Liquid Biopsy: The Clinical Utility of Circulating Tumor Cells

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Tala Tayoun

A liquid biopsy test is a simple laboratory test done to sample and analyze non-solid patient biological tissue, i.e. blood. The era of liquid biopsy has revolutionized the field of cancer management. Over the last few years, we have witnessed significant technological advances in the detection and characterization of liquid biopsy analytes obtained from blood samples, including circulating tumor cells (CTCs), circulating cell-free tumor DNA (ctDNA). Indeed, a blood draw is easier to obtain compared to a tissue biopsy, which could be painful and invasive. Importantly, such assays may enable real-time monitoring of the evolving tumor landscape and resistance mechanisms¹. Recently, the use of ctDNA in the clinical workflow has been approved for sequential tumor genotyping over time to inform and guide the choice of targeted therapy².

CTCs are of particular interest as they play a pioneer role in metastasis, the primary cause of cancer-related deaths. Detached from the primary tumor or its metastases into the bloodstream, CTCs may carry important information about the tumor profile³. However, these cells are extremely rare in patient blood. In fact, only very few survive stress in circulation (~0.01%) and acquire the capacity to seed tumors, which constitutes a key challenge for their detection in patient blood and characterization. Nevertheless, technological advances over the past 20 years have significantly contributed to a more in-depth understanding of CTC biology taking into account their heterogeneity as well as their role in the metastatic cascade.

There are two key aspects of CTC research: 1) investigation of their function as a liquid biopsy component, which includes their role as predictive clinical biomarkers and 2) investigation of their metastatic potential through functional studies. We will focus below on their role as a liquid biopsy analyte and discuss the clinical interest of CTCs.

The CellSearch® system is the only FDA-approved technology to detect and enumerate CTCs in a blood sample based on their phenotype⁴. Today, the clinical interest of CTCs mainly relies on the assessment of their count as a prognostic biomarker. A plethora of studies has validated the prognostic significance of CTC count using CellSearch in several advanced cancers. For example, in lung cancer, CTC levels of ≥5 CTCs in 7.5-ml blood in non-small cell lung cancer and ≥50 CTCs in 7.5-ml blood in small cell lung cancer have been associated with worse prognosis⁵. Furthermore, dynamic changes in CTC counts may occur in response to treatment, highlighting their role as a pharmacodynamic biomarker. Recently, exciting findings from a recent phase III CTC trial called the STIC trial have demonstrated that CTC count can help guide first-line therapeutic choice between endocrine therapy (if count is <5 CTCs/7.5 ml) and chemotherapy (if count is ≥5 CTCs/7.5 ml) in metastatic breast cancer⁶. This is the only study to date to reveal the real clinical utility of CTCs.

More recently, the effect of circadian rhythm on CTC release in patient blood and cancer spread has been demonstrated. Researchers have shown that CTCs have higher metastatic ability during sleep than during activity⁷. These findings are very promising and, with further investigation, may help inform the most adequate time frame to provide patient treatment.    

Nevertheless, the clinical validation of CTC biomarkers remains a very challenging task mainly due to the lack of standardized technology and, most importantly, CTC scarcity in patient blood. This thus significantly delays the integration of CTC use in the clinical workflow. The challenge today is to perform high-throughput functional studies such as genomics, transcriptomics and proteomics on CTC-derived models and patient CTCs. This could help identify CTC-specific vulnerabilities and develop anti-metastasis therapies.

In a nutshell, CTC research witnessed tremendous improvements over the last 15 years but there is still a long way to go and so much more to learn!

Edited by Sushma Teegala

Header image courtesy: Panabières & Pantel, Nat Biomed Eng 2017

Works Discussed:

1.     Alix-Panabières, C. & Pantel, K. Liquid Biopsy: From Discovery to Clinical Application. Cancer Discovery 11, 858–873 (2021).

2.     Pascual, J. et al. ESMO recommendations on the use of circulating tumour DNA assays for patients with cancer: a report from the ESMO Precision Medicine Working Group. Annals of Oncology 33, 750–768 (2022).

3.     Massagué, J. & Ganesh, K. Metastasis Initiating Cells and Ecosystems. Cancer Discov 11, 971–994 (2021).

4.     CELLSEARCH® | About CELLSEARCH® | How the CELLSEARCH® CTC Test Works? https://www.cellsearchctc.com/about-cellsearch/how-cellsearch-ctc-test-works.

5.     Tayoun, T. Genomic instability of non-small cell lung cancer circulating tumor cells as a driving force for their metastatic potential. (Université Paris-Saclay, 2022).

6.     Bidard, F.-C. et al. Efficacy of Circulating Tumor Cell Count–Driven vs Clinician-Driven First-line Therapy Choice in Hormone Receptor–Positive, ERBB2-Negative Metastatic Breast Cancer: The STIC CTC Randomized Clinical Trial. JAMA Oncology 7, 34–41 (2021).

7.     Diamantopoulou, Z. et al. The metastatic spread of breast cancer accelerates during sleep. Nature 607, 156–162 (2022).