Metastasis: The spreading of the initial (primary) tumor to another site in the body (secondary tumor).
Peripheral blood: Blood circulating through arteries, veins, capillaries, etc. Not what’s in your liver, lymphatic system, bone marrow, etc.
PSA: Prostate-specific antigen, a protein secreted by the prostate, and elevated in cancer. Measuring PSA levels is a standard clinical tool when assessing prostate cancer, read about the test here.
What is a circulating tumor cell?
Cancer is public health problem receiving increasing scrutiny, resulting in over 500,000 deaths in 2011 alone1. However, most cancer deaths are not from intial tumor formation, but from metastases2. The diagram to the left gives a simple picture of a metastatic process. Within the primary tumor, a subpopulation of cells are able to break away from the tumor and worm their way into the lymphatic system, or blood circulation. Cells that enter the bloodstream we call circulating tumor cells (CTCs), and a subset of these cells are believed to be capable of secondary tumor (metastasis) formation.
CTCs’ existence has been known since the 1800s, when physician Thomas Ashworth observed abnormal, cancerous-looking, cells in the peripheral blood of a metastatic cancer patient3. However, it’s only in the last ten years or so that devices have been able to isolate CTCs from blood efficiently. Why has it taken so long? Because CTCs are extraordinarily rare, in one milliliter of blood there may be single or tens of CTCs as compared to over one billion blood cells! In a future post, I will discuss the engineering strategies employed to overcome this problem.
Why counting CTCs is important
Once researchers and clinicans could isolate CTCs efficiently, the first studies focused on counting how many were in patients’ blood. Several studies showed that CTCs can be used as a prognostic indicator of survival, i.e. the number of CTCs in someone’s blood over time predicted patient survival. An example Kaplan-Meier plot—a frequently used method of data presentation for clinical audiences—below, shows that patients with fewer than 5 CTCs in 7.5mL of blood survived almost twice as long as patients who did not (click to enlarge). If you’re interested, there’s a great guide to the statistics behind Kaplan-Meier plots here.
A more traditional engineering metric, an ROC curve, shows that CTC enumeration is a much better sensor/marker of patient death than a standard blood test for prostate cancer patients (PSA). Similar studies have shown that enumerating CTCs is a prognostic indicator for a variety of cancers4,5, and also correlates with patient response to cancer treatment (i.e. patient progression)6,7. These types of data helped CTC isolation technologies move rapidly into the clinic.
Why is CTC isolation technology still growing?
As researchers began to compare and contrast CTC isolation technologies, they showed that the sensitivity of each technique was variable for each cancer type. Additionally, different technologies would give different results for the same samples. An example I show here is for two commercial products, it compares the percentage of patient blood samples each method flagged as containing CTCs, for multiple categories of cancer. As you can see, the results can vary tremendously. This indicated there was still room for more engineering work to be done, ranging from device design to CTC biomarker identification. I will talk about both in future blog posts.
1 Siegel et al. Cancer Statistics 2011. CA: A Cancer Journal for Clinicians 2012
2 World Health Organization (WHO)
3 Ashworth. A case of cancer in which cells similar to those in the tumours were seen in the blood after death. Australian Medical Journal 1869
4 Cristofanilli et al. Circulating Tumor Cells, Disease Progression, and Survival in Metastatic Breast Cancer. New England Journal of Medicine 2004; 351:781-789
5 Allard et al. Tumor cells circulate in the peripheral blood of all major carcinomas but not in healthy subjects or patients with nonmalignant diseases. Clinical Cancer Research 2004; 10:6897
6 Aktas et al. Stem cell and epithelial-mesenchymal transition markers are frequently overexpressed in circulating tumor cells of metastatic breast cancer patients. Breast Cancer Research 2009; 11:R46
7 Kirby et al. Functional characterization of circulating tumor cells with a prostate-cancer-specific microfluidic device. PLoS ONE 2012; 7(4): e35976