Circulating tumor DNA (ctDNA) may be a useful biomarker for minimal residual disease (MRD) in patients with early-stage non–small cell lung cancer—and MRD may be a good predictor of relapse. In the TRACERx study, a ctDNA assay confirmed MRD negativity in more than 99% of patients—and detected MRD in patients who relapsed before their disease was picked up by standard imaging.
Circulating tumor DNA (ctDNA) may be a biomarker for minimal residual disease (MRD) in patients with early-stage non–small cell lung cancer (NSCLC)—and MRD may predict relapse. In the TRACERx study, a ctDNA assay confirmed MRD negativity in more than 99% of patients who didn't relapse and could detect MRD in patients who relapsed before disease was picked up by standard imaging.
Patients with high-risk early-stage (stage I to III) NSCLC treated with surgery and adjuvant therapy generally fare better than those who undergo the same treatment for metastatic disease, suggesting that early-stage disease is more vulnerable to treatment. Thus, “if we want to improve outcomes further in non–small cell lung cancer, we really need to focus on innovation in the early-stage space,” said Chris Abbosh, MD, of University College London, who presented the results at the American Association for Cancer Research Virtual Annual Meeting I: April 27–28, 2020.
However, studying adjuvant therapy is challenging due to an inability to separate patients successfully treated with surgery from those who will relapse, necessitating large, multiyear adjuvant trials. “The promise of an MRD-driven adjuvant trial is that you can differentiate between these populations, and that you can adapt adjuvant trials in smaller, more relevant populations when you are only escalating treatment in patients destined to relapse,” Abbosh explained.
Abbosh reported on a personalized assay that he and the TRACERx team developed to detect MRD via ctDNA in patients with NSCLC. The assay involves performing deep exome sequencing on multiple regions of a patient's tumor to identify common, region-specific, or immunogenic single-nucleotide variants and prioritize those most likely to distinguish MRD status. Researchers then use a technique called anchored multiplex PCR to enrich the patient's cell-free DNA for next-generation sequencing to track these variants and determine whether there is a ctDNA signal that would indicate the presence of MRD. In 37 patients with NSCLC who didn't relapse after surgery, the assay confirmed MRD negativity at 99.3% of 271 timepoints.
Confirming previous findings that lung squamous cell carcinomas are more likely to shed ctDNA prior to surgery than lung adenocarcinomas, the assay determined that rates of shedding were 100% and 49%, respectively, in these histologies. Importantly, preoperative shedders and nonshedders differed in their patterns of relapse: 91% of shedders had detectable ctDNA at or before relapse, with a median of 164 days between first detection of ctDNA after surgery and relapse, and a median disease-free interval of 362 days after surgery. By contrast, only 64% of nonshedders had detectable ctDNA at or before relapse, with a median of 22 days between postoperative ctDNA detection and relapse, and a median disease-free interval of 640 days. “What these data suggest is that preoperative ctDNA detection status will be a proxy of the potential utility of ctDNA as an MRD biomarker in a clinical setting,” Abbosh said.
MRD might then predict relapse before standard imaging: Nine of 10 of patients who tested positive for MRD on the assay but tested negative on one or more subsequent surveillance scans eventually relapsed.
“We think now that the technology is getting to the point at which you can start to leverage these biomarkers in clinical trials to direct or escalate adjuvant treatment,” Abbosh said.
Pasi Jänne, MD, PhD, of Dana-Farber Cancer Institute in Boston, MA, agreed. “If ctDNA could identify high-risk patients, this could significantly change the way we do adjuvant trials,” he said, resulting in smaller trials that could be completed more quickly. Now, he is eager for results from prospective trials testing whether adjuvant treatment prolongs overall survival and time to tumor recurrence in patients who are MRD positive. Such trials are under way in triple-negative breast cancer and colorectal cancer and are being planned in NSCLC.
“I am very excited by this—I believe that ctDNA has the potential to enhance or even replace radiographic surveillance for patients after curative-intent treatment for lung cancer,” said Joshua Bauml, MD, of the Perelman School of Medicine at the University of Pennsylvania in Philadelphia.
Although more research is needed before the TRACERx assay can be implemented in clinical practice, he added, “it is clear to me that ctDNA will be a critical component of research and clinical care moving forward.” –Catherine Caruso