CIRCULATE-US Study Will Utilize Signatera MRD Test to Inform Treatment Decisions in Resected CRC

Georges Azzi, MD

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

For the trial, investigators plan to enroll approximately 2,000 patients with stage II or III CRC who have undergone resection. Patients determined to have MRD negativity by the Signatera assay will be randomized to receive either standard-of-care (SOC) adjuvant chemotherapy or to undergo observation unless circulating tumor DNA (ctDNA) is subsequently detected. Those identified to have MRD positivity will be randomized to receive SOC chemotherapy or an intensified regimen of mFOLFIRINOX (oxaliplatin, leucovorin, irinotecan, and 5-fluorouracil).

The study’s primary end point is to compare disease-free survival (DFS) in MRD-negative patients between immediate vs delayed adjuvant chemotherapy, as well as MRD-positive patients between SOC vs intensified adjuvant chemotherapy.

“Adjuvant chemotherapy, as it currently stands, does not cure all our patients. The premise here is to try to improve current adjuvant chemotherapy regimens that we give to patients after surgery,” Georges Azzi, MD, the co-director of the Department of Hematology/Oncology for Prostate Cancer at Holy Cross Health, said in an interview with OncLive®. “The best [strategy] to do that is to be able to escalate [treatment] in those patients who are at the highest risk. The most valuable tool we have in the clinic to evaluate where patients sit on that spectrum of risk is tumor-informed ctDNA for the assessment of MRD.”

Signatera is a custom-built ctDNA test for treatment monitoring and MRD assessment in patients previously diagnosed with cancer. The test is available for both clinical and research use and has been granted 3 breakthrough device designations from the FDA for multiple cancer types and indications.

The personalized and tumor-informed assay provides each patient with customized blood tests for each unique signature of clonal mutations found in the tumor; this maximizes the test’s accuracy for detecting the presence or absence of residual disease in blood samples. Moreover, the test is intended to detect and quantify how much cancer is left in the body, determine the likelihood of recurrence, and guide treatment decisions.

CIRCULATE-US is part of an international collaboration that had been announced during the 2019 ESMO Congress, the goal of which being to tailor adjuvant chemotherapy by using emerging ctDNA technologies.

Part of the project is the prospective, observational CIRCULATE-Japan trial, investigators set out to monitor MRD status and to establish the registry data in patients with stage II to IV or relapsed CRC who are amenable to radical surgical resection.² This trial also leveraged the personalized, tumor-informed ctDNA assay based on whole-exome sequencing of tumor tissue sample. Here, ctDNA analysis was performed at pre- and post-surgical time points and continued periodically for up to 2 years.

A total of 941 patients were enrolled between June 5, 2020, and January 13, 2021; 541 patients were excluded due to an unprocessed preoperative ctDNA result (n = 506), withdrawn consent (n = 2), and unavailable pathological data (n = 33). The analysis presented at the 2021 ASCO Annual Meeting included 400 patients. Preoperative ctDNA was available in 400 patients and 363 patients had post-operative ctDNA results available. A total of 4425 genes were selected for the 400 patients.

Preoperative ctDNA was detected in more than 90% of patients with stage II to III disease. Post-operative ctDNA status was found to be significantly linked with certain known clinicopathological risk factors for disease recurrence, and ctDNA positivity was linked with a very short term of recurrence. Lastly, sensitivity of relapse detection at 12 weeks was noted to be 92% in the post-operative setting.

“If we do not use an assay like this, [we are] unable to tell who is high risk and who is not, Azzi said. “We see the pathological criteria, and even positive lymph nodes. The hazard ratio is not as good for the prediction of DFS as [it is with] the ctDNA assay and a tumor-informed approach. This is the best assay we have to be able to differentiate high risk from lower risks.”

References

1. Natera’s Signatera test selected for NRG Oncology’s landmark CIRCULATE-US study of MRD-guided treatment in stage II-III colon cancer. News release. Natera, Inc. September 7, 2021. Accessed December 8, 2021. https://bit.ly/3EOTJ2c
2. Yukami H, Nakamura Y, Watanabe J, at al. Minimal residual disease by circulating tumor DNA analysis 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