Role of circulating tumor DNA in lung cancer detection, treatment 'exciting' for field
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Within the past decade, data have emerged indicating an effective role of circulating tumor DNA in identifying lung cancer at an early stage and in matching patients with appropriate treatments.
“This is an exciting time for the field. There are applications for circulating tumor DNA [ctDNA] that are quite mature —not everyone realizes that a good amount of promising research has been conducted thus far,” Justin Jee, MD, PhD, researcher at Memorial Sloan Kettering Cancer Center, told Healio. “There is a common perception among some clinicians that they do not need a liquid biopsy when they are already obtaining tissue biopsy. I would counter that there are some very good reasons why we should consider doing liquid biopsy along with tissue biopsy.”
One reason is that many times it is very difficult to obtain tumor tissue, Jee said.
“Even at academic medical centers that are very well-resourced, there are many reasons why tissue is not able to be obtained from a patient,” he said. “For example, a patient may have a poor performance status, or maybe the patient is refusing biopsy, or maybe they had their initial workup at an outside institution and despite best efforts, tissue material cannot be obtained. There is now a fair amount of literature showing that liquid biopsy can be useful in the way that tissue biopsy cannot.”
Treatment guidance
Matching patients to the best targeted treatment is potentially the most mature application of ctDNA, according to Jee.
“We have seen in several different studies that there are many patients for whom sequencing is missed because of the obstacles to getting tissue biopsies and tissue sequencing. These are the situations where the patient would have missed therapeutic opportunities but is where liquid biopsies can really shine,” Jee said. “All we need is a tube of blood and the turnaround time is much faster, and there is a good chance that we will be able to identify the same alterations that we would have with tissue sequencing.”
In a study presented by Jee and colleagues during last year’s virtual ASCO Annual Meeting, data showed that ctDNA can match patients with advanced non-small cell lung cancer to the best appropriate treatment.
“One of the things we found was that patients who have copy number changes in blood but are missing those copy number changes in tissue have a much worse prognosis,” Jee said. “Whenever there is a discordance between the blood and tissue, this means that there is something going on with that patient’s cancer that is spatially heterogenous and is a poor prognostic marker. Separately, other research groups have shown that if ctDNA alterations are targetable, then we can give targeted therapy and these patients respond to treatment. This is just another example where ctDNA liquid biopsy is supplying information that tumor biopsies cannot.”
Another restriction of tissue biopsy is that it only allows a sample of one part of the tumor, but the tumor may be large or there may be many tumors in a patient who has metastatic disease, Jee added.
“The genomics that we obtain just from tissue biopsy may not represent what is going on in the rest of the patient’s cancer. This is yet another example of where we see that liquid biopsy is helpful because it will provide more information on whatever the dominant mutations are that are being shed into the blood and we can apply that information to our treatment decisions,” he said.
Active area of research
Jee said ctDNA has also shown great promise in the early detection of lung cancer.
“This is a very active area of research. If a patient does not yet have a diagnosis, the best thing that we have right now to screen for lung cancer is an annual low-dose CT scan in patients who we know are high-risk, such as those with a smoking history,” Jee said. “However, there are now promising blood tests that look for DNA mutations, methylation changes and proteins or circulating tumor cells. We are still working to identify the ‘best recipe’ for this, but the early detection of cancer is something that there is a lot of early promising data for.”
In a study published in Journal of Clinical Oncology, Fahrmann and colleagues assessed the performance of a four-marker protein panel in combination with a lung cancer risk prediction model. Results showed the combination significantly improved patient selection for lung cancer screening.
Researchers then compared the combination with current U.S. Preventive Services Task Force lung cancer screening criteria among prediagnostic case and non-case sera from the NCI Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial. They found that compared with current USPSTF criteria, the combination had significantly higher sensitivity (88.4% vs. 78.5%) and specificity (56.2% vs. 49.3%) among individuals included in the PLCO cohort.
In another study published in Chest, researchers found that ctDNA analysis resulted in similar usefulness to tissue biopsy analysis and that tissue biopsy missed more mutations in targetable genes compared with ctDNA analysis.
Roosan and colleagues retrospectively examined 370 adult patients with NSCLC receiving treatment at City of Hope in Los Angeles between November 2015 and August 2019. They assessed the efficacy of ctDNA in identifying mutations, survival outcomes, tumor evolution and concordance with matched tissue samples in 32 genes.
Results showed that among the 473 ctDNA samples obtained, 177 showed at least one actionable mutation with currently available FDA-approved NSCLC treatments. In addition, low cumulative percent ctDNA levels were associated with longer PFS (HR = 0.56; 95% CI, 0.37-0.85).
Of note, researchers found that more mutations in targetable genes were detected in ctDNA compared with tissue biopsy samples, and treatment response and tumor evolution throughout time were detected in repeated ctDNA samples.
“The evaluation of ctDNA in conjunction with tissue biopsy samples may help to detect additional targetable mutations to improve clinical outcomes in advanced NSCLC,” Roosan and colleagues wrote.
Looking ahead
Jee said several large-scale clinical trials are evaluating ctDNA in this space.
Researchers for the ongoing prospective, multicenter PATHFINDER study are assessing whether ctDNA can be used to supplement CT scans and routine physical exams to detect early-stage lung cancer.
“If it works, then it can conceivably be a way of prolonging life because we know that for many cancer types, if they are detected early enough, we can cure patients,” Jee said.
References:
- Fahrmann JF, et al. J Clin Oncol. 2021;doi:10.1200/JCO.21.01460.
- Jee J, et al. Abstract 9009. Presented at: ASCO Annual Meeting (virtual meeting); June 4-8, 2021.
- Roosan MR, et al. Chest. 2021;doi:10.1016/j.chest.2021.04.016.
For more information:
Justin Jee, MD, PhD, can be reached at Memorial Sloan Kettering Cancer Center, 1275 York Ave., New York, NY 10065.
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