Disclosure: There is only one company, Veridex, (a subdivision of J&J) that currently markets a commercial assay for circulating tumor cells. My research group is in the process of formally finalizing a research collaboration agreement with Veridex.

I receive and have no plans to receive payment of any kind, including salary, honorarium or research funding from Veridex.

What are circulating tumor cells (CTCs)?  Leukemias as a case in point
Circulating tumor cells, or CTCs are just what they sound like: cancer cells that circulate in the bloodstream alongside normal cells such as white blood cells, red blood cells, and platelets. The classic examples of circulating tumor cells are the leukemias, or blood cancers.

As every criminal starts his or her life as a baby then crosses the line into criminality somewhere along the way, every cancer cell starts its life as a normal cell.  Leukemia cells start as bone marrow cells.  The normal job of bone marrow cells is to provide blood cells, so it’s no surprise that leukemia, by its very nature, circulates in the blood.  This gives leukemia a unique property—it can be biopsied every day with extremely minimal risk to the patient, because the biopsy entails just a simple blood draw.  For this reason, leukemias were the first cancer to have detectable CTCs — the technique is called flow cytometry.

Flow cytometry works by separating the cells in the blood by size, the scatter of light (which in turn measures the complexity of the nucleus) and cell surface markers (they’re mostly named CD-something).  You get plots of each cell seen and if they don’t look normal, you’ve not only identified the cancer, but you’ve learned what surface makers it bears.  This test is a routine part of sub-typing leukemia; an example of flow results from a patient with M1 leukemia is shown below.  Leukemias, like lung cancers, have molecular tests that help determine treatment (for example, BCR-Abl for CML, JAK2 for the myeloproliferative disorders, and FLT-3 for AML) and they are routinely tested on blood because of the large quantity of CTCs found there.

(click on image to enlarge)

 The theory of CTCs in solid (non-leukemia / non-lymphoma) cancers
We’ve believed that CTCs are sometimes present in other cancers for a long time.  In the process of going from a local cancer to a metastatic one, cancer spreads to lymph nodes then to distant sites.  We have long believed that these cells travel through blood to get to distant sites.  Therefore, the idea that we might one day be able to detect these cells is not new.  There are two main reasons to care about detecting these cells: to count them, and to characterize them.  Achieving both of these aims could potentially improve patient care and speed research.  If CTCs are detected early in chemotherapy for metastatic disease, and the chemo is successful, then we would expect to find fewer (or no) CTCs in the blood.  Perhaps through this method, CTCs could allow earlier detection of progression.  Earlier detection of progression might allow for greater safety in chemotherapy breaks.  When the sad day of progression happens, you’d rather catch it early as an increase in CTCs than pain in your belly because of liver mets.  Maybe CTCs can even decrease the number of CT scans needed, decreasing radiation exposure, increasing patient convenience, and decreasing the cost of care.

Perhaps the presence or absence of CTCs can help predict who will benefit from adjuvant chemotherapy.  Maybe patients with CTCs detected before surgery have a higher risk of micrometastatic disease and perhaps they benefit more from adjuvant chemotherapy.  Finally, if we can study the CTCs, perhaps patients can have full molecular characterization of their cancer without the risk and discomfort of a biopsy.  If the latter goal were achieved, a key barrier in lung cancer research would also be lifted — we would always have “biopsies” for molecular correlate studies to better understand how novel therapies are affecting cancer cells and to target which patients benefit most from which therapies.

Technical issues in CTC detection for solid malignancies
Most of the cells circulating in the blood in a patient with a “solid” cancer such as lung cancer are normal blood cells, particularly white blood cells.  Because of this issue, flow cytometry has trouble detecting the relatively small numbers of CTCs against this large background. That’s why the technology for seeing the CTCs is new, even though the idea that they were there is older. The basic idea is to exploit what is unique about CTCs as compared to the larger numbers of white blood cells surrounding them. Non-cancerous epithelial cells don’t circulate in the blood; in contrast, cancers such as lung, prostate, breast, and colon cancer that are derived from them do. These cancer cells tend to bear the same cytokeratins that their non-cancerous ancestors do, they bear a nucleus (as do the large number of surrounding white bloods cell) and (unlike white blood cells) do not bear CD45.  The basic idea is depicted graphically below:

The state of CTCs in other cancers
The cellsearch technology is FDA approved in breast, prostate, and colon cancer.  The most promising data for the value of counting CTCs are from an article in the Journal of Clinical Oncology from November, 2009.  The authors observed 68 patients being treated for breast cancer.  They collected blood from these women every 3-4 weeks and re-imaged them every 9-12 weeks.  They then looked to see how well CTC assessment correlated with progression-free survival, with a “positive” CTC result defined as > 5 cells detected and a “negative” result as <5 cells detected.  The test had much better sensitivity than specificity:

The CTC test had a strong discriminatory power for progression-free survival:

The authors continue to observe these patients for survival, intending to present data on the correlation between CTC findings and overall survival once the data are sufficiently mature.

CTCs have also been studied in colon and prostate cancer, where the technology is also FDA approved. I chose to focus on the breast results because I think that they are the most advanced and best show what we may be able to achieve in lung cancer. We’ll turn to CTCs in lung cancer next.

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