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New Blood Test That Counts Circulating Tumor Cells To Be Developed
By gdpawel at 2011-01-04 22:03
New Blood Test That Counts Circulating Tumor Cells To Be Developed

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.

http://www.medicalnewstoday.com/articles/212627.php

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.



6 comments | 14490 reads

by gdpawel on Tue, 2011-01-04 22:06
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.

by gdpawel on Fri, 2011-01-07 22:40
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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