SAN DIEGO — The blood-based biomarker of circulating tumor DNA (ctDNA) may catapult the management of nonmetastatic lung cancer into the age of precision medicine, suggest new study results presented here at the American Society for Radiation Oncology (ASTRO) 2017 Annual Meeting.
Currently, only patients with metastatic lung cancer have their treatment guided via biomarkers such as EGFR mutations and positivity for programmed cell death ligand-1 (PD-L1).
In earlier-stage disease, treatment is not guided by biomarkers and also leaves considerable numbers of patients with minimal residual disease (MRD), which means the cancer is not cured after curative-intent radiotherapy or surgery.
But identifying those problematic patients with routine post-treatment surveillance imaging is difficult because of, among other things, the inability to detect microscopic disease, said lead study author, Aadel Chaudhuri, MD, PhD, from Stanford University in Palo Alto, California.
So Dr Chaudhuri and colleagues experimented with a ctDNA test as a method for identifying MRD; ctDNA is used in the management of leukemia but has no current role in lung cancer.
They looked at blood samples from 41 patients with lung cancer (mostly non-small cell) treated with curative intent for stage I to III disease (mostly stage III). Median follow-up was 35 months.
Shortly before the curative-intent treatment took place, the team detected ctDNA in 39 of the 41 patients (93%). Thirty-four of 39 patients also had blood drawn within 4 months after treatment completion (the prespecified MRD landmark) and were eligible for subsequent analysis.
Among the 34 patients with ctDNA MRD pretreatment, more than half (n = 19) had detectable residual disease after treatment. All of these patients subsequently relapsed, compared with only 1 of the 15 patients without detectable ctDNA MRD.
Dr Chaudhuri called the results “dramatic” at a meeting press conference yesterday. The results were simultaneously published in Cancer Discovery
“Our findings suggest that ctDNA analysis, unlike CT [computed tomography] scans, can identify shortly after treatment completion if a patient with localized lung cancer has likely been cured by radiation or surgery or if he or she still has cancer cells present in their body,” Dr Chaudhuri said in a press statement. “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.”
Liquid biopsy approaches are a “promising strategy” for disease surveillance in solid tumors, the study authors write in their paper. ctDNA has been shown to identify MRD in nonmetastatic breast and colon cancers using other assays, they observe. However, these studies were marred by the fact that ctDNA was not detected in greater than 50% of the patients whose disease ultimately recurred. Increased sensitivity is needed, Dr Chaudhuri and his coauthors suggest.
Paul Harari, MD, from the Carbone Cancer Center of the University of Wisconsin, Madison, who moderated the press conference, said the new results were “strikingly” predictive as all patients with lung cancer patients who had ctDNA progressed after treatment.
ctDNA status may identify patients who need additional adjuvant therapy vs those who do not, said Dr Harari. The testing could facilitate an “adaptive treatment approach, which essentially means you are switching gears mid-treatment” — before more obvious clinical signs of disease progression occur, he said.
Given the small numbers in the current study, the testing needs further study, Dr Harari added. But it has the potential to be used beyond lung cancer, he added.
Henning Willers, MD, from the Massachusetts General Hospital Cancer Center, Boston, stressed that ctDNA, if validated in larger studies, would be especially useful for patients with stage III disease, who currently all receive chemoradiation that is not highly effective, with more than 50% having distant failure at 5 years.
Currently there is no way to predict who will fail or succeed. “It would be nice if we could identify the nonresponders,” said Dr Willers, who attended the meeting and was asked for comment.
The new study “looks pretty exciting,” Dr Willers told Medscape Medical News.
“Having a predictive biomarker of nonresponse or poor response for stage III would change the paradigm of how we currently practice — it would be dramatic,” he said.
He also said the timing of the new study is “perfect” given the recently reported results from the PACIFIC trial, which showed that giving the anti–PD-L1 checkpoint inhibitor durvalumab (Imfinzi, AstraZeneca) after chemoradiotherapy doubled progression-free survival compared with placebo, increasing it by 11 months. Previous chemotherapy had failed in all the study patients, who had stage III, locally advanced non-small cell lung cancer. “We might have a marker [ctDNA] that will tell us who will [be candidates to] benefit from adjuvant checkpoint inhibitor therapy,” said Dr Willers.
Having an intervention that can actually improve outcomes is key to the utility of a test such as ctDNA because it is not sufficient to merely identify patients in whom standard treatment will likely fail, he further explained.
Worse Progression and Survival With Detectable ctDNA
In the study, Cancer Personalized Profiling by Deep Sequencing (CAPP-Seq), which was developed by the authors, was used to assess whether ctDNA was present.
The study involved 41 patients, with a median age of 67 years; most (67%) were male. A majority of patients received chemoradiation therapy (66%), with a minority receiving radiation therapy alone (27%) and surgery alone (7%).
Patients with detectable ctDNA MRD after treatment had worse freedom from progression and worse survival than patients without detectable ctDNA MRD (freedom from progression hazard ratio [HR], 41.0, P < .00001; disease-specific survival HR, 25.3, P < .00001; overall survival HR, 12.9, P < .00002).
Post-treatment ctDNA detection preceded radiographic progression in 72% of patients by a median of 5.2 months. Notably, 53% of patients harbored ctDNA mutation profiles that are “associated with favorable responses to tyrosine kinase inhibitors or immune checkpoint blockade,” the authors observe.
“Collectively, these results indicate that ctDNA MRD in lung cancer patients can be accurately detected using CAPP-Seq and may allow personalized adjuvant treatment while disease burden is lowest,” conclude the authors.
The study was supported by grants from the Radiological Society of North America, the National Science Foundation, the Department of Defense, the National Cancer Institute, and the Ludwig Fund for Cancer Research, among others. Three of the authors are co-inventors of the CAPP-Seq. Multiple authors have financial ties with industry.
Cancer Discovery. Published online September 24, 2017. Abstract
American Society for Radiation Oncology (ASTRO) 2017 Annual Meeting. Abstract 2. Presented September 24, 2017.
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