Patients with stage I to III colorectal cancer and a high risk for disease recurrence may be identified by serial testing of circulating tumor DNA (ctDNA) after resection, according to a study in which ctDNA was more reliable than carcinoembryonic antigen (CEA) surveillance or standard radiologic imaging.
“Patients with ctDNA detected immediately after surgery had a high risk of recurrence, and longitudinal monitoring increased the predictive power of ctDNA,” said Tenna V. Henriksen, a doctoral student at Aarhus University in Denmark, who presented the findings during the 2021 Gastrointestinal Cancers Symposium (Abstract 11).
Molecular recurrence, as identified on ctDNA, was detected a median of 8 months before radiologic detection of disease, and longitudinal testing with ctDNA greatly outperformed CEA for prediction as well, she said.
This work was a collaboration between researchers at Aarhus University and the INCLIVA Institute in Spain, which together provided data on 260 patients with stage I to III colorectal cancer, and the Natera company in the United States, which created the ctDNA detection strategy used in the study (Signatera, which was granted a Breakthrough Device designation by the U.S. Food and Drug Administration).
The ctDNA tool is a “custom-built, tumor-informed” blood-based next-generation sequencing assay that traces the 16 most frequent tumor-specific single-nucleotide variants exclusive to each patient.
"Patients with ctDNA detected immediately after surgery had a high risk of recurrence, and longitudinal monitoring increased the predictive power of ctDNA."— Tenna V. Henriksen
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Study Design and Key Findings
The 260 patients in the study included 166 with stage III disease, 90 with stage II disease, and 4 with stage I disease; all patients underwent tumor resection, and 165 patients also received adjuvant treatment. Relapse occurred in 48 patients. Plasma samples (n = 1,503) were collected at various time points (30 days, 3 months, and then every 3 months postsurgery for 3 years) for a median time of 29.9 months.
The presence or absence of ctDNA identified two distinct prognostic groups at multiple time points. Postresection, 80% of patients with detectable ctDNA after surgery experienced disease recurrence, as compared with only 13% of patients with undetectable ctDNA, translating to an 11-fold increase in the risk for relapse (P < .0001).
Similarly, after the completion of adjuvant chemotherapy, 83% of patients with detectable ctDNA relapsed, as compared to only 12% of patients with undetectable ctDNA (P < .0001). This translated into a 12-fold increase in risk, Ms. Henriksen reported.
The best use of ctDNA testing was longitudinally, which demonstrated the strongest prognostic power overall. The recurrence rate reached 89% for patients with detectable ctDNA at any time, as compared with a rate of only 3% for patients with consistently undetectable ctDNA. This means the risk for recurrence was 51 times greater for patients with ctDNA detectable on any test (P < .0001) during a median follow-up of nearly 30 months.
Better Predictor Than CT or CEA
Notably, initial detection of ctDNA preceded radiographic evidence of progression (by computed tomography [CT]) by a median of 8.1 months. Furthermore, ctDNA outperformed CEA as a biomarker for disease relapse. In a multivariate analysis, longitudinal CEA assessment failed to reach statistical significance as a prognostic biomarker (hazard ratio [HR] =1.8, P = .184), whereas longitudinal ctDNA assessment emerged as a very strong independent one (HR = 80.55; P < .0001).
In closing, Ms. Henriksen said ctDNA could help identify the 10% to 15% of stage I and low-risk stage II patients who are undertreated and the approximately 60% of stage II patients who are overtreated. For all patients, risk can be identified early and intervention initiated, or treatment delayed until patients show evidence of ctDNA negativity. Better use could also be made of imaging, which could be intensified in ctDNA-positive patients and eliminated in ctDNA-negative patients, with serial ctDNA testing applied instead.
The study authors concluded, “Postoperative ctDNA positive status was associated with markedly reduced recurrence-free survival compared to CEA. The study also shows that effective therapy can be curative in a portion of MRD-positive patients. In a longitudinal setting, ctDNA analysis predicted the risk of recurrence and is a more reliable biomarker for treatment response monitoring.”
DISCLOSURE: For full disclosures of the study authors, visit coi.asco.org.
