Dr. Zhang Kaitai of Chinese Academy of Medical Sciences: CTC Detection — A Gem in Precision Medicine

Early detection and diagnosis of tumors primarily rely on imaging, histological biopsy, and serum biomarkers. However, these classic methods each have their own limitations. The major drawback of tumor detection via imaging is its lag; by the time imaging provides a definitive assessment and detection, the disease is often already at an intermediate or advanced stage. Currently used serum biomarkers suffer from low specificity and poor sensitivity, failing to meet clinical needs for early-stage assessment. Solid tissue histological biopsy remains the most critical method for confirming a tumor diagnosis and is currently the gold standard for definitive tumor identification. Nevertheless, solid tissue biopsy is invasive, and it is often difficult to accurately obtain tumor lesion tissue through biopsy in cases of early-stage tumors.

CTC, as the primary method of liquid biopsy, can provide highly valuable information for clinical practice in early diagnosis, treatment response assessment, and prognosis evaluation.

First, CTC detection offers timeliness. Once a malignant tumor forms, cancer cells continuously breach the vascular wall and enter the peripheral blood circulation. Moreover, current studies indicate that the quantity and characteristics of CTCs are closely correlated with the clinical status of tumor disease. Second, detecting CTCs in peripheral blood is a non-invasive approach that can be performed repeatedly, facilitating dynamic monitoring of disease status.

The most significant role of CTC testing in precision medicine is to assist clinicians in formulating individualized tumor treatment plans. Typically, it is very challenging to determine whether a pulmonary nodule approximately 1 cm in size is malignant or benign based solely on imaging findings. CTC testing can provide highly valuable auxiliary information to guide clinical decisions regarding the timely initiation of surgical intervention. Furthermore, the application of CTC testing is even more extensive in the management of intermediate- and advanced-stage tumors. Treatment efficacy can be evaluated based on CTC test results, allowing for adjustments to chemotherapy dosages and regimens. Therefore, CTC testing provides clinicians with reasonably accurate clinical information, facilitating the realization of precision oncology.

Most cancer-related deaths are caused by recurrence and metastasis. Monitoring tumor recurrence and metastasis, as well as formulating postoperative chemotherapy regimens, present significant challenges. For instance, after surgical resection of early-stage tumors, although the primary tumor tissue has been removed, minimal residual disease often persists locally and in the peripheral blood. Detecting the quantity and molecular phenotype of circulating tumor cells in peripheral blood can largely enable early monitoring or warning of tumor recurrence and metastasis. This allows for timely clinical intervention before morphological examinations reveal any abnormalities, thereby blocking or delaying tumor recurrence and metastasis.

Challenges in the clinical application of CTC detection lie in its sensitivity, specificity, and reproducibility. First, CTCs are extremely rare, with only approximately one CTC hidden among every 10 million to 100 million normal blood cells. Second, they exhibit heterogeneity. Similar to primary or metastatic tumors, CTCs display heterogeneity, with significant differences at the cellular and molecular levels observed among different subpopulations and even between individual CTCs. Third, their biological characteristics are highly variable. Epithelial-mesenchymal transition (EMT) is particularly prominent in CTCs, especially following chemotherapy or radiotherapy. Consequently, CTC capture methods based on either physical or biological properties face varying degrees of challenges. Improving the specificity, sensitivity, and stability of CTC detection technologies remains an urgent and critical issue to be addressed and refined.

In fact, the biggest bottleneck in the development of circulating tumor cell (CTC) detection technology is not technical, but rather lies in our understanding of CTCs. We do not even know how many subpopulations of CTCs exist, what biological characteristics these subpopulations possess, or what harm they may cause to the human body. After being released from the primary tumor, approximately 90% of CTCs are attacked and eliminated by immune cells, while the remaining 10% circulate in the peripheral blood and may be detected. Therefore, for certain tumors, recurrence and metastasis can be predicted or warned against through CTC detection. However, a subset of CTCs remains in a quiescent state, similar to stem cells, which may render them undetectable; yet, when conditions are favorable, they can reactivate. Thus, our understanding of CTCs is incomplete. No matter how advanced CTC detection technology becomes, it can only capture a partial view of the CTC population. This reflects the heterogeneity of CTCs, which mirrors tumor heterogeneity: the rapid changes outpace the ability of clinicians to adjust treatment plans accordingly.

Circulating tumor cells (CTCs) were first discovered over a century ago; however, their successful capture, isolation, and validation have only been achieved in the past decade or so. The recognition of CTC heterogeneity has emerged even more recently, within the last two years. CTCs not only comprise distinct subpopulations but also undergo continuous dynamic changes in response to external stimuli. For instance, through epithelial-mesenchymal transition (EMT), they can transform from epithelial to mesenchymal phenotypes, and even revert from mesenchymal back to epithelial states. This plasticity facilitates their survival and evolution.

To achieve precision medicine, we must first understand our adversary so that we can tailor our treatment strategies accordingly. Just as a missile requires radar lock-on to strike a target, it cannot be launched if the target remains unseen. Therefore, precise diagnosis is the prerequisite for precision medicine, and accurate diagnosis hinges on a thorough understanding of the essential nature and developmental patterns of the disease. Consequently, precision medicine remains a long-term and arduous goal.