As cancer cells die, they release ctDNA into the bloodstream, where it can be detected within the cell-free DNA that is found in the serum or plasma. Testing for ctDNA allows for both the quantification of ctDNA and the ability to do genomic testing. In general, the more disseminated a person’s NSCLC, the more likely you are to pick up ctDNA. In those whose tumor is confined to the lung, you are less likely to pick up ctDNA compared with those whose cancer has spread to the bones, liver, or brain. I often counsel clinicians that ctDNA testing is not a substitute for obtaining adequate tumor biopsies to use for genomic testing. 

In general, there is very high concordance between the oncogenic drivers identified in ctDNA and tumor DNA. If you see different mutations in the ctDNA and the tumor biopsy, the patient has a poorer prognosis than someone who has a direct match. This is probably because the mismatch reflects the development of heterogeneous metastases. 

It is much simpler to do a blood test than a tissue biopsy, so ctDNA is particularly useful in patients for whom biopsies are difficult to obtain, such as patients with brain metastases. ctDNA is also useful for monitoring patients with advanced disease who are receiving targeted therapy who would otherwise need serial biopsies. Additionally, ctDNA and next-generation sequencing can be used to generate an estimate of the tumor mutation burden, so you can get useful information on the likelihood of immunotherapy being effective. Another important application of ctDNA is in research that helps identify molecular mechanisms of resistance, as Awad and colleagues reported for the KRAS inhibitor adagrasib. Defining resistance can lead to the modification of existing drugs or the addition of a second drug to try to make the treatments more effective. 

Looking to the future, there is hope that ctDNA can be used to identify patients who are likely to benefit from adjuvant therapy following local definitive therapy. Patients who have tumor markers in their cell-free DNA following local therapy have a much higher chance of disease recurrence than if their ctDNA is undetectable. For patients who have had surgical resection, we can also identify the specific mutations in the tumor and then monitor the patient’s ctDNA for these specific mutations to return.

ctDNA testing is certainly the future in NSCLC because it is much more precise than radiology at measuring disease burden. However, ctDNA testing is currently used primarily in the research setting because its sensitivity remains suspect. As Dr Johnson noted, it is difficult to detect ctDNA in patients with early disease, whereas there is greater confidence that the ctDNA can be detected in patients with more advanced disease.

If a patient is positive for ctDNA, it can be used quantitatively to follow a response. However, having undetectable ctDNA does not mean that the patient no longer has cancer. So, when I use ctDNA I also get a tissue biopsy. The best example of this was seen in a trial in which patients were randomized to receive adjuvant atezolizumab or placebo. Patients seemed to benefit from atezolizumab regardless of whether they were ctDNA positive or negative. To me, that suggests that ctDNA is not yet sensitive enough to detect disease as early as we would like. 

Looking ahead to the future, I do think that we will be using ctDNA more often. It might help answer several important questions, such as: Who should receive more therapy after neoadjuvant therapy, and how many cycles should someone receive for immunotherapy? These are all things that are important to look at, and ctDNA may be a useful tool. 

One of the main uses of ctDNA is for the molecular characterization of the tumor, and this is already part of the standard of care soon after diagnosis. This molecular assessment of cancers identifies oncogenic driver mutations that can be treated with targeted therapy. It can identify an actionable molecular target such as EGFR or ALK. If a ctDNA test does give you an answer, it is just as good as any tissue test. But if the blood test does not reveal a molecular target, you need to test tumor tissue to confirm. While ctDNA is extremely useful for molecular profiling, it is limited both by a lower sensitivity compared with tissue samples, particularly in patients with early-stage disease, and by the inability to provide information such as PD-L1 expression levels. Additionally, there are times when you need to know whether the tumor has changed its character (eg, gone from an adenocarcinoma to a small cell carcinoma), and you really cannot tell that from a blood test right now. 

Another main use of ctDNA is to estimate disease burden, but this is still a work in progress. You cannot use the current tissue-naive molecular diagnostic ctDNA assays to determine minimal residual disease. To do that, you need a tissue-informed test that is very sensitive and specific to the mutations that are found in the patient’s tumor tissue at baseline. There are several platforms that use a tissue-informed test approach. The technology, sensitivity, and specificity vary between these assays, but they all use the same concept. A variety of clinical trials in NSCLC are evaluating tumor-informed ctDNA testing as a means of post-treatment surveillance to assess treatment response and to predict clinical outcomes based on the presence or absence of residual cancer after definitive therapy. Ultimately, this might be one of the biggest uses of ctDNA in NSCLC.