A simple blood draw can now reveal what’s happening inside a tumor — no surgery required.
A Complementary Tool to Monitor Disease, Treatment Response, and Detect Resistance
What Is ctDNA?
Cancer cells continuously release tiny fragments of DNA into the bloodstream as they grow and die. These fragments are known as cell-free DNA (cfDNA), but only a portion comes directly from cancer cells. This cancer-specific fraction is called circulating tumor DNA (ctDNA).
Because ctDNA can be detected from a simple blood draw rather than a surgical procedure, the test is often referred to as a liquid biopsy. Unlike a traditional tissue biopsy, liquid biopsy requires no surgery or anesthesia and can be repeated over time, allowing doctors to monitor how a cancer changes throughout treatment.
Please note: ctDNA is a blood-based complimentary tool that is not aimed at replacing CT scans, PET scans, or tissue biopsies. Scans and biopsies remain essentials to cancer treatment and care.
Key Takeaways
What Can ctDNA Testing Do?
Doctors may use ctDNA in cancer patients to answer several important questions. ctDNA testing can provide valuable information including:
ctDNA: A Complementary Way to Monitor the Disease and Identify Resistance
ctDNA can be used to monitor treatment response and detect treatment resistance. A decrease in ctDNA levels may indicate that treatment is effectively controlling the disease. If the cancer begins to grow despite therapy, ctDNA may identify new resistance mutations before or at the time progression becomes apparent on imaging.
Resistance to RET therapies can occur in different ways. Some tumors develop new alterations within the RET gene itself, such as kinase domain mutations or solvent-front mutations like RET G810. Others activate alternative growth pathways, including MET amplification, allowing the cancer to bypass RET inhibition. Identifying the specific resistance mechanism may help physicians select the next treatment strategy, whether that involves a clinical trial, combination therapy, a next-generation RET inhibitor, or local treatment for isolated resistant lesions.
Whenever feasible, a tissue biopsy of a progressing lesion remains the gold standard for identifying resistance mechanisms. Tissue provides the most comprehensive view of the cancer, allowing pathologists to evaluate not only genetic changes but also the tumor’s cellular characteristics and microenvironment. However, obtaining a tissue biopsy is not always possible because some lesions are difficult or unsafe to access.
ctDNA testing offers a less invasive alternative by analyzing tumor DNA released into the bloodstream. It can identify many acquired resistance mutations and may capture genetic changes. However, liquid biopsy has limitations. Some tumors release very little DNA into the blood, and certain resistance mechanisms (such as MET amplification in some cases) may be detected more reliably in tissue. For this reason, tissue biopsy and liquid biopsy should be viewed as complementary tools, and when possible, the information from both can provide the most complete picture of why a RET inhibitor has stopped working.
ctDNA to Monitor Minimal Residual Disease (MRD)
Beyond monitoring for progression, ctDNA can also be used in certain settings to monitor for minimal residual disease (MRD). MRD refers to tiny amounts of cancer that may remain in the body after treatment, even when scans show no evidence of disease. These remaining cancer cells may eventually grow and cause the cancer to return (recurrence). Highly sensitive, personalized ctDNA tests can sometimes detect this microscopic disease months before it becomes visible on imaging, potentially providing an early warning that cancer has returned. This approach is particularly promising after surgery or other curative-intent treatment, although its role in RET-positive lung cancer is still being investigated. Please note that ctDNA is a promising complementary tool for monitoring treatment response including MRD but it does not replace imaging studies or regular clinical evaluation. Rather, ctDNA provides an additional layer of molecular information that can help physicians make more informed treatment decisions.
ctDNA Testing Platforms Used in Cancer Care
Different liquid biopsy tests are designed for different clinical purposes. Some analyze a predefined panel of cancer-related genes (Fixed-Panel) to identify actionable mutations and resistance mechanisms. Others create a personalized assay (Personalized ctDNA Testing) based on the genetic profile of an individual’s tumor to monitor for minimal residual disease (MRD) or recurrence.
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Testing Companies Offering Fixed-Panel Liquid Biopsy Tests
The ctDNA fixed-panel assays do not require a tissue biopsy and can identify multiple genomic alterations from a single blood sample. They are particularly useful when cancer progresses on a RET inhibitor because they may reveal newly acquired resistance mutations. However, their performance depends on how much tumor DNA is circulating in the blood. If ctDNA levels are very low, important alterations may not be detected.
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Testing Companies Offering ctDNA Personalized MRD Tests
Unlike fixed-panel assays, personalized MRD tests are designed specifically for each patient’s tumor. After sequencing the tumor tissue, the laboratory identifies mutations unique to that cancer and creates a customized blood test to monitor those mutations over time. These tests are exceptionally sensitive for detecting minimal amounts of residual disease but are generally intended for recurrence surveillance rather than identifying new resistance mechanisms.
An Important Limitation: A Negative ctDNA Test Does Not Always Mean No Cancer
Patients responding well to targeted therapy may have very low levels of tumor DNA in the blood, making it harder for ctDNA tests to detect remaining disease. Some resistance mechanisms, such as MET amplification, may also be detected more reliably with a tissue biopsy. Therefore, ctDNA results should always be interpreted together with imaging, symptoms, and clinical evaluation. If there is evidence of progression, a tissue biopsy may still be needed.
When Might RET Cancer Patients Consider ctDNA Testing?
ctDNA test and Insurance Coverage
Insurance coverage for ctDNA testing varies depending on why the test is being ordered, the specific test being used, and the patient’s insurance plan.
In general, liquid biopsy tests used to identify actionable genomic alterations or resistance mechanisms in patients with advanced cancer are more likely to be covered when they are considered medically necessary. Many commercial insurers and Medicare provide coverage for FDA-approved or guideline-supported liquid biopsy tests in appropriate clinical situations, such as when tissue is unavailable or when cancer progresses after targeted therapy.
Coverage for minimal residual disease (MRD) testing is more variable. While some insurers cover MRD testing for certain cancers, its use after surgery in RET-positive non-small cell lung cancer is still considered investigational by many payers. As a result, insurance approval may depend on the specific test, the clinical indication, and the patient’s individual policy.
Before testing, patients may wish to discuss the following questions with their healthcare team:
- Will my insurance cover this test?
- Is prior authorization required?
- Will I have any out-of-pocket costs?
- Does the testing company offer financial assistance or patient support programs?
Many testing companies have dedicated reimbursement teams that can verify insurance benefits, obtain prior authorization when needed, estimate potential out-of-pocket costs, and provide financial assistance for eligible patients.
Important: Insurance policies change over time. Patients should check with both their healthcare provider and insurance company to confirm coverage before testing is performed.
