NEW YORK (GenomeWeb) – Two independent research teams have found clues that circulating tumor DNA (ctDNA) can offer clinically useful insights into colorectal cancers (CRC) that have not progressed to metastasis.
In the first of these studies, published online today in JAMA Oncology, a team from the US, Australia, and Sweden focused on 58 individuals with non-metastatic stage I to III CRCs that had undergone resection surgery at hospitals in Sweden, collecting more than 300 blood samples from these patients in the months and years after surgery. While most of the patients did not have detectable levels of ctDNA in their blood after surgery, their search for known patient tumor mutations, using the Safe-SeqS assay, identified more than a dozen patients who were positive for ctDNA.
The researchers found that disease recurrence and relapse occurred in all but three of the 13 early-stage CRC patients with post-surgical ctDNA, pointing to the potential benefit of ongoing testing for ctDNA after surgical tumor resection. On average, the ctDNA turned up in relapsing patients some three months before clinicians could see the recurrent disease by radiologic screening or clinical symptoms.
The team did not see disease recurrence over an average of more than four years of follow up in the 45 remaining, ctDNA-free CRC patients.
"Serial circulating tumor DNA levels during post-operative surveillance can be used as a triage test to stratify patients with resected colorectal cancer on the basis of their risk of recurrence," wrote co-senior and co-corresponding authors Louise Olsson, a researcher in the Department of Molecular Medicine and Surgery at the Karolinska Institute, and Bert Vogelstein, a researcher at Johns Hopkins University's Ludwig Center for Cancer Genetics and Therapeutics, together with their colleagues.
For their own prospective study, also published in JAMA Oncology, researchers from Aarhus University Hospital, Natera, and elsewhere used ultradeep sequencing to quantify cell-free ctDNA levels in nearly 800 samples collected over time — up to two weeks before and in the months after surgery — in 125 individuals with stage I, stage, II, or stage III colorectal cancer. Again, the presence of ctDNA seemed to line up with disease recurrence, while almost 82 percent of samples with ctDNA contained potentially actionable mutations.
Using multiplex PCR and deep, barcoded, multiplex amplicon sequencing focused on single nucleotide variants or small insertion and deletions that were previously detected by tumor exome sequencing, that team saw signs that ctDNA is an independent risk factor for relapse, outside of other clinicopathologic risk factors.
In 108 out of 122 patients tested before surgery, for example, the researchers identified ctDNA, including 40 percent of individuals with stage I CRC, 92 percent of individuals with stage II disease, and 90 percent of stage III cases. Post-treatment, ctDNA that remained or reappeared in the blood was significantly tied to disease recurrence, they noted, typically picking up relapse earlier than standard imaging tests.
The researchers noted that relapse risk was particularly pronounced in patients who had ctDNA in their blood in the first month after surgery. The risk was even higher for seven patients who were positive for ctDNA not long after completing adjuvant chemotherapy.
From these and other findings, the authors concluded that ctDNA analyses can potentially change the post-operative management of CRC by enabling risk stratification, adjuvant chemotherapy monitoring, and early relapse detection.
In a related editorial, Scott Kopetz of the University of Texas MD Anderson Cancer Center and colleagues discussed findings from the early-stage CRC studies, noting that they "extend our understanding of the clinical utility of ctDNA for patients with CRC beyond risk stratification and provide early insights into ctDNA as a biomarker that, pending more robust data from prospective trials, in the future may be used routinely in CRC for surveillance and, ideally, for identifying patients for whom adjuvant chemotherapy may be advantageous."
The authors cautioned that "payers in the United States have not yet approved the routine use of ctDNA technologies in patients with early-stage CRC after resection," but suggested "compelling data on ctDNA as a robust prognostic marker should be a reason to reassess coverage."