Tracking Down Cancer: The Hunt for Circulating Tumor Cells in the blood

A sample of blood/body fluid can help in the early detection of cancer, determine the diagnosis, identify metastases , prognosis and management of cancers. In simple words , this is called a liquid biopsy. Liquid biopsy encompasses several elements — Circulating tumor cells (CTCs),circulating tumor DNA(ctDNA), exosomes and others.

Circulating tumor cells (CTCs) were first described by Thomas Ashworth, in 1869 .These are malignant cells that have broken off from a primary tumor and are present in the bloodstream. They can be detected in a sample of blood . In cancers of some organs, scientists have shown that there is more shedding of CTCs and thereby easier to detect in the blood.

CTCs can identify tumor confined to the primary organ of origin or at the metastatic site. It, therefore, addresses the challenges faced by tissue biopsy due to heterogeneity (only sampled site can be analysed on tissue biopsy while liquid biopsy can assess presence of tumor at any location in the body). The biology of cancers evolves over a period of time and liquid biopsies help capture these changes on a real time basis It can be really helpful in understanding how the cancer cells are evolving over time.

CTCs are cancerous cells that can move either singly or in clusters (CTC clusters), migrate, and enter blood vessels due to a process called epithelial-mesenchymal transition (EMT). Unfortunately, they’re usually the main cause of metastasis in tumors.The circulating tumor cells contain the same details as primary tumor cells. Looking at what CTCs provide us with, we can get an overall understanding of the organ of origin and diagnosis of a tumor.Liquid biopsy offers a way to continuously sample and analyze cancer tumor mutations as well as figure out the diversity of drug resistance.

CTCs (Circulating Tumor Cells) have the potential to be used as biomarkers for determining minimal residual disease after successful treatment of cancers.It could be beneficial in studying the phenotype (morphologic or physical attributes )and genotype (molecular or genetic attributes ) of tumors which is a great addition to the existing ctDNA tracking. This can help detect any relapse patterns over time.

CTCs have been used in the early detection of breast cancers (Crook et al) prostate cancers (Gullet G et al, Limaye et al ). Researchers have also used CTCs to stratify stage 4 breast cancer for tailoring treatment due to vast heterogenity in these tumours (Cristofanilli et al )

CTCs, at this time , have some advantages over cfDNA and exosomes in clinical applications (Masuda T et al). Morphology and molecular profiling can be done on the CTCs which may not be feasible on the latter.

CTCs have potential advantages and disadvantages as a marker for disease progression and treatment response.

Advantages:

• CTCs can be easily obtained via a simple blood draw, making them a non-invasive alternative to traditional tissue biopsy
• CTCs can be used to monitor treatment response and disease progression, allowing for personalized treatment adjustments
• CTCs can provide insight into the genetic makeup of the tumor, which can aid in identifying potential therapeutic targets

Points to ponder:

• CTCs are rare and difficult to detect, making their detection and analysis technically challenging. Nevertheless, due to the emergence of highly sensitive methods, Circulating Tumor Cell (CTC) technology has been gaining traction and is increasingly being used in clinical settings. CTC technology provides a sensitive approach to cancer diagnosis, prognosis and treatment.
• Pre-analytical (collection,transportation and storage), analytical, and post-analytical issues in liquid biopsy samples are important in improving the sensitivity of these techniques (Umberto Mallapalle et al)
• The clinical utility of CTCs in select cancers is still under investigation and more research is needed to fully understand their potential as a biomarker in different cancers .However , preliminary results shared by researchers are encouraging and these tests are poised to become complementary tools in early detection, diagnosis ,monitoring and management of cancers.

With the influx of different types of detection technologies for CTCs, circulating tumor DNA, and exosomes, there’s a huge need for standard guidelines, internal quality control (IQC) & external quality assessment (EQA) procedures to be put in place (Jia S, Jinming Li et al) Innovations in this very important science -the liquid biopsy segment is believed to make rapid strides in cancer care and is an exciting time for doctors and scientists in the oncology space to contribute their bit.

References

• TR Ashworth A case of cancer in cells similar to those in the tumors were seen in the blood , Aust Med J , 14,146–149 (1869)
• Masuda T, Hayashi N, Iguchi T, Ito S, Eguchi H, Mimori K. Clinical and biological significance of circulating tumor cells in cancer. Mol Oncol. 2016;10(3):408–17
• Umberto Malapelle, Pasquale Pisapia, Alfredo Addeo, Oscar Arrieta, Beatriz Bellosillo, Andres F. Cardona, Massimo Cristofanilli, Diego De Miguel-Perez, Valeria Denninghoff, Ignacio Durán, Eloísa Jantus-Lewintre, Pier Vitale Nuzzo, Ken O’Byrne, Patrick Pauwels, Edward M. Pickering, Luis E. Raez, Alessandro Russo, Maria José Serrano, David R. Gandara, Giancarlo Troncone & Christian Rolfo (2021) Liquid biopsy from research to clinical practice: focus on non-small cell lung cancer, Expert Review of Molecular Diagnostics, 21:11, 1165–1178
• Crook T, Leonard R, Mokbel K, Thompson A, Michell M, Page R, Vaid A, Mehrotra R, Ranade A, Limaye S, Patil D, Akolkar D, Datta V, Fulmali P, Apurwa S, Schuster S, Srinivasan A, Datar R. Accurate Screening for Early-Stage Breast Cancer by Detection and Profiling of Circulating Tumor Cells. Cancers. 2022; 14(14):3341
• Galletti G, Portella L, Tagawa ST, Kirby BJ, Giannakakou P, Nanus DM. Circulating tumor cells in prostate cancer diagnosis and monitoring: an appraisal of clinical potential. Mol Diagn Ther. 2014 Aug;18(4):389–402
• Sewanti Limaye, Simon Chowdhury, Nitesh Rohatgi, Anantbhushan Ranade, NeloferSyed, Johann Riedemann, Raymond Page, Darshana Patil, Dadasaheb Akolkar et al ,Accurate Prostate Cancer Detection based on Circulating Tumor Cell Profiling , medRxiv 2022.05.11.22274934, preprint
• Cristofanilli M, Pierga JY, Reuben J, Rademaker A, Davis AA, Peeters DJ, Fehm T, Nolé F, Gisbert-Criado R, Mavroudis D, Grisanti S, Giuliano M, Garcia-Saenz JA, Stebbing J et al The clinical use of circulating tumor cells (CTCs) enumeration for staging of metastatic breast cancer (MBC): International expert consensus paper. Crit Rev Oncol Hematol. 2019 Feb;134:39–45.
• Jia S, Zhang R, Li Z, Li J. Clinical and biological significance of circulating tumor cells, circulating tumor DNA, and exosomes as biomarkers in colorectal cancer. Oncotarget 2017;8(33):55632–45

Disclosure : The author, Dr Sudha S Murthy is the Director (Clinical Support ) and an Oncopathologist at Datar Cancer Genetics, India .This article is written only for creating awareness . Views are her own . References have been cited as appropriate. Information on availability of these tests may be obtained from www.datarpgx.com

Keywords: Circulating tumor cells, CTCs, metastasis, cancer, blood, liquid biopsy.