A liquid biopsy assay that tests for only six circulating tumor DNA (ctDNA) methylation markers has shown high accuracy in identifying the risk for relapse among patients with colorectal cancer (CRC).
Patients who were ctDNA methylation-positive 1 month after surgery were 17.5 times more likely to relapse compared with ctDNA-negative patients. And following adjuvant chemotherapy, ctDNA-positive patients had a significantly shorter recurrence-free survival than their ctDNA-negative peers.
Overall, “we found that ctDNA methylation was the most significant prognostic factor for recurrence-free survival among all clinico-pathologic risk factors on multivariable analysis,” the authors, led by Shaobo Mo, MD, Fudan University Shanghai Cancer Center in China, reported in research published this month in JAMA Oncology.
Van Morris, MD, an oncologist with University of Texas MD Anderson Cancer Center in Houston who was not involved in the research, noted that other commercially available ctDNA assays have achieved similar findings, but this assay involves the least number of biomarkers.
More notably, the broader message emerging from this research is that “ctDNA is a powerful tool in oncology that is here to stay,” said Morris.
Morris added a note of caution, however: Despite the study providing further support for this technology in CRC, “we do not have definitive predictive utility for routinely guiding adjuvant chemotherapy decisions with the use of this [or other] ctDNA assays.”
Recurrence Common, Predictors Important
CRC has a relatively high recurrence rate even after curative-intent therapies, with a 5-year survival rate as low as 60%. Adjuvant chemotherapy in patients with stage III CRC generally lowers the risk of recurrence by about 10% to 20%; however, the benefits of adjuvant chemotherapy among patients with stage II CRC remain unclear.
Strategies to identify patients most likely to relapse after adjuvant therapy largely focus on CRC stage and clinical risk factors, though postoperative ctDNA testing has emerged as a tool to help identify patients at risk for recurrence. Often, however, this approach involves ultradeep next-generation sequencing, which limits the strategy’s ease of implementation and cost effectiveness.
As an alternative, the authors used a plasma ctDNA methylation test, ColonAiQ, which identifies the presence of six genomic biomarkers hypermethylated in CRC. This test avoids the complex process of primary tumor profiling among individual patients.
In the multicenter, prospective longitudinal cohort study, conducted from December 2019 to February 2022, Mo and colleagues evaluated 1228 blood samples from 299 patients with stage I to III CRC. Samples were collected before and after surgery, during and after adjuvant chemotherapy, and every 3 months for up to 2 years.
Of 296 patients with preoperative samples available, as many as 232 (78.4%) tested positive for at least one of the 6 ctDNA methylation markers. The detection rates were 65.1% for stage I CRC, 82.7% for stage II disease, and 81.5% for stage III disease.
At postoperative month 1, ctDNA methylation-positive patients were 17.5 times more likely to relapse compared with ctDNA-negative patients (hazard ratio [HR], 17.5; P < .001).
When integrating carcinoembryonic antigen testing alongside ctDNA testing, patients with positive test results had significantly worse prognoses compared with those who had negative results (HR, 19.0; P < .001).
The association of ctDNA methylation positivity at postoperative month 1 and CRC recurrence was consistent across varying durations and intensities of adjuvant chemotherapy. The researchers found that ctDNA methylation analysis detected CRC recurrence a median of 3.3 months earlier than radiologically confirmed recurrence.
Patients who were ctDNA-positive also had significantly shorter periods of recurrence-free survival following adjuvant chemotherapy compared with ctDNA-negative patients (HR, 13.8; P < .001). That effect was enhanced when positive ctDNA status was maintained longitudinally compared with those who were persistently ctDNA-negative (HR, 68.8; P < .001).
More specifically, 140 patients exhibited sustained ctDNA-positive status over time; 6 of 7 ctDNA-positive patients experienced recurrence within 12 months, whereas 129 of 133 ctDNA-negative patients (97%) remained relapse free. And being ctDNA-negative before surgery indicated patients’ relapse risk, with 95.3% of patients who were ctDNA-negative presurgery remaining relapse free.
Mo and colleagues concluded that the simplicity of the assay workflow and convenience of taking blood samples make this approach practical and cost-effective in the clinical setting.
In an editorial published alongside the study, Juan Ruiz-Bañobre, MD, PhD, and Ajay Goel, PhD, noted that the field is evolving rapidly but “there is substantial value in prospectively validating the clinical importance of ColonAiQ in randomized clinical trials.”
“If successful, this liquid biopsy assay could represent a simple and cost-effective means for a more accessible and facile decentralized implementation in routine clinical practice,” said Ruiz-Bañobre, of the University of Santiago de Compostela, A Coruña, Spain, and Goel, from City of Hope Comprehensive Cancer Center in Duarte, California.
Several of the study co-authors are employees of Singlera Genomics, which makes the ColonAiQ test. Ruiz-Bañobre reported grants from the Spanish Cooperative Group for the Treatment of Digestive Tumors and support from Institute of Health Carlos III. Morris is the principal investigator on the NRG GI005 trial of the Guardant Reveal liquid biopsy, sponsored by Guardant Health in collaboration with funding support from the National Cancer Institute.
JAMA Oncology. Published April 20, 2023. Abstract, Editorial
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