COSMOS-CRC-01: Clinicopathologic Correlation of ctDNA With RFS

1. Please summarize the statistically significant recurrence-free intervals across the postoperative, post-ACT, and paired pre- and post-ACT analyses in the COSMOS-CRC-01 study.

2. Please address the prognostic value of serial, tissue-free, epigenomic ctDNA assays in detecting MRD in real time vs a single postchemotherapy time point.

Videos

Yoshiaki Nakamura, MD, PhD, discusses how the COSMOS-CRC-01 study demonstrated statistically significant recurrence-free intervals across various postoperative and adjuvant chemotherapy time points, highlighting the prognostic value of serial, tissue-free ctDNA assays for real-time detection of MRD vs single postchemotherapy assessments.

COSMOS-CRC-01: Study Design and Methodology

1. Please explain the rationale, enrollment criteria, objectives, and methodology of the COSMOS-CRC-01 study

2. What patient and/or disease factors motivated the decision to obtain the first plasma sample for ctDNA analysis at postoperative day28?

In your experience, how soon after resection for R0 (ie, microscopically margin negative) stage II to III CRC can ctDNA sequencing be conducted and reliably detect potential MRD at the micrometastatic level?

3. Please review the timing of pre-and postadjuvant chemotherapy plasma sampling from patients who received ACT.

In postoperative adjuvant chemotherapy, should the patient complete all cycles before submitting a plasma sample for ctDNA analysis?

Are there circumstances when a ctDNA sample might be obtained 

Yoshiaki Nakamura, MD, PhD, discusses how the COSMOS-CRC-01 study was designed to evaluate the efficacy of ctDNA analysis for MRD detection, outlining the rationale for patient enrollment, the timing of plasma sample collection, and the implications for monitoring disease post surgery and during adjuvant chemotherapy.

Risk of Recurrent Colorectal Cancer Following Definitive Therapy

1. Please briefly discuss the prevalence of stage II to III colon cancer recurrence after definitive therapy and the advantages of MRD detection through tissue-free ctDNA analysis, especially in cases of limitedtumor specimen availability.

a. What are some challenges to accuratelystratifying the risk of recurrence among patients with resectable stage II to III CRC?

b. Compared with tissue-based biopsy and molecular profiling, what are the short- and long-term logisticalbenefits of serial, cell-free ctDNA epigenomic assays in patients with CRC who are at risk of recurrent disease after initial definitive therapy?

Yoshiaki Nakamura, MD, PhD, discusses how the use of tissue-free circulating tumor DNA (ctDNA) analysis for detecting minimal residual disease (MRD) can enhance the prediction of recurrence in stage II to III colorectal cancer (CRC), particularly when tumor specimens are limited.

Yoshiaki Nakamura, MD, PhD, National Cancer Center Hospital Japan East, discusses updated findings from an analysis of the association between circulating tumor DNA (ctDNA) minimal residual disease (MRD) status and disease-free survival (DFS) in the GALAXY trial, an observational arm of the ongoing CIRCULATE-Japan trial (UMIN000039205) in patients with resected colorectal cancer (CRC).

At the 2023 ESMO Congress, Nakamura presented results from an updated 24-month DFS analysis in patients with stage II to IV radically resected CRC from the GALAXY trial. In this trial, the MRD window was 2 to 10 weeks post-surgery prior to initiating any adjuvant therapy. The ctDNA dynamics were measured from the MRD window until 3 months post-surgery. In these updated results, ctDNA MRD positivity was associated with shorter DFS rates (HR, 12.46; 95% CI, 9.85-15.76; 

 < 2.0e-16), which was consistent with previously reported data from this trial, Nakamura says.

This analysis of ctDNA MRD dynamics showed that patients with persistently negative ctDNA MRD levels had the highest DFS rates, followed by those who converted to ctDNA MRD negativity, those who converted to ctDNA MRD positivity, and those who had persistently positive ctDNA MRD levels, with respective 24-month DFS rates of 90.3% (95% CI, 88.1%-92.1%), 53.9% (95% CI, 42.1%-64.3%), 20.7% (95% CI, 4.7%-44.5%), and 9.8% (95% CI, 4.4%-17.7%). The respective DFS hazard ratios in the converted negative, converted positive, and persistently positive cohorts were 6.06 (95% CI, 4.18-8.79; 

 < 2.0e-16), and 38.4 (95% CI, 27.94-52.78; 

 < 2.0e-16). Patients who converted from negative to positive ctDNA MRD levels were classified as high-risk, and they should receive specific interventions, Nakamura emphasizes.

Additionally, an evaluation of the benefit of adjuvant chemotherapy showed that in the ctDNA-negative cohort, the 24-month DFS rates were 88.3% (95% CI, 84.4%-91.2%) in patients who received adjuvant chemotherapy vs 89.9% (95% CI, 87%-92.1%) in those who did not (HR, 1.39; 95% CI, 0.88-2.20; 

 = .156). In the ctDNA-positive cohort, the 24-month DFS rates were 38.6% (95% CI, 29.6%-47.5%) in patients who received adjuvant chemotherapy vs 16.1% (95% CI, 6%-30.6%) in those who did not (HR, 3.29; 95% CI, 2.13-5.07; 

Dr Nakamura reports honoraria from Chugai and Guardant Health AMEA; and research grants from Taiho, Chugai, Guardant Health, Genomedia, Daiichi Sankyo, Seagen, and Roche Diagnostics.

Yoshiaki Nakamura, MD, PhD, discusses updated findings from an analysis of the association between circulating tumor DNA minimal residual disease status and disease-free survival in the GALAXY trial, an observational arm of the ongoing CIRCULATE-Japan trial in patients with resected colorectal cancer. 

Yoshiaki Nakamura, MD, PhD

Articles

COSMOS-CRC-01: Clinicopathologic Correlation of ctDNA With RFS

COSMOS-CRC-01: Study Design and Methodology

Risk of Recurrent Colorectal Cancer Following Definitive Therapy

Dr Nakamura on the Association Between MRD Negativity and DFS in Resected CRC