Circulating CellsA typical cancerous tumour contains millions of cells with genetic mutations which induce the cells to proliferate and invade the local tissue. As the cells multiply, some are shed from the tumour and swept away by the bloodstream or lymphatic system. These circulating tumour cells (CTCs) can remain loose in circulation, cluster together or lodge themselves in new tissues eventually forming new tumours.

Not only do these CTCs play a role in spreading cancer to other parts of the body, they possess genetic information about the original tumour that researchers think could be the key to cancer diagnosis or treatment.

Analyzing CTCs may function as a liquid biopsy. Instead of removing tissue samples through a needle inserted into a solid tumour, the cancer cells can be analyzed directly from the blood stream, making analysis quicker and easier.

CTCs have been detected in the peripheral blood of patients with advanced stages of most types of solid tumour cancers. In 2004, researchers had found that breast cancer patients with fewer CTCs in their blood lived longer than those with more CTCs1.

In 2011, Dr. François-Clement Bidard and colleagues from Institut Curie in Paris reported monitoring CTCs in 267 patients starting chemotherapy for metastatic breast cancer in 5 French Cancer Centres. They found that persistence of a high level of CTC before the second cycle of chemotherapy was a strong and early predictive marker of poor progression-free survival2. Their findings set the stage for interventional trials designed to see if improved outcomes could be achieved by modifying treatment based on CTC counts.

“In metastatic breast cancer, it is time now for interventional randomized trials which will try to demonstrate that CTC-based strategies of treatment lead to a better clinical outcome, or at least to a benefit in the cost/efficacy ratio of treatment,” Dr Bidard said3.

Researchers have used CTC to monitor patients undergoing treatment not only for metastatic breast cancer but also for colorectal and prostate cancer. They found evaluation of CTC during the course of disease was predictive of overall survival4.

Analysis of CTC from patients with lung cancer offered the possibility of monitoring changes in the tumour during the course of treatment5. A reduction in the number of captured CTC was associated with a reduction in tumour size; an increase in the number of cells was associated with tumour progression. Also, emergence of drug resistance in the tumour during the course of therapy could be monitored by characterization of the genetic makeup of CTCs providing a strategy for non invasive monitoring of the tumour during treatment. When patients CTC carried a mutation known to cause drug resistance it resulted in faster disease progression than in those whose CTCs lacked the mutation.

A number of cases have shown that CTC numbers change prior to changes being seen with anatomical imaging, and that CTC analysis may be a more robust surrogate of survival than anatomical imaging. The problem is that CTCs are extremely rare. In a millilitre of blood there are usually several billion red blood cells, several million white blood cells but fewer than ten circulating tumour cells.

Many groups are looking for ways to isolate CTCs and their efforts fall essentially into two categories: biochemical, trapping cells using antibodies that bond to them and mechanical, filtering them out. A wide range of assay platforms are currently under development with the developers seeking to optimize both sensitivity and specificity for detecting CTCs and to avoid generation of artifacts.

An example of a promising technique reported in March this year in the journal Advanced Materials was of a velcro-like technology that works on the nanoscale to detect and isolate CTCs in prostrate cancer6. With this system, a patient’s blood is pumped through the NanoVelcro Chip and tiny hairs protruding from the cancer cells stick to the nanofiber structures on the device’s surface, much like Velcro hooks grabbing onto available loops. Then, scientists selectively cut out the cancer cells which are sequenced revealing mutations which may help doctors personalize therapies to a patient’s unique cancer.

CTCs consequently offer clues to how the cancer may progress in an individual patient – and how to best tailor a personalized treatment for them.

References

  1. Cristofanilli M, et al. Circulating tumor cells, disease progression, and survival in metastatic breast cancer. N Engl J Med 2004; 351(8):781–791.
  2. F. Bidard F et al. Circulating Tumor Cells And Cyfra 21-1 As Outcome-Associated Biomarkers In First Line Metastatic Breast Cancer: Results Of The Ic 2006-04 Study. Annals of Oncology, 2011; 22: Supplement 2
  3. Strong evidence supports prognostic value of circulating tumour cells in breast cancer (2011, May 9) Science Daily
  4. Miller MC, et al. Significance of circulating tumor cells detected by the CellSearch system in patients with metastatic breast colorectal and prostate cancer. J Oncol 2010; 617421
  5. Maheswaran S, et al. Detection of mutations in EGFR in circulating lung-cancer cells. N Engl J Med 2008; 359(4):366–377
  6. Zhao L, et al. High-Purity Prostate Circulating Tumor Cell Isolation by a Polymer Nanofiber-Embedded Microchip for Whole Exome Sequencing. Advance Materials, 2013; DOI: 10.1002/adma.201205237
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