Circulating Tumor Cells and Indicators in Cancer

What are circulating tumor cells?

Circulating tumor cells (CTCs) are cancer cells that have broken away from the primary tumor. Doctors can detect them in a patient’s blood. These cells drive metastasis: when some of them move out of the bloodstream, they act like seeds and start secondary tumors in other parts of the body. Less than 0.1% of CTCs actually go on to form metastatic tumors, but they are the main cause of cancer coming back after remission and of cancer-related deaths.1 Scientists first spotted CTCs in the blood under a microscope almost 150 years ago. Only in recent years have we started to understand how they work, what they mean for a cancer patient’s prognosis, and how we can target them better in treatment.2

Why are CTCs valuable?

Analyzing CTCs can provide valuable information that helps researchers and clinicians:

• Detect cancer earlier
• Predict disease prognosis
• Choose a therapeutic approach with the greatest chance of success
• Monitor cancer progression during and after treatment
• Detect early signs of relapse after cancer remission

Early detection is the leading factor in long-term survival rates for many cancers, so early detection methods matter a great deal. Analyzing blood for CTCs can reveal the stage and type of cancer much earlier than other, more invasive methods, though CTCs can be hard to detect before a tumor is large enough to show up on imaging.3,4 CTCs are rare in the bloodstream compared to other cell types, but drawing blood is far less invasive and safer than a surgical biopsy of the tumor mass. Doctors can also test for CTCs before, during, and after treatment, which helps them monitor disease progression, gauge how well a treatment is working, and confirm that a patient stays in remission.

How CTCs function

Although CTCs come from the primary tumor, they often pick up distinct features that help them start metastases. These changes activate genes and pathways tied to the epithelial-to-mesenchymal (EMT) transition and give CTCs stem cell-like traits. Those traits let CTCs survive in the hostile blood environment, escape immune detection, and, for a very small percentage, go on to establish distant secondary tumors.

CTCs interact with many other cell types in the blood, including neutrophils, platelets, and macrophages, to survive and dodge the immune system.5 Using these interactions, they can even use their own ability to exit the bloodstream and invade nearby tissue.6

The utility of CTCs in cancer prognosis

Analyzing a patient’s CTCs can give doctors a window into the likely prognosis and estimated survival rate. Patients with high CTC counts are more likely to have a poor prognosis, and if a treatment lowers CTC counts, that can be a good sign for longer-term survival.7

Researchers have identified a wide variety of CTC-specific molecular markers linked to many cancers, each with different clinical significance. For certain cancers, the presence of specific markers is crucial for guiding treatment decisions and improving survival rates. The most important factors for predicting cancer prognosis are the proportion of CTCs expressing mesenchymal or stemness-related markers and the overall CTC count. Tracking the level of genomic instability in CTCs over time can also strongly signal the emergence of tumor resistance and a poor prognosis.

Most recently, analysis of the DNA methylome in CTCs from breast cancer patients showed that hypomethylated states link to a poor prognosis — and that targeted treatment could reverse this methylation profile and suppress metastasis.8 Discoveries like these are opening new paths toward better treatment outcomes.

Analyzing CTCs in research

Monitoring CTCs during clinical studies gives researchers an accurate, non-invasive way to assess how well a treatment is working. For example, if CTC counts stay high, that could signal a lack of efficacy in a particular cancer subpopulation, or suggest a higher dose or a combination therapy is needed.

CTC testing can support novel drug development and cancer studies, but it is not considered a surrogate endpoint in cancer clinical studies. Current standards still typically require overall survival or progression-free survival as the primary efficacy endpoints.9 This means cancer studies often run quite long while researchers collect that data, which raises drug discovery costs, delays approval, and ultimately slows patient access to new treatments.

CTC enumeration is the CTC analysis tool most often used in both research and the clinic, but more comprehensive CTC analysis technologies are paving the way for personalized medicine. Analyzing the genetic makeup of CTCs, along with their growth pathways and receptor activation, can reveal even more about which therapeutics might work better for certain cancers. A better understanding of the EMT pathway, in particular, is key to developing therapeutic targets that might prevent tumor spread and eliminate these problematic cells. By deepening our understanding of CTC characteristics, researchers can sort patient populations more effectively and improve their chances of demonstrating that a therapy works. The wide variation in cancer mutations from person to person truly calls for a more personalized approach.

Right now, doctors still use CTC biomarkers in a limited way for cancer screening, treatment monitoring, and prognosis, with most CTC detection work still happening in research rather than the clinic. Making full use of existing CTC technology, and exploring new ways to characterize CTCs, could turn this into a critical non-invasive tool — not just for cancer drug development, but for personalizing treatment and improving long-term cancer outcomes in the clinic.

References

1. Sethi N, Kang Y. Unravelling the complexity of metastasis – molecular understanding and targeted therapies. Nat Rev Cancer. 2011;11(10):735–748.
2. Lin D, Shen L, Luo M, et al. Circulating tumor cells: biology and clinical significance. Signal Transduct Target Ther. 2021;6(1):404.
3. Hosseini H, Obradović MMS, Hoffmann M, et al. Early dissemination seeds metastasis in breast cancer. Nature. 2016;540(7634):552–558.
4. Alix-Panabières C, Pantel K. Challenges in circulating tumour cell research. Nat Rev Cancer. 2014;14(9):623–631.
5. Rejniak KA. Circulating Tumor Cells: When a Solid Tumor Meets a Fluid Microenvironment. Adv Exp Med Biol. 2016;936:93–106.
6. Garrido-Navas C, de Miguel-Perez D, Exposito-Hernandez J, et al. Cooperative and Escaping Mechanisms between Circulating Tumor Cells and Blood Constituents. Cells. 2019;8(11):E1382.
7. Murlidhar V, Reddy RM, Fouladdel S, et al. Poor Prognosis Indicated by Venous Circulating Tumor Cell Clusters in Early-Stage Lung Cancers. Cancer Res. 2017;77(18):5194–5206.
8. Gkountela S, Castro-Giner F, Szczerba BM, et al. Circulating Tumor Cell Clustering Shapes DNA Methylation to Enable Metastasis Seeding. Cell. 2019;176(1–2):98-112.e14.
9. Gold B, Cankovic M, Furtado LV, Meier F, Gocke CD. Do Circulating Tumor Cells, Exosomes, and Circulating Tumor Nucleic Acids Have Clinical Utility? The Journal of Molecular Diagnostics. 2015;17(3):209–224.