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Blood Test for Tumor Cell DNA May Help Predict Localized NSCLC

Samson, Kurt

doi: 10.1097/01.COT.0000527184.95526.07
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SAN DIEGO—A blood test for circulating tumor cells was able to detect residual tumor DNA to predict outcomes in patients with localized non-small cell lung cancer (NSCLC), according to research from a prospective study presented at the American Society for Radiation Oncology Annual Meeting (Abstract 2).

If confirmed by others, such testing could give oncologists a head start on personalizing treatment, Aadel Chaudhuri, MD, PhD, told a news briefing.

Aadel Chaudhuri, MD, PhD
Aadel Chaudhuri, MD, PhD:
Aadel Chaudhuri, MD, PhD

“Blood tests that can detect minute traces of cancer that remain after treatment could improve recurrence monitoring and potentially offer physicians months of additional lead time to tailor treatments and improve our patients' outcomes and quality of life,” said Chaudhuri, Chief Resident in Radiation Oncology at Stanford University in Palo Alto, Calif.

The researchers tested the approach in 41 patients who had been treated with radiotherapy (11 patients), chemoradiation (27), or surgery alone (7). They discovered that patients with detectable levels of circulating tumor DNA (ctDNA) shortly after treatment all had recurrences within 2 years. Among those lacking detectable ctDNA, all but one of the subjects remained disease-free and had long-term survival.

Imaging techniques, however, were unable to predict either recurrence or survival. “The current standard of care after treatment is to follow patients serially with imaging, either CT or MRI scans. Unfortunately, by the time the tumor is big enough to be detected on imaging, treatment options may be very limited,” Chaudhuri explained.

Because lung cancer is often aggressive, long-term management is difficult, he noted, and because NSCLC tends to progress even after being treated, regular monitoring for recurrence is necessary. But CT scans that are typically used for this are often unable to detect microscopic tumor deposits or distinguish normal tissue changes caused by treatment from those caused by recurrent disease, he explained.

“Our findings suggest that ctDNA analysis, unlike CT scans, can identify, shortly after treatment, if a patient with localized lung cancer has been cured by radiation or surgery or if he or she still has cancer cells present in their body. While we expected that ctDNA detection of molecular residual disease would predict poor clinical outcomes, we were surprised by how strongly predictive the test was for recurrence and survival,” Chaudhuri stated.

Methods, Results

The researchers measured ctDNA as a biomarker of residual disease (MRD) at the molecular level in 41 patients with stage I-III NSCLC. Assays were performed immediately before, shortly after completing treatment, and at the midpoint (average 3 weeks) in a subset of patients (13 of 27) given chemoradiotherapy.

The team used Cancer Personalized Profiling by Deep Sequencing (CAPP-Seq) to determine the presence of ctDNA, while CT surveillance scans were evaluated using the Response Evaluation Criteria In Solid Tumors (RECIST). CAPP-Seq is an ultra-sensitive blood-based assay that uses next-generating sequencing to quantitate circulating tumor DNA.

The median patient age was 67 years (range 47-91 years), and most patients (67%) were male. The median follow-up was 35 months and ranged from 7 to 56 months.

In 38 of the 41 patients, ctDNA was detected pretreatment, and 34 of these 38 patients had blood tested within 4 months after treatment was completed. Among these 34, more than half (56%) had detectable residual disease and all subsequently developed recurrent lung cancer, compared with only 1 of 15 patients without detectable ctDNA MRD.

Patients with detectable ctDNA MRD after completing treatment had worse disease progression and poorer survival than did those without detectable ctDNA MRD. The freedom from progression hazard ratio (HR) was 37.7; disease-specific survival was HR = 24.2; and overall HR was 12.3. Concurrent CT imaging was not prognostic of survival, nor was ctDNA levels before treatment.

In eight of the 13 patients who were assessed mid-treatment, ctDNA accounted for 0.1 percent or more of all cell-free DNA and mid-treatment ctDNA levels predicted eventual disease progression (HR = 2.7).

Sixty percent of the patients with less than 0.1 percent ctDNA mid-treatment were progression-free at 2 years following treatment, compared to none of the patients with 0.1 percent or higher levels, the researchers found.

Looking Forward

Maximilian Diehn, MD, PhD, senior author of the study and Assistant Professor of Radiation Oncology at Stanford, said such a test could eventually help screen patients for the best treatment approach.

“In the future, clinicians may be able to use ctDNA analysis to identify patients who could benefit from additional treatment after first-line therapy,” he said.

He pointed to another study also presented at the meeting in which the researchers found that ctDNA analysis was able to detect disease recurrence an average of 5.5 months before standard-of-care CT for localized lung cancer. It also helped with interpreting follow-up imaging.

“This suggests that ctDNA analysis could open a window to treat patients with residual cancer early, while disease burden is minimal,” he said.

Panel moderator Brian G. Czito, MD, Associate Professor of Radiation Oncology at Duke University in Durham, N.C., commented on the findings.

Brian G. Czito, MD
Brian G. Czito, MD:
Brian G. Czito, MD

“The results are strikingly predictive in that all patients with circulating tumor DNA following treatment progressed after treatment with only one patient with undetectable circulating DNA eventually progressing,” Czito said. “This unique strategy has the potential to impact future patient care after definitive treatment, and their circulating DNA status may allow for determination of patients who may require additional therapy versus not.”

It could be useful during the course of treatment as well, he said, noting that measurements could help determine better treatment for patients who may not be responding to their therapy.

“This could facilitate an adaptive treatment approach, which essentially means you are switching gears mid-treatment,” he said. “Other potential avenues for this technique would be using it to screen patients for cancer recurrence during follow-up rather than relying on conventional CT or PET scanning.”

Both the researchers and Czito noted that, because the study involved a relatively small number of patients, more study is necessary. However, they also noted that the technique has the potential to be used in other cancers.

Kurt Samson is a contributing writer.

Wolters Kluwer Health, Inc. All rights reserved.
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