CIRCULATING TUMOR CELL SCIENCE

There is no such disease as cancer (Superscript - 1). Cancer is instead a vast class of diseases characterized by uncontrolled cell growth caused by a combination of environmental and hereditary risk factors. Many different tissue types can become malignant. Even single tumors are heterogeneous, with some cancer cells having mutations absent in other cells nearby. Only in recent years have DNA sequencing and other genetic analysis techniques progressed enough to enable researchers to understand some cancers at a cellular and molecular level, attribute specific cancers to associated genetic changes and molecular pathways, and determine how these changes manifest in a patient.

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CTC BIOLOGY

Cancer metastasis is a “complex, multistage process.(Superscript - 2)” A primary tumor produces metastatic Circulating Tumor Cells (CTCs). These cells must leave the primary tumor, invade the bloodstream, and then survive there long enough to arrive at a hospitable distant tissue. There they must exit the bloodstream, colonize the new tissue, and grow into a new tumor (a “Met”). Even in late-stage cancer patients CTCs are relatively rare in the bloodstream with perhaps as few as 1-10 cells per 10 mL of blood (the size of a standard blood sample).(Superscript - 3) Most CTCs die in circulation, but a small fraction of them leave tumors as a cluster of cells, and these CTC clusters are significantly more likely to form a met.(Superscript - 4)

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CTC MEASUREMENT AND CORRELATION WITH SURVIVAL OUTCOMES IN CANCER PATIENTS

Currently the only FDA-approved means of evaluating CTC counts in humans is the CellSearch system, which uses a biological assay to count the numbers of CTCs in a blood sample. Many studies have shown that low CTC level correlates with increased patient survival in a variety of cancers, including prostate (Shaffer et al. 2007, Danilla et al. 2007, Moreno et al. 2005), colorectal (Meropol et al. 2007), and breast (Wang et al. 2016). Patients with prostate cancer with CTC counts below 5 / 7.5 mL of blood do significantly better than those with counts above that threshold. When patients who are treated using conventional therapies moved from above the threshold prior to treatment to below that threshold post-treatment, their survival time was significantly longer than that of patients whose CTC counts did not decrease (de Bono et al. 2008, Lorente et al. 2016).

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CTC REMOVAL EXPERIMENTS IN ANIMALS

Scientists have developed a variety of methods to remove CTCs in animal models to test the therapeutic potential of removing CTCs. None of these methods are usable in humans, but they do provide insight on the potential value of doing so. Mice were injected with human breast cancer cells and, once tumors formed, the mice were treated with a drug-peptide combination that targeted CTCs 3 times a week for two weeks. At the end of those two weeks metastasis within the mice was significantly decreased, including a decrease in lung metastasis of more than 75% (Salem et al. 2018). In a different series of experiments, mice were injected with cancer lines modified to be sensitive to light, then given time for the cells to form tumors. The mice were then exposed to lasers tuned to destroy the CTCs. Mice treated for 1 week showed a statistically significant survival gain and decreased met formation over untreated mice, and those treated for 2 weeks showed a stronger effect (Kim et al. 2018). In a third set of experiments, mice injected with prostate cancer cells were given time to form tumors then treated with a protein that triggers cell death in CTCs once every three days. Treated mice showed no macroscopic metastases (Wayne et al. 2016).

References

1. The Emperor of All Maladies, Siddhartha Mukherjee 

2. Cancer is a complex, multistage process reference

3. reference perhaps as few as 1-10 cells per 10 mL of blood reference

4. These CTC clusters are significantly more likely to form a met reference