The CIRCULATE-US study will use the Signatera MRD test to inform treatment decisions in resected CRC

The Signatera personalized minimal residual disease test will be used in the Phase 2/3 CIRCULATE-US trial to inform treatment strategies in patients with early-stage colorectal cancer.

The Signatera personalized minimal residual disease (MRD) test will be used in the Phase 2/3 CIRCULATE-US trial (NRG-GI008) to inform treatment strategies in patients with colorectal cancer (CRC) at an early stage.1

For the trial, the researchers plan to enroll approximately 2,000 patients with stage II or III CRC who have undergone resection. Patients whose MRM has been determined by the Signatera test will be randomized to receive standard adjuvant chemotherapy (SOC) or to be observed, unless circulating tumor DNA (ctDNA) is subsequently detected. Those identified as positive for MRM will be randomized to receive SOC chemotherapy or an intensified treatment regimen of mFOLFIRINOX (oxaliplatin, leucovorin, irinotecan and 5-fluorouracil).

The primary endpoint of the study is to compare disease-free survival (DFS) in MRD-negative patients between immediate and delayed adjuvant chemotherapy, as well as MRD-positive patients between SOC and intensified adjuvant chemotherapy.

“Adjuvant chemotherapy, in its current state, does not cure all of our patients. The premise here is to try to improve the current adjuvant chemotherapy regimens that we give to patients after surgery, ”said Georges Azzi, MD, co-chair of the prostate cancer hematology / oncology department at Holy Cross Health. , in an interview with OncLive®. “The best [strategy] to do that is to be able to climb [treatment] in patients most at risk. The most valuable tool we have in the clinic for assessing where patients fall within this risk spectrum is tumor-based ctDNA for the assessment of MRM.

Signatera is a tailor-made cDNA test for treatment monitoring and evaluation of MRD in patients previously diagnosed with cancer. The test is available for both clinical and research use and has received 3 breakthrough device designations from the FDA for several types and indications of cancer.

The personalized, tumor-based test provides each patient with personalized blood tests for each unique signature of clonal mutations found in the tumor; this maximizes the accuracy of the test for detecting the presence or absence of residual disease in blood samples. Additionally, the test is intended to detect and quantify the amount of cancer remaining in the body, determine the likelihood of recurrence, and guide treatment decisions.

CIRCULATE-US is part of an international collaboration that was announced at ESMO 2019, the objective of which is to adapt adjuvant chemotherapy using emerging cDNA technologies.

Part of the project is the CIRCULATE-Japan prospective observational trial, researchers set out to monitor MRM status and establish registry data in patients with stage II to IV or relapsed CRC who are suitable for radical surgical resection.2 This assay also took advantage of the personalized tumor-based ctDNA test based on whole exome sequencing of a sample of tumor tissue. Here, cDNA analysis was performed at pre- and postoperative times and continued periodically for up to 2 years.

A total of 941 patients were included between June 5, 2020 and January 13, 2021; 541 patients were excluded due to an untreated preoperative cDNA result (n = 506), withdrawal of consent (n = 2) and unavailable pathological data (n = 33). The analysis presented at the ASCO 2021 annual meeting included 400 patients. Preoperative cDNA was available in 400 patients and 363 patients had postoperative cDNA results available. In total, 4425 genes were selected for the 400 patients.

Preoperative cDNA has been detected in over 90% of patients with stage II to III disease. The postoperative status of the cDNA was found to be significantly related to some known clinicopathologic risk factors for disease recurrence, and the positivity of the cDNA was related to a very short term of recurrence. Finally, the sensitivity of relapse detection at 12 weeks was noted at 92% postoperatively.

“If we don’t use a test like this, [we are] unable to say who is high risk and who is not, Azzi said. “We see the pathological criteria, and even positive lymph nodes. The risk ratio is not as good for predicting DFS as [it is with] the ctDNA test and a tumor-based approach. This is the best test we have to be able to differentiate high risk from lower risk. “

The references

  1. Natera’s Signatera test selected for NRG Oncology’s CIRCULATE-US study of MRD-guided therapy in stage II-III colon cancer. Press release. Natera, Inc. September 7, 2021. Accessed December 8, 2021. https://bit.ly/3EOTJ2c
  2. Yukami H, Nakamura Y, Watanabe J, et al. Minimal residual disease by analysis of circulating tumor DNA for colorectal cancer patients receiving radical surgery: an initial report from CIRCULATE-Japan. J Clin Oncol. 2021; 39 (suppla 15): 3608. doi: 10.1200 / JCO.2021.39.15_suppl.3608


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