Strategies Employing MRD-Guided Treatment for CRC Shows Promise

Data in patients with colorectal cancer indicates that the Signatera MRD test may help guide treatment decisions in patients with resectable disease.

Updated results regarding the Signatera molecular residual disease (MRD) assay show that patients with colorectal cancer (CRC) may benefit from therapy strategies that are informed by circulating tumor DNA (ctDNA) assessment, according to a press release from Natera.1

The results were from the CIRCULATE-Japan trial (UMIN000039205) that is investigating ctDNA-guided treatment strategies for patients with stage I to IV CRC. Information regarding the first 808 patients examined will serve as a benchmark for testing future patients with this disease.

“CIRCULATE-Japan is a landmark prospective trial, and based on these strong interim results, we are highly optimistic they will lead to changes in practice guidelines in early-stage colorectal cancer,” Alexey Aleshin, MD, vice president of medical affairs and oncology at Natera, said in a press release. “At our core, we are a data-driven company, and these data very clearly demonstrate that Signatera can be an important and accurate tool for helping patients avoid unnecessary treatment.”

The prospective, observational GALAXY study looked at ctDNA results prior to and after curative surgery to track tumor biomarker status over time.2 Investigators used ctDNA in plasma and conducted follow-up periodically over 2 years, which revealed that MRD positivity vs negativity was strongly correlated with poorer survival (HR, 46.8).

This study analyzed 400 patients for pathological and tumor biomarker status. Mutation frequency for RAS(42%) and BRAF V600E (6%) was noted as well as microsatellite instability (MSI)–high status (8%). Additionally, pre-surgery ctDNA was observed in 92% of patients with stage I to III disease.

Investigators found positive ctDNA status had significant associations with advanced pStage (P = .004), pT (P<.001), and lymphovascular invasion (P = .043). No significant associations were noted between positive ctDNA and either RAS/BRAF or DNA mismatch repair status. Patients who had BRAF V600 mutations had higher presurgical ctDNA than those with mutant or wild-type RAS/BRAF in stage II or III disease.

Four weeks post-surgery, patients who were ctDNA positive were not associated with RAS and BRAFmutational status, whereas MSI-high patients had a lower ctDNA levels that were not found to be statistically significant. 

In another study of ctDNA-informed treatment strategies, 7 patients with pancreatic adenocarcinoma (PDAC) and 1 with ampullary adenocarcinoma were enrolled to examine patient-specific ctDNA assays designed using whole-exome sequencing for variant detection in plasma samples. Patients were monitored for carcinoembryonic antigen (CEA) and cancer antigen (CA) 19-9 as well as radiological imaging.3

Seven patients received adjuvant chemotherapy and 2 received additional rounds of gemcitabine/oxaliplatin and gemcitabine/paclitaxel. Additionally, 3 patients had plasma collected after surgery with 2 being positive for ctDNA (MRD rate 66%). Patients who were found to have positive MRD were more likely to experience poorer recurrence-free survival (HR, 10.14; P = .03).

During follow-up, 4 patients relapsed. Detection of ctDNA was associated with reduced recurrence-free survival (HR, 10.14; 95% CI, 1.07-1347.9; P = .03) and was observed in all patients who relapsed. CEA and CA 19-9 was found to have discordance with imaging and led to other elevated conditions like gastritis.

Signatera is a custom-built ctDNA assay that has a breakthrough therapy designation from the FDA for multiple cancer types. Signatera tailors blood testing to find unique clonal mutations in individual tumors and helps to detect and quantify the amount of cancer left in the body, assess the risk of recurrence, and guide treatment decisions.

“We are very encouraged by how quickly we have been able to generate this large, high-quality dataset and look forward to growing it even further through our collaboration with Natera,” said the CIRCULATE-Japan study’s Principal Investigator, Takayuki Yoshino, MD, of the National Cancer Center Hospital East, Kashiwa-shi, Chiba, Japan, in a press release.


1. New results from the landmark prospective CIRCULATE trial expand clinical utility of the Signatera MRD test in colorectal cancer. News Release. Natera. July 2, 2021. Accessed July 14 2021.

2. Shirasu H, Taniguchi H, Watanabe J, et al. Monitoring molecular residual disease by circulating tumor DNA in resectable colorectal cancer: Molecular subgroup analysis of a prospective observational study GALAXY in CIRCULATE-Japan. Ann Oncol. 2021;32(3): S222-S223.doi: 10.1016/j.annonc.2021.05.015

3. Abderlrahim M, Esmail A, Katz T, et al. Circulating tumor DNA for early relapse detection and monitoring disease status in patients with early-stage pancreatic adenocarcinoma. Ann Oncol. 2021; 32(3): S135. Doi: 10.1016/j.annonc.2021.05.163

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