Circulating tumor cells may be promising alternative for tumor biopsies

[News]

Circulating tumor cells (CTCs) may be a promising alternative, noninvasive source of tumor materials for biomarker assessment, according to data presented at the Fourth AACR International Conference on Molecular Diagnostics in Cancer Therapeutic Development.

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[gdpawel]

CTC technology has great potential - for drug selection - ten or twenty years down the road, and they should continue to try and make strides. However, 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. 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 level of documentation of the sensitivity and specificity of the drug recommendations that are generated by this procedure has never been the subject of a single peer-reviewed article.

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.

[gdpawel]

Is the microchip arrays just an alternative to RT-PCR or is it inferior to RT-PCR?

Basically, RT-PCR is more accurate, but it can't be done on such a massive scale. RT-PCR is practical for testing tens to hundreds of genes, while microchip arrays can be used for thousands to tens of thousands of genes.

The use of RT-PCR and DNA microchip arrays in personalized oncology is analogous to the introduction of the personal computer. Dazzling hardware in search of a killer application. This was wonderful technology and the geekiest of people bought them and played with them, but they really didn't start to do anything for a mass market until the introduction of the first killer application, which was a spreadsheet program called Visicalc.

So what research scientists in universities and cancer centers have been doing for the past ten years is to try and figure out a way to use this dazzling technology to look for patterns of gene expression which correlate with and predict for the activity of anticancer drugs. Hundreds of millions of dollars have been spent on this effort.

Academics are besides themselves over the promise of genome sequencing. It seems so cool that it simply must be good for something. How about in the area of identifying drugs which will work in individual patients? All DNA or RNA-type tests are based on "population" research. They base their predictions on the fact that a higher percentage of people with similar genetic profiles or specific mutations may tend to respond better to certain drugs. This is not really "personalized" medicine, but a refinement of statistical data.

The particular sequence of DNA that an organism possess (genotype) does not determine what bodily or behaviorial form (phenotype) the organism will finally display. Among other things, environmental influences can cause the suppression of some gene functions and the activation of others. Our 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. This view is not shared by all molecular biologists, who disagree about the precise roles of genes and other factors, but it signals many scientists discomfort with a strictly deterministic view of the role of genes in an organism's functioning.

It could be vastly more beneficial to measure the net effect of all processes (systems) instead of just individual molecular targets. The cell is a system, an integrated, interacting network of genes, proteins, and other cellular constituents that produce functions. One needs to analyze the systems' response to drug treatments, not just one or a few targets (pathways/mechanisms).

There are many pathways/mechanisms to the altered cellular (forest) function, hence all the different "trees" which correlate in different situations. Improvement can be made by measuring what happens at the end (the effects on the forest), rather than the status of the indivudal trees.

The "success" or "failure" is in the drug or drug combinations. Cell function analysis doesn't change cancer biology, it helps to "reveal" the cancer biology. It lowers the "probability" that certain drugs won't work, and raises the "probability" that others will work. The functional profiling platform is showing the "effaciousness" of the particular drug or drug combinations.

[gdpawel]

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.”

http://www.cnn.com/2011/OPINION/01/1...x.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.

http://www.scientificamerican.com/ar...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."