What You Should Know
- Early ctDNA changes may offer a faster read on treatment response. In advanced NSCLC, patients whose circulating tumor DNA became undetectable within the first few weeks of immunotherapy had longer progression‑free and overall survival, suggesting blood‑based monitoring could provide earlier insight than scans.
- “Minimally invasive liquid biopsy analyses can be highly informative for tracking tumor response during therapy, especially for immunotherapy, where the timing and depth of response may not be accurately captured by conventional imaging,” Dr. Valsamo Anagnostou, a researcher at Johns Hopkins University School of Medicine-Sidney Kimmel Comprehensive Cancer Center, tells SurvivorNet.
- ctDNA‑guided treatment is promising but not yet proven. Trials in EGFR‑mutated lung cancer (including FLAURA, AURA3, and the ongoing PACE‑LUNG study) show that early ctDNA clearance correlates with better outcomes, but researchers have not yet demonstrated that changing treatment based on ctDNA improves survival.
- Standard imaging remains essential. Professional guidelines, including ASCO’s, emphasize that ctDNA testing should not replace routine scans or standard‑of‑care testing.
- Variability in tumor DNA shedding, complex interpretation, and lack of standardized response definitions mean ctDNA is useful for research and select clinical situations — but not a standalone decision‑making tool.
Today, doctors often rely on scans every few months to look for changes. Scans are valuable, but they may not provide an early or clear answer about whether treatment is working. New research suggests that a blood test may provide useful information sooner.
Read MoreWhen ctDNA drops sharply or becomes undetectable after treatment begins, it may be an early sign of a favorable response to treatment.
“These improving ctDNA tests will also help us decide when to change a patient’s therapy,” Dr. Marron explains to SurvivorNet. “Often, standard CT scans can’t tell exactly when cancer becomes refractory to immunotherapy. Often lung cancer patients have bad lungs to begin with, and we can’t tell the difference [between] inflammation from infections or other conditions such as sarcoidosis [and] true progression of disease.”
“So liquid biopsies could help those decisions on when to switch to other standard treatments or consider second-line clinical trials,” Dr. Marron adds.
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Researchers at Johns Hopkins Medicine recently reported on 109 patients with advanced non-small cell lung cancer (NSCLC) receiving immunotherapy. Patients whose ctDNA became undetectable within about three to nine weeks of starting treatment had longer progression-free and overall survival than those whose ctDNA remained detectable. This was an association, not evidence that changing treatment based on ctDNA improves survival.
Dr. Marron says it takes several weeks to determine whether the treatment is working because of how immunotherapy makes some tumors behave.
“With immunotherapy, is that — when it is working, sometimes tumors may get larger before they get smaller, a concept known as pseudoprogression, which results from the activated immune cells entering and killing tumor cells, causing inflammation, akin to our arms getting inflamed when we get our COVID shot.”
He continues: “As such, when we treat patients with immunotherapy alone, we have to wait at least 9 weeks, if not longer, to really know if the drug is working or if the tumor is larger because it is not responding.”
The study was designed to determine whether early ctDNA changes predict outcomes, not whether doctors should change treatment based on the results. The authors also noted that the specific test used in the study is not yet validated for routine clinical or regulatory use.
In short, the findings suggest that an early blood test may help identify patients more likely to have a favorable treatment course, but they do not yet justify changing treatment.
“This is an encouraging study because it suggests we may be able to identify within weeks, rather than months, which patients with advanced lung cancer are more likely to benefit from immunotherapy,” Dr. Lee Hong, a medical oncologist at City of Hope Orange County in Irvine, California, tells SurvivorNet.
“An important strength is its prospective design and a liquid biopsy approach that helps distinguish true tumor DNA from other genetic changes in the blood, potentially making the test more reliable and practical for clinical use,” Dr. Hong says.
A question is whether doctors could use an early blood test to decide whether to intensify or switch therapy rather than waiting for changes on a scan. Researchers are studying this approach particularly in EGFR-mutated lung cancers treated with the targeted therapy osimertinib.
Analyses of the FLAURA and AURA3 trials found that patients whose EGFR-mutated ctDNA cleared by about week three tended to have longer periods without cancer progression than those with persistent detectable ctDNA.
Building on these findings, the PACE-LUNG trial is testing whether adding chemotherapy for patients with detectable EGFR ctDNA at week three can improve outcomes. Importantly, this study does not yet prove that ctDNA-guided treatment improves survival.
For now, ctDNA testing does not replace standard imaging or other standard-of-care testing.
Dr. Hong adds that a key limitation is the study’s relatively small size, and that we still need prospective clinical trials showing that changing treatment based on these early ctDNA results improves patient outcomes.
The American Society of Clinical Oncology (ASCO) recommends that ctDNA testing not replace standard testing, except in specific clinical circumstances. Outside clinical trials, ctDNA testing should generally be used when the result can lead to an evidence-based clinical action or help resolve uncertainty in standard testing.
Why the Caution?
- Some tumors release very little DNA into the bloodstream, so an “undetectable” result does not necessarily mean the cancer is gone.
- Blood cells can carry genetic changes unrelated to the cancer, which can complicate interpretation.
- There is not yet a single agreed-upon definition of a meaningful ctDNA response or the optimal time to test.
The exciting possibility is that a blood test may someday give doctors an earlier window into what is happening inside a tumor, helping identify which patients are more likely to benefit from treatment and who may be at higher risk of progression. The next question is whether acting on this information by changing treatment actually improves outcomes.
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