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Re: CTCs as pharmacodynamic as biomarker in early clinical oncological trials
Cancer Treat Rev. 2011 Dec;37(8):579-89. doi: 10.1016/j.ctrv.2011.04.006. Epub 2011 May 17.
Circulating tumor cells as pharmacodynamic biomarker in early clinical oncological trials.
Devriese LA, Voest EE, Beijnen JH, Schellens JH.
Division of Clinical Pharmacology and Experimental Therapy, The Netherlands Cancer Institute, Amsterdam.
Abstract
Circulating tumor cells (CTCs) have received a lot of attention from both researchers and clinicians because of their prognostic value for progression-free and overall survival in selected tumor types. CTCs are readily available by single venipuncture, thereby posing little burden on the patient and allowing for repeated, sequential sampling during therapy. Nowadays, the sensitivity of several CTC detection and capture techniques allow for further characterization and analysis of specific targets of interest on the CTC itself. These techniques have given CTCs the potential to be used as a pharmacodynamic read-out in drug development. In this review, we explore the utility of CTCs as a pharmacodynamic biomarker in early clinical oncological trials. We present an overview of current literature on assays for CTCs as pharmacodynamic biomarker, their different targets of interest and their level of validation, followed by discussion of their limitations.
PMID: 21592671
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.
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 (like Caris) 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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