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Colon Cancer Recurrence Clues Identified in Post-Treatment ctDNA Detection

NEW YORK – By analyzing circulating tumor DNA (ctDNA) samples after treatment, it may be possible to identify stage III colon cancer patients who are at increased risk of relapse and disease progression, new research suggests.

"Our study highlights the potential clinical utility of ctDNA to guide therapeutic decision-making," corresponding author Jeanne Tie, a medical oncologist and personalized oncology researcher specializing in colorectal cancer at the Walter and Eliza Hall Institute of Medical Research, and her colleagues wrote. 

Tie and her colleagues from other centers in Australia and the US analyzed blood samples from almost 100 individuals with stage III colon cancer, using somatic mutation clues gleaned from available tumor tissue. Their results, published online yesterday in the journal JAMA Oncology, pointed to shorter recurrent-free survival times in the patients with detectable ctDNA in their blood after treatment, particularly after both surgery and adjuvant chemotherapy.

Given their results so far, the authors suggested that "post-chemotherapy ctDNA analysis could lead to a more informed selection of patients who could benefit from additional therapeutic approaches, supporting the pursuit of clinical trials of novel agents in this high-risk population."

The researchers focused on 96 patients between the ages of 26 and 82 years old who were treated for stage III colon cancer from December 2018 to late June of this year. Over 11.6 months to almost four years, or 28.9 months, on average, they followed patients who had completed surgery and six months of adjuvant chemotherapy. During the follow-up period, 24 patients experience recurrence, while 72 did not.

The team first tracked down patient-specific somatic mutations through targeted sequencing on 15 colorectal cancer-related genes. From there, it searched for these alterations in serially collected blood plasma samples analyzed with a DNA barcode-based approach called Safe-Sequencing (Safe-SeqS), designed to identify low-frequency alterations in ctDNA and minimizing errors introduced during the amplification and sequencing protocol. 

Tie presented work outlining the use of Safe-SeqS on samples from stage II colon cancer patients at the American Society of Clinical Oncology annual meeting in 2016, while insights from the stage III colon cases outlined in the new JAMA Oncology paper were initially shared at the ASCO conference in 2018.

The team detected ctDNA in blood samples collected after surgery in 20 of the stage III patients, or 21 percent of those included in the study. For 17 patients, the ctDNA persisted even after adjuvant chemotherapy.

When they compared recurrence-free survival intervals in individuals with or without ctDNA at these points in the treatment process, the researchers estimated that just 30 percent of patients with ctDNA in their blood post-chemo would be recurrence-free after three years, compared with some 77 percent of patients who did not have detectable ctDNA with the Safe-SegS after chemo.

A similar pattern turned up in patients with ctDNA that was picked up after surgery, the team reported, even after adjusting for other clinical or pathological features previously implicated in increased progression risk. 

"[T]he treatment of patients with detectable ctDNA levels but without radiological evidence of disease after adjuvant chemotherapy could, in theory, eradicate residual disease and increase the chance of cure," the authors concluded. "This possibility is being further explored in a series of randomized studies that are currently recruiting."

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