It is well-known that cancer management presents numerous challenges, challenges that crop up from the beginning of care—at diagnosis. Often, it is not possible to conduct proper follow-up or obtain adequate tissue samples from primary or metastatic sites in patients with advanced cancer. During my clinical career managing a wide variety of malignancies, this reality became clearly evident. I have encountered numerous patients in which diagnosis or adequate sampling was not feasible. As a result, predicting disease progression was extremely difficult, and neither I nor my colleagues had any reliable parameters to determine the likelihood of relapse.
In such settings, liquid biopsy can be highly valuable, such as the circulating tumor DNA (ctDNA) test. This approach relies on detecting fragments of genetic material shed by primary and metastatic tumors into the peripheral blood. The greater the tumor burden, the higher the amount of ctDNA detected in a blood sample. This enables a direct correlation between ctDNA levels and disease extent. The major advantage is that this information is obtained without invasive procedures such as surgery or tissue biopsy.1-3
This approach has notable limitations, however. Because ctDNA consists of highly fragmented DNA, it provides only a partial genomic picture of the tumor. Moreover, the presence of specific genetic alterations in ctDNA does not necessarily mean these alterations are actively expressed or functionally driving tumor behavior, which can be misleading in some cases. In addition, ctDNA may also come from the less aggressive (“well-behaved”) parts of the tumor that do not drive disease progression or reflect the tumor’s true resistance to treatment. As a result, relying on ctDNA alone may lead clinicians to draw incomplete or potentially misleading conclusions, which could affect treatment decisions.2-4
Liquid Biopsies in Oncology
Other forms of liquid biopsy include the analysis of circulating tumor cells (CTCs), which are intact tumor cells shed from primary or metastatic sites that enter the bloodstream and play a key role in metastasis and disease progression. Another form involves extracellular vesicles (EVs)/bubbles, which are small membrane-bound particles released by tumor cells that facilitate intercellular communication by carrying various biomolecules.1-3
Although EV analysis remains relatively new and not yet fully standardized, CTC analysis is well-established in both research and clinical settings. Because metastasis is mediated through CTCs, these cells offer comprehensive, real-time information about the tumor, including its phenotype, functional behavior, and response to treatment. In addition, the number of CTCs strongly correlates with disease burden and therapeutic outcomes. It is also important to note that CTCs can appear in the bloodstream at very early stages of disease.1-4
These features give CTCs not only strong prognostic value, but also significant diagnostic and predictive value in precision oncology. All these advantages allow CTC analysis to overcome many of the key limitations of ctDNA testing and provide superior information with prognostic, diagnostic, and therapeutic value.1-4
Practical Implications
To fully realize the clinical benefits of CTC analysis, careful implementation is required. CTC testing offers multiple actionable insights for clinical decision-making:
- Analysis of tumor-derived DNA that is clinically relevant
- Assessment of gene overexpression or downregulation through transcriptomic and genomic profiling
- Predict how the cells behave when exposed to different therapeutic agents
- Predict where these tumor cells are coming from (primary or metastatic tumors) and where they are meant to migrate to create new sites of metastases
- Detect mechanism that can transform the cells and make them resistant to therapy after long exposure
- Identify novel therapeutic targets to guide new drug development
These capabilities highlight the practical clinical value of CTC analysis. When clinicians face challenges in selecting the optimal therapeutic approach, in particular, in heavily pretreated or advanced-stage patients, CTC analysis can provide actionable insights and alternative options.1-4
By evaluating both the quantity and phenotype (ie, how the tumor cells change in their morphological appearance and characteristics) of CTCs, clinicians can better predict potential resistance to specific therapies. Furthermore, comparing CTC findings with the original primary tumor biopsy allows for more informed treatment decisions when metastatic sites behave differently from the primary tumor. This approach is applicable not only to medical, surgical, and radiation oncology, but also to integrative cancer therapies.
Conclusion
After many years working in clinical practice and the field of precision oncology, it is evident that liquid biopsy—in particular, CTC analysis—is an extremely valuable tool for managing difficult cases and predicting disease behavior. Because CTC analysis currently requires advanced laboratory facilities and specialized skills, the next frontier is to develop simpler, faster, and equally accurate methods. This is precisely what the emerging field of “lab-on-a-chip” technology aims to achieve. We anticipate that easier and more accessible CTC analysis options will soon become available.1
References
- Wang X, Wang L, Lin H, et al. Research progress of CTC, ctDNA, and EVs in cancer liquid biopsy. Front Oncol. 2024; 25;14:1303335. doi:10.3389/fonc.2024.1303335
- Tan CR, Zhou L, El-Deiry WS. Circulating tumor cells versus circulating tumor DNA in colorectal cancer: pros and cons. Curr Colorectal Cancer Rep. 2016;12:151-161. doi:10.1007/s11888-016-0320-y
- Alemzadeh E, Allahqoli L, Dehghan H, et al. Circulating tumor cells and circulating tumor DNA in breast cancer diagnosis and monitoring. Oncol Res. 2023;31(5):667-675. doi:10.32604/or.2023.028406
- Kong SL, Liu X, Tan SJ, et al. Complementary sequential circulating tumor cell (CTC) and cell-free tumor DNA (ctDNA) profiling reveals metastatic heterogeneity and genomic changes in lung cancer and breast cancer. Front Oncol. 2021;11:698551. doi:10.3389/fonc.2021.698551