner pointed out that Dr. Welch may have mised the point of this technology. It was developed primarily to help oncologists monitor tumors in patients who already are known to have disease. For example, doctors could check for new, resistance-conferring mutations in patients who are already on a cocktail of meds for lung cancer.

The blood test could obiate the need for repeatedly doing CT scans and biopsies to measure disease, the extent of disease and new mutations in people undergoing cancer treatment.

The June issue of Oncology News International (June 2010, V 19, No 6) quotes a Duke University study of the use of high-tech cancer imaging, with one representative finding being that the average Medicare lung cancer patient receives 11 radiographs, 6 CT scans, a PET scan, and MRI, two echocardiograms, and an ultrasound, all within two years of diagnosis. A study co-author (Dr. Kevan Schulman) asks: "Are all these imaging studies essential? Are they all of value? Is the information really meaningful? What is changing as a result of all this imaging?"

So the investment by Johnson and Johnson, which was what the news was about, makes it more likely this will actually happen in non-research clinics. The technology has the potential to make cancer patients' lives easier and less costly and for doctors to stop giving them meds to which they've acquired resistance.

[url]http://www.scientificamerican.com/article.cfm?id=a-chip-against-cancer

My comment is not really about early cancer diagnosis. It is about prognostication and drug selection with the CTC (circulating tumor cells) technique. The number of cells discovered in the CTC technique has turned out to be a good prognosticator of how well treatments are working. Monitoring CTCs could be utilized for confirmation after the patient is administered either empiric or assay-directed most beneficial therapeutic agents.

But CTCs really aren't useful with respect to drug selection. The problem is with isolating (even by size) and analying single cancer cells. The supposition is that common cancers can be detected and cured through analysis at a genetic level of a small number of cells or even a single wayward cell. CTCs are free-floating cancer cells that can remain in isolation from a tumor for over twenty years.

And what is the relationship of such long-lasting cells to the tumor cells that needed to be attacked through tested substances? And in regards to some molecular tests utilizing living cells, generally of individual cancer cells in suspension, sometimes derived from tumors and sometimes derived from CTCs, this was tried with the old human clonogenic assay, which had been discredited long ago.

One testing approach to find CTCs actually can miscount non-tumor epithelial cells as tumor cells. And also highly invasive cells may not be detected if you are looking for epithelial antigens because the CTC also goes through a phase called "epithelial to mesenchymal transition", where you will miss locating that tumor cell if you are targeting the antigen.

The key is to look for the tumor cell and not something else that "hangs with the tumor cell."

Basically, CTC labs use "negative selection" to isolate alleged circulating tumor cells. What that means is methods to "selectively" remove circulating normal cells, such as monocytes, lymphocytes, neutrophils, circulating endothelial cells, etc. The problem is that these normal cells outnumber circulating tumor cells by a factor of a million to one, and no "negative selection" procedure (or combination of procedures) can possibly strip away all the normal cells, leaving behind a relatively pure population of tumor cells.

What you have to do is to use a "positive selection" procedure, meaning selectively extracting the tumor cells out of the vastly larger milieu of normal cells. The problem is, when you do this, there is only a teeny tiny yield of tumor cells:

Here's from Wikipedia:

Circulating tumor cells are found in frequencies on the order of 1-10 CTC per mL of whole blood in patients with metastatic disease. For comparison, a mL of blood contains a few million white blood cells and a billion red blood cells.

So, from a typical 7 ml blood draw into a purple top tube, you are going to get, on average, 7 to 70 tumor cells -- total. This may be sufficient for certain molecular type tests (although the degree to which this tiny sample of cells is representative may be questioned), but it isn't nearly sufficient to test even a single drug in a cell culture assay, where one requires millions of cells for quality testing, including requirements for negative and positive controls.
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Old 05-16-2011, 09:28 PM
gdpawel gdpawel is offline
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Default Can circulating tumor cells be effective in the determination of treatment?

Many people are interested to learn about a new blood test (which is still in early stages) said to capture migrating cancer cells so that cancer can be detected earlier; determine whether it is spreading; or if the current treatment is even working. These circulating cells are at such a low level in the bloodstream, they are normally hard (or impossible) to detect. The only test currently on the market to find tumor cells in the blood, CellSearch by Johnson & Johnson, can give a cell count, however it doesn't capture the whole cells that doctors need to analyze.

Although the test offers some amazing advances for the diagnosis of early-stage disease, Robert Nagourney, MD, medical director of Rational Therapeutics, cautions that it may not be as effective in the determination of treatment. "The circulating tumor cells may be evaluable for very specific gene profiles, but the biological behavior of isolated individual cells in response to drugs and combinations because these few cells may not reflect the same behavior as those in the micro spheroid (cancer cells in clusters, as they exist in the body) environment.

The test uses a microchip, similar to a lab slide. When blood is placed across the slide, the cancer cells stick and can be collected. J&J in conjunction with Veridex, will be working on improving the microchip. They will be trying different designs and a cheaper plastic to make it more practical for mass production.

The American Cancer Society's Dr. J. Leonard Lichtenfeld reminded us on his blog that this is not a new breakthrough. It is not something that has been proven effective in improving cancer detection and treatment. The researchers have signed a contract with a company to further develop this research and determine whether in fact it can be applied successfully to large numbers of patients in a more efficient and less expensive manner.

Oncologist Dr. Elaine Schattner has reminded us on her blog that this technology was developed, primarily, to help oncologists monitor tumors in patients who already are known to have disease. For example, doctors could check for new, resistance-conferring mutations in patients who are already on a cocktail of meds for lung cancer. The blood test could obviate the need for repeatedly doing CT scans and biopsies to measure disease the entent of disease and new mutations in people undergoing cancer treatment.

The June 2010 issue of Oncology News International (V 19, No 6) quotes a Duke University study of the use of high-tech cancer imaging, with one representative finding being that the average Medicare lung cancer patient receives 11 radiographs, 6 CT scans, a PET scan, and MRI, two echocardiograms, and an ultrasound, all within two years of diagnosis. A study co-author (Dr. Kevan Schulman) asks: "Are all these imaging studies essential? Are they all of value? Is the information really meaningful? What is changing as a result of all this imaging?"

The number of cells discovered in the circulating tumor cell (CTC) technique has turned out to be a good prognosticator of how well treatments are working. Monitoring CTCs could be utilized for confirmation after the patient is administered either physician-directed or assay-directed most beneficial therapeutic agents.

But CTCs really aren't useful with respect to drug selection. The problem is with isolating and analying single cancer cells. The supposition is that common cancers can be detected and cured through analysis at a genetic level of a small number of cells or even a single wayward cell. CTCs are free-floating cancer cells that can remain in isolation from a tumor for over twenty years.

Regardless of all of this, most of the cells that leave home don't survive the journey in the blood or lymph systems and many cancerous cells that eventually do lodge in a distant organ simply remain dormant, leaving it up to the immune system to take care of them.

Full-blown metastasis is an extremely challenging trade and the great majority of cancer cells are not up to the task. Even those malignant characters that manage to slither their way into the blood or lymph system, usually fail to do anything further.

Most tumor cells lack the streamlined form of the blood and immune cells that are designed for cross-body trafficking, shear forces in the smaller vessels may rip the intruders apart. These free-floating cancer cells can remain in isolation from a tumor for over twenty years (Gupta, G.P., and J. Massague. 2006. Cancer metastasis: building a framework. Cell. 127:679-95).
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Last edited by gdpawel : 01-30-2013 at 01:34 PM. Reason: additional info
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Old 12-21-2013, 11:39 AM
gdpawel gdpawel is offline
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Default Changing Chemotherapy Not Beneficial for MBC Patients With Elevated CTCs

Changing Chemotherapy Not Beneficial for Metastatic Breast Cancer Patients With Elevated Circulating Tumor Cells

SAN ANTONIO — For women with metastatic breast cancer who had elevated amounts of circulating tumor cells (CTCs) in their blood after a first line of chemotherapy, switching immediately to a different chemotherapy did not improve overall survival or time to progression, according to the results of a phase III clinical trial presented here at the 2013 San Antonio Breast Cancer Symposium, held Dec. 10–14, 2013.

“We concluded that CTCs are not a good marker in helping to decide when to switch between chemotherapies,” said Jeffrey B. Smerage, M.D., Ph.D., clinical associate professor at the University of Michigan Comprehensive Cancer Center in Ann Arbor. “It had been hoped that switching would both increase the chances of being on an effective therapy and decrease the exposure to toxicity from less effective or ineffective therapies, and as a result it had been hoped that this early switching would result in improved survival and time to progression.

“The most important implication is that we have validated that the group of patients with elevated CTCs at both baseline and 21 days [after starting their first chemotherapy] has a worse prognosis with regard to both time to progression and overall survival,” added Smerage. “Although chemotherapy may work for these patients, it clearly does not work as long as one would like. This suggests that this patient population needs more effective treatment options beyond traditional chemotherapy. Given that these patients have higher cancer-related risks, early consideration of clinical trial participation would be appropriate.”

About 75 percent of patients with metastatic breast cancer have CTCs detectable in their blood, and the number of CTCs is elevated in about half of these patients. The presence of elevated CTCs in blood indicates poor prognosis and relatively short time to progression, and the goal of this trial was to evaluate if switching to a different chemotherapy is beneficial for patients whose elevated CTCs did not drop after initial chemotherapy.

This trial found that changing therapy for patients with elevated CTCs after one cycle of initial chemotherapy did not improve their overall survival, the primary endpoint of this study.

“An important secondary endpoint was to evaluate whether the levels of CTCs before and after starting a chemotherapy provided prognostic information on how long a patient might live,” Smerage said. “This study confirmed that patients who have low numbers of CTCs before starting chemotherapy have a much better survival. They had a median overall survival of 35 months, which means that half of these patients lived three years or longer, and some substantially longer.

“On the other hand, patients for whom CTCs remained elevated after one cycle of chemotherapy had substantially worse survival. They had a median overall survival of only 13 months,” he explained. “This suggests that chemotherapy may not be as effective for these cancers in which CTCs remain elevated after one cycle of chemotherapy. This doesn’t mean that chemotherapy has no benefit, but it suggests that the benefit is limited.”

Smerage and colleagues conducted a prospective, randomized, phase III trial, called the SWOG S0500 trial, to which they recruited 624 patients between 2006 and 2012. All participants had either measurable disease or evaluable disease that included bone metastases.

Of the 595 patients who were eligible for the trial, 276 had low CTCs at baseline, and were observed on arm A. These patients continued to receive the initial chemotherapy.

The remaining 319 patients had elevated CTCs at baseline, and 286 had a CTC result available at day 21 of the first cycle of chemotherapy. At day 21, CTCs decreased to lower levels in 163 patients, who were observed on arm B. These patients continued to receive the initial chemotherapy.

The 123 patients who continued to have elevated CTCs at day 21 were either randomly assigned to arm C1 and continued to receive the initial chemotherapy (64 patients) or were randomly assigned to arm C2 and had their treatment changed to a second-line chemotherapy (59 patients).

“This study was based on counting the number of CTCs in blood,” said Smerage. “Several groups are now investigating the presence of biological markers such as estrogen receptor, HER2, and others on CTCs. It is hoped that the measurement of these markers may allow for better prediction of what therapies will work best for these patients.”

This study was funded by the National Cancer Institute, and in part by Veridex. Smerage declares no conflicts of interest.

Source: American Association for Cancer Research
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