Predicting Postoperative Recurrence in Stage I to III Colorectal Cancer With Circulating Tumor DNA

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Patients with stage I to III colorectal cancer who have a high risk for recurrence may be identified by serial testing of circulating tumor DNA (ctDNA) after resection, according to a study in which ctDNA proved more reliable than carcinoembryonic antigen (CEA) surveillance or standard radiologic imaging.1

“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, PhD Candidate, of Aarhus University, Denmark, who presented the findings during the 2021 Gastrointestinal Cancers Symposium.

“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, PhD Candidate

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Molecular recurrence, as identified by ctDNA, was detected a median of 8 months before radiologic detection of disease, and longitudinal testing with ctDNA seemed to outperform CEA surveillance for prediction as well. Risk for recurrence was found to be 51 times greater for patients with ctDNA detectable at any time during a median follow-up of nearly 30 months, she reported.

“Even though a high proportion of patients are offered treatment with curative intent, relapse rates in these patients are around 20% to 30%. Earlier detection of recurrence could increase the proportion of patients we treat with curative intent after recurrence, thereby hopefully improving the survival of this entire patient group,” said Ms. Henriksen.

Assay, Study Design

This work was a collaboration between researchers at Aarhus University and the INCLIVA Institute in Valencia, Spain, as well as the Natera company in the United States, which created the ctDNA detection strategy used in the study. Together, they provided data on 260 patients with stage I to III colorectal cancer. Signatera, which was granted a Breakthrough Device designation by the U.S. Food and Drug Administration, is a “custom-built, tumor-informed” blood-based next-generation sequencing assay that traces 16 clonal tumor-specific single nucleotide variants exclusive to each patient.

Of the 260 patients, 166 had stage III disease, 90 had stage II disease, and 4 had stage I disease; all underwent tumor resection, and 165 patients also received adjuvant treatment. Relapses occurred in 48 patients. Plasma samples (n = 1,503) were collected at various time points (30 days, 3 months, and then every 3 months after surgery for 3 years), for a median time of 29.9 months.

Postoperative ctDNA Detection

The presence or absence of ctDNA identified two distinct prognostic groups at multiple time points.

After resection, 80% of patients with detectable ctDNA experienced disease recurrence, as compared with 13% of patients with undetectable ctDNA, translating to a significant 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 with 12% of patients with undetectable ctDNA (P < .0001). This translated into a 12-fold increase in the risk for relapse, 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 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.


  • A “custom-built” circulating tumor DNA (ctDNA) assay may reliably prognosticate recurrence risk after colorectal cancer resection.
  • Patients who tested positive for ctDNA at any time point during the study had a risk for recurrence that was 51 times greater than for patients who consistently tested negative for ctDNA, at a median follow-up of nearly 30 months.

Better Predictor Than CT or CEA?

Notably, initial detection of ctDNA preceded radiographic evidence of disease progression (by computed tomography [CT]) by a median of 8.1 months. Furthermore, ctDNA outperformed CEA as a biomarker for disease recurrence. 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 strong independent predictor (HR = 80.55; P < .0001).

ctDNA Approaches Under Study

In closing, Ms. Henriksen presented a few scenarios that illustrate how ctDNA may improve surveillance over the current standards of care. She estimated that between 10% and 15% of patients with stage I and low-risk stage II disease are undertreated because chemotherapy is not considered necessary, whereas 60% of patients with stage III disease are overtreated because their actual recurrence risk is low. With ctDNA, patients at risk could be identified and treated early with chemotherapy; those with negative tests could undergo ctDNA surveillance, with intervention only as necessary. 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. These approaches are actually being tested in the IMPROVE-IT ( Identifier: NCT03748680) and IMPROVE-IT2 (NCT04084249) clinical trials. 

DISCLOSURE: Ms. Henriksen reported no conflicts of interest.


1. Henriksen TV, Tarazona N, Reinert T, et al: Circulating tumor DNA analysis for assessment of recurrence risk, benefit of adjuvant therapy, and early relapse detection after treatment in colorectal cancer patients. 2021 Gastrointestinal Cancers Symposium. Abstract 11. Presented January 16, 2021.


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