How Liquid Biopsies Are Changing Cancer Care

What is a Liquid Biopsy?

Liquid biopsy refers to the analysis of biomarkers found in body fluids, most commonly blood, but also potentially urine, saliva, or other fluids. A frequently used biomarker is circulating tumor DNA (ctDNA) from a regular blood draw. 

ctDNA are tiny fragments of DNA shed by cancer cells into the bloodstream. ctDNA makes up less than 1% of all freely circulating DNA in our blood, but only when cancer is present!

When cancer is not present, there is no ctDNA in circulation.

Only recently have we developed the technology to identify such minuscule amounts of ctDNA in blood. (Currently, ctDNA is the most relevant type of liquid biopsy to understand, since ctDNA tests have already been approved for clinical use in the USA.)

Cancer diagnosis and treatment monitoring have traditionally relied heavily on tissue biopsies, which involve surgically removing a sample of the tumor for analysis. While effective, these procedures are invasive, can be painful, and carry the risk of complications. Liquid biopsies have the potential to spare people from a surgical biopsy or enhance our understanding of a given cancer after a surgical biopsy.

 In the grand scheme, a liquid biopsy is a form of tumor profiling, where characteristics of a tumor are determined by looking at its genes. Tumor profiling has been used for decades, but the requirement for actual tumor tissue often complicated the logistics. Now, with a simple blood draw, liquid biopsies can easily provide genetic information before, during, or after treatment. By detecting and analyzing ctDNA, clinicians can gather genetic information about a tumor without requiring a direct tissue sample, and this is a game-changer.

Key Applications and Advantages of ctDNA Analysis

The use of liquid biopsy, particularly ctDNA analysis, offers several functional advantages:

1. Reduced Need for Invasive Procedures: It provides tumor-related information through less invasive means than traditional biopsies, which can be beneficial when tissue samples are difficult or risky to obtain.
2. Potential for Early Detection: Research is actively exploring the use of ctDNA tests to detect certain cancers at earlier stages, sometimes before any symptoms manifest. Assays like CancerSEEK and others aim to identify ctDNA signatures associated with various cancer types.
3. Guiding Treatment Selection: ctDNA analysis can identify specific genetic mutations within a tumor. This information helps oncologists select targeted therapies—treatments designed to act on specific molecular pathways associated with those mutations.
4. Tracking Treatment Response: Serial liquid biopsies allow doctors to monitor changes in ctDNA levels over time. A decrease may indicate treatment effectiveness, while an increase could suggest tumor growth or treatment resistance, prompting a potential change in strategy.
5. Detecting Minimal Residual Disease (MRD): After surgery or treatment that has possible cure (ie, "curative intent'), ctDNA tests can help detect very small amounts of remaining cancer cells (MRD) when they are present. Identifying MRD may indicate a higher risk of recurrence and influence decisions about further therapy. If there is truly no MRD, as shown by the absence of any ctDNA, then there is likely no benefit to adjuvant chemotherapy. When there is circulating ctDNA, chemotherapy can benefit patients. Before the use of ctDNA, it was impossible to tell who benefited and who did not from chemo, but now, by selecting only those with ctDNA, we can spare a large number of people who wouldn't have derived any benefit anyways! 
6. Assessing Tumor Heterogeneity: Cancer cells within a single patient can vary genetically (heterogeneity), and these variations can change over time. Liquid biopsy may offer a broader snapshot of a tumor's genetic landscape compared to a single-site tissue biopsy, potentially revealing resistance mechanisms. This is most relevant to needle biopsies, where only one area of a tumor is removed and sent to pathology. ctDNA reflects the entire tumor, so it is a more thorough characterization of the genetics of the tumor.

Current Clinical Uses

Liquid biopsy techniques are currently utilized in managing several cancer types:

• Non-Small Cell Lung Cancer (NSCLC): To detect mutations (e.g., EGFR, ALK, ROS1) guiding targeted therapy use, especially when tissue is insufficient, and to identify resistance mutations (e.g., EGFR T790M).
• Breast Cancer: To identify mutations (e.g., PIK3CA, ESR1) informing treatment decisions, particularly in advanced or metastatic settings.
• Colorectal Cancer (CRC): Used in some screening approaches (detecting SEPT9 methylation) and potentially for monitoring and guiding therapy (e.g., RAS mutations for anti-EGFR therapy).
• Prostate Cancer: To detect alterations (e.g., related to Homologous Recombination Deficiency or HRD) that predict response to specific drug classes like PARP inhibitors.

Challenges and Future Directions

Despite its utility, liquid biopsy faces several technical and practical challenges:

• Sensitivity and Specificity: Detecting very low levels of ctDNA requires highly sensitive assays. Ensuring tests accurately distinguish ctDNA from normal DNA is crucial.
• Pre-analytical Variability: ctDNA is fragile. Sample collection, handling, and storage procedures must be carefully optimized and standardized.
• Biological Factors: Normal blood cells can sometimes carry mutations (clonal hematopoiesis or CHIP) that might be confused with tumor DNA, requiring careful interpretation.
• Standardization and Reporting: Consistent methods and clear reporting standards across different laboratories are still developing.

Research continues to refine these techniques and explore new applications. This includes analyzing other biomarkers in blood (like circulating tumor cells or proteins) and evaluating the utility of liquid biopsy in other body fluids. Often, liquid biopsy is seen as complementary to traditional tissue analysis, with each approach providing valuable information.

Takeaway:

Liquid biopsy, particularly the analysis of ctDNA, represents a milestone development in approaching cancer diagnosis and treatment. It offers a minimally invasive means to obtain molecular information about tumors, aiding detection, treatment selection, and disease monitoring. While technical challenges are still being addressed through ongoing research and standardization efforts, liquid biopsy certainly qualifies as a breakthrough in better cancer care. Oncologists are well aware of the various options for ctDNA testing, so ask your oncologist if such a test could be helpful for you or your loved one. 

For a more technical update on liquid biopsies, see "Liquid Biopsy in Solid Tumours: An Overview" (March, 2025) 

or, Circulating ctDNA to Monitor Treatment Response... (March, 2025)

Some references for further reading (also linked in the text above)

1. Bartolomucci, A., Nobrega, M., Ferrier, T. et al. Circulating tumor DNA to monitor treatment response in solid tumors and advance precision oncology. npj Precis. Onc. 9, 84 (2025).

2. Telekes A, Horváth A. The Role of Cell-Free DNA in Cancer Treatment Decision Making. Cancers (Basel). 2022;14(24):6115.

3. https://www.cancer.gov/news-events/cancer-currents-blog/2024/colorectal-cancer-ctdna-may-guide-adjuvant-therapy The National Cancer Institute: ctDNA May Guide Who Needs Chemo After Colorectal Cancer Surgery Accessed April 20, 2025.