Circulating tumor DNA predicts relapse risk among patients with colorectal cancer
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Circulating tumor DNA analysis outperformed an established biomarker in predicting risk for colorectal cancer recurrence after surgery, according to study results presented at Gastrointestinal Cancers Symposium.
“Although a high proportion of patients with colon cancer are treated with curative intent, relapse rates remain around 20% to 30%,” Tenna V. Henriksen, a PhD candidate at Aarhus University in Denmark, said during her presentation. “If we are able to identify molecular residual disease, we can enable better recurrence risk assessment. Earlier detection of recurrence could increase the proportion of patients treated with curative intent after recurrence, thereby improving survival for this entire patient group. We believe that circulating tumor DNA [ctDNA] is a promising biomarker for minimal residual disease detection.”
Henriksen and colleagues aimed to use ctDNA to classify patients as high or low risk for recurrence.
“We also wanted to assess the post-therapy risk in ctDNA-positive patients, as well as determine the lead time for ctDNA detection compared to CT recurrence,” Henriksen said. “We did this by recruiting patients from surgical centers in Denmark and Spain and collecting their tumor tissue.”
The analysis included 260 patients with colorectal cancer. Most had stage III disease (n = 166), followed by stage II (n = 90) and stage I (n = 4). A portion of patients (n = 165) were treated with adjuvant therapy.
To detect ctDNA, the researchers employed a tumor-informed strategy in which they exome-sequenced tumor and peripheral blood cells to identify mutations. They then chose 16 clonal mutations to design a Signatera (Natera) ctDNA assay, which they compared against plasma samples to monitor ctDNA levels, Henriksen said.
Researchers collected tumor tissue and plasma samples before and after surgery, as well as every 3 months after surgery for up to 3 years.
Patients also were monitored by CT scans at 12 months and 36 months after surgery.
“CT scans formed the clinical basis for which ctDNA data were compared with plasma samples,” Henriksen said.
Overall, 48 patients experienced relapse. Median follow-up for patients who did not relapse was 29.9 months (range, 1.2-51).
Among the 218 patients with postoperative ctDNA status assessed before adjuvant treatment, 20 were minimal residual disease (MRD) positive, including 15 (75%) who eventually relapsed. The five patients who were MRD positive and did not relapse received adjuvant treatment.
In contrast, among the 198 patients who were MRD negative, the relapse rate was 13.6% (HR = 11; 95% CI, 5.7-20).
Researchers found that a positive ctDNA test after adjuvant treatment was associated with a recurrence rate of 83.3% vs. 12.5% among those with a negative ctDNA test (HR = 12; 95% CI, 4.9-27).
In addition, longitudinal ctDNA-positive status after adjuvant therapy, which researchers observed among 202 patients, was associated with an HR of 36 (95% CI, 16-81).
“If we include longitudinal samples every 3 months after surgery, we can shift a portion of the ctDNA-negative patients to being ctDNA-positive at a later time point simply by including more sampling,” Henriksen said.
MRD was detected with serial ctDNA up to a median of 8.1 months (interquartile range, 2.2-11.4) before radiologic relapse among a subset of 29 patients, according to Henriksen.
Researchers also found that ctDNA-positive status was significantly associated with RFS (HR = 7.1; 95% CI, 3.4-15) compared with carcinoembryonic antigen (HR = 1.2; 95% CI, 0.46-3.1), an established biomarker.
“We found that patients with ctDNA detected immediately after surgery were at high risk for recurrence,” Henriksen said. “Longitudinal monitoring increased the predictive power of ctDNA, and we had a lead time of 8 months before radiological detection of recurrence using ctDNA. Longitudinal testing with ctDNA outperformed carcinoembryonic antigen in recurrence-free survival prediction.”
The researchers have initiated two clinical trials in Denmark, IMPROVE-IT and IMPROVE-IT2, to further assess the strategy in different clinical settings.
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Henriksen TV, et al. Abstract 11. Presented at: Gastrointestinal Cancers Symposium (virtual meeting); Jan. 15-17, 2021.
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