Circulating Tumour Cells Predict Chances Of Survival......

wallycat....great questions...keep us posted!

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 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.

Barbe

When it comes to "drug selection" (predictive analysis), investigators can only measure those analytes (substance or chemical constituent) in paraffin wax that they know to measure. If you are not aware of and capable of measuring a biologically relevant event, you cannot seek to detect it.

The cell-lines in paraffin-embedded tissue can change over time. The pathologist establishes a cell-line (immortalizes it) with your tumor cells. A cell-line is a product of immortal cells that are used for biological research (not drug selection). Cell-lines can perpetuate division indefinitely. Regular cells can only divide approximately 50 times.

Cell-lines are useful for experimentation in labs as they are always available to researchers as a product and do not require harvesting (acquiring of tissue from a host) every time cells are needed in the lab. They can clone cells from a cell line (HeLa cells).

Problem is, cell-lines don't recapitulate "drug response" patterns which exist in the body. These proliferating populations of cells are biologically distinct in their behavior from "fresh" live cells that comprise human tumors.

Tissue that is frozen, miniced, fixed, formalin-fixed or paraffin-embedded (cell-lines) have always played and continue to play an important role in drug screening in drug development. The problem is that cell-lines do not predict for disease or patient-specific drug effects (drug selection).

Greg

Well then! I find it amazing that I was told I have/had CTCs then, even more!!!

I had a CTC blood test done that came out negative...zero circulating cells that could be detected.  Does this mean I have a very low prognosis for the cancer returning?

Kaara

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).

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.

Greg

Dang it all!! Forget all my comments unless they make sense. It was ITC's that I have/had...Isolated Tumour Cells. What the heck is the difference??

ITCs?

As Roseanne Roseannadanna would say, "Never Mind!"

Barbe

What I know about isolated tumor cells is that cells are routinely broken up by mechanical and enzymatic means, which alters their subsequent behavior. As Jennt states, ITCs (or micrometastases) are tumor cells situated in nearby tissue but not physically associated with the main tumor. Some previous methods of cell culture assays had limited their analysis only to isolated tumor cells and failed to incorporate the crucial contribution of non-tumorous elements to the cancer phenomenon.

Researchers at Cold Spring Harbor, NY had found that micrometastases recruit EPCs (endothelial progenitor cells) from the bone marrow. These EPCs, in turn, regulate the angiogenic switch that activates blood-vessel growth and transforms these dormant lesions into life-threatening macrometastases. EPCs are a population of cells that circulate in the blood with the ability to differentiate into endothelial cells (cell that make up the lining of blood vessels). They participate in angiogenesis.

Biologically, it appears that many cancers diagnosed at an earlier stage with screening are so aggressive that even at the time of earliest possible detection, there are already micrometastases, meaning that earlier extirpation of the primary tumor does not influence outcomes in a meaningful way. But, most commonly, tumors are so indolent that metastases would not have occurred, even had diagnosis been delayed by one, two, or several years (i.e. until the lesion became palpable and was diagnosed in the former, pre-screening manner). Hence the controversy with mammograms.

Modern-day cell-death functional profiling has incorporated all of these elements into their analysis (these guys have been way ahead of their time). 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 a few targets (mutations, mechanisms, pathways). That's why just examining a patient's DNA cannot determine treatment plans for patients. It cannot determine treatment plans for patients. It cannot  test (chemo) sensitivity to any of the targeted therapies, just "theoretical" candidates.

Greg 

I'm confused. I thought there was no test for circulating tumor cells. Is this something we can ask for at the oncologists office now? 

I have had 4 CTC blood tests, all requested by my ONC. The blood is put in a special tube and the test is conducted by CellSearch (If I recall correctly).

My first CTC was drawn after the second or third neoadjuvant chemo infusion. It came back "2".

2nd test was taken at last chemo infusion. Came back "1".

3rd test was done after surgery. Came back "0".

4th test was done with less than one week left in Radiation treatment. I havent picked up the result yet.



I do believe that my ONC uses them to determine if treatment was working. I don't know if he will continue to take them, along with all of the other tumor marker and blood panel checkups.



My insurance (Anthem Blue Cross Blue Shield PPO) has paid for all of them.

My onco replied. Below is her post.

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There is continuing controversy about the meaning of this finding in the blood of women who had early stage breast cancer. This adds to the knowledge base but is still too early to make any treatment changes for these patients....

And, no, everyone should not be tested. I think there is just too many "false positives" in almost any test we do on an otherwise healthy group of people... ;-)