How do we choose between CTC and ctDNA for cancer testing?

What is ctDNA

Circulating tumor DNA (ctDNA) refers to small fragments of DNA that are shed into the bloodstream from cancer cells. ctDNA can provide valuable information about the genetic and epigenetic alterations associated with cancer, making it a potential biomarker for cancer detection, monitoring treatment response, and assessing disease progression.

ctDNA is detectable in various conditions, including healthy individuals, those with benign tumors, and cancer patients, which underscores its role as a non-invasive marker for cancer-related changes. Tests for ctDNA typically target specific genetic alterations, such as mutations in oncogenes or tumor suppressor genes, to confirm that the detected DNA is indeed derived from tumor cells

ctDNA is largely from dead or dying tumor cells. ctDNA is primarily derived from tumor cells that have undergone processes such as apoptosis (programmed cell death) or necrosis (cell death due to injury or disease).

How ctDNA is being used in cancer tests?

ctDNA is used in cancer testing for several reasons:

Assessment on tumor’s genetic changes: ctDNA provides information about the tumor’s genetic changes. It reflects the state of the tumor, including any mutations that may have developed in response to treatment, which helps in tracking disease progression and response to therapies.

Detection of Mutations: ctDNA analysis can identify specific mutations associated with cancer, including actionable mutations that may guide targeted therapies. For example, detecting mutations in genes such as EGFR or KRAS can inform treatment strategies.

Monitoring Treatment Response: Changes in ctDNA levels can indicate how well a treatment is working. A decrease in ctDNA after treatment may suggest a positive response, while an increase might indicate resistance or disease progression.

Detection of Recurrence: ctDNA can potentially detect cancer recurrence earlier than conventional imaging methods.

What is the limitation of ctDNA in cancer test?

real-time tumor activity: ctDNA is largely from dead or dying tumor cells. Because ctDNA is derived from dead cells, it may not reflect real-time tumor activity accurately. For example, if the ctDNA comes from tumor cells that have already died, it may not provide a complete picture of the current tumor burden or its biology, especially in cases of tumor heterogeneity

Tumor Heterogeneity: ctDNA analysis is primarily optimized for detecting specific mutations associated with cancer. However, if the relevant mutations are not present in the cell populations that have died, they may not be identified through ctDNA testing, potentially leading to false negative results.

No information on Gene expression: While ctDNA can provide information on specific mutations, it does not give insights into the tumor’s gene expression, which can be critical for understanding tumor behavior and treatment response. Gene expression profiles of cancer cells are crucial for personalized treatment because they provide insights into the specific biological characteristics of an individual’s tumor. This information can guide therapeutic decisions, allowing for more tailored and effective treatment strategies.

Low Abundance of ctDNA may lead to false-negative in early stage of cancer: ctDNA is often present in very low quantities, especially in early-stage cancers, making it difficult to detect. It can represent as little as 0.01% of the total cell-free DNA in circulation, which complicates reliable detection and quantification.

It is possible to have cancer and still test negative on a ctDNA test, especially in very early stages of the disease. The detection of ctDNA can be challenging in early-stage cancer because the amount of circulating tumor DNA may be very low, often below the detection threshold of current testing methods.

Limited information from ctDNA test: ctDNA is primarily used as a biomarker to monitor tumor dynamics and assess the genetic alterations associated with cancer. It provides information about the presence of mutations and the overall tumor burden in the bloodstream, but it does not contain viable cancer cells that can be used for drug & natural substances testing.

What Are CTCs?
Circulating Tumor Cells (CTCs) are cancer cells that detach from a primary tumor and enter the bloodstream, either as single cells or clusters. Detecting and analyzing these cells can provide critical insights into cancer progression and treatment planning.

What is CTC method for cancer test?
The CTC (Circulating Tumor Cell) method for cancer testing involves the detection and analysis of tumor cells that have detached from a primary tumor and entered the bloodstream. This method is considered a form of “liquid biopsy,” allowing for non-invasive monitoring of cancer progression, treatment response, and potential recurrence. CTC testing typically employs various techniques for the isolation and enumeration of these cells from a blood sample, including Flow Cytometry. We can have more than 99% of viability of the isolated cells from the flow cytometry technique. With this high viability, we can directly analyze chemotherapeutic drugs, targeted drugs, and natural substances on cancer cells to see which are effective for the patient’s body and their cancer type.

What are the differences between ctDNA & CTC?

real-time monitoring of tumors : While ctDNA is largely from dead or dying tumor cells, through Flow Cytometry, we can test and analyze viable cancer cells. CTCs can perform real time monitoring of tumors, as they are shed into the bloodstream from the primary tumor or metastases. This means that analyzing CTCs can provide up-to-date information about tumor dynamics, rather than past activity from ctDNA from dead cancer cells.

Tumor Heterogeneity: CTC tests are considered better in capturing tumor heterogeneity. CTCs can reflect various subpopulations of tumor cells, including those undergoing epithelial-to-mesenchymal transition (EMT) and those that may harbor different mutations compared to the primary tumor. This allows for a more comprehensive understanding of the tumor’s biological diversity

CTCs can retain mutations that may not be present in the primary tumor or metastases, highlighting their potential as a source for understanding intra-tumoral heterogeneity.

No information on Gene expression: ctDNA does not give insights into the tumor’s gene expression. While CTC can be analyzed for gene expression due to several key factors. CTCs provide live tumor cells that retain their original genomic and transcriptomic profiles, allowing for a comprehensive analysis of gene expression. Analyzing gene expression of cancer cells is very important in personalized cancer treatment.

Early stage cancer detection: ctDNA is often present in very low quantities, especially in early-stage cancers, making false-negative possible. While CTC can test for cancer in very early stages. CTCs may be released into the bloodstream even before a clinically detectable tumor is formed. This early dissemination of cancer cells can occur shortly after tumor initiation, allowing for the possibility to identify aggressive cancers that require immediate treatment

Directly testing cancer drugs on cancer cells: CTCs can be isolated from blood samples and cultured to evaluate their response to various cancer drugs and natural substances. For instance, we can perform drug sensitivity testing on CTCs to see which drugs are the most effective for the patient.

Conclusion

Not only can ctDNA provide information on a tumor’s genetic changes and help identify specific mutations associated with cancer, but it can also monitor treatment response. However, unlike circulating tumor cells (CTCs), which can reflect the real-time status of cancer, ctDNA is derived from dead or dying tumor cells and may not provide a complete picture of the current tumor. Additionally, ctDNA is often present in very low quantities, particularly in early-stage cancers, which can lead to false negatives. In contrast, CTCs can be used to detect cancer in its very early stages. Furthermore, while we can perform drug sensitivity testing on viable CTCs, such testing is not possible with ctDNA.