In a large and comprehensive prospective analysis of circulating tumour DNA (ctDNA) in GALAXY, an observational arm of the ongoing CIRCULATE-Japan study, the investigators demonstrated that postsurgical ctDNA status is a most significant prognostic biomarker than the currently used high-risk clinicopathological features in resectable colorectal cancer and can potentially be predictive of adjuvant chemotherapy benefit. In this study conducted among patients with clinical stage II to IV or recurrent colorectal cancer who underwent radical surgery, patients with ctDNA positivity 4 weeks after surgery had a significantly higher risk of recurrence than those with ctDNA negativity 4 weeks after surgery. Except for BRAF and RAS status, ctDNA was observed to be the most significant risk factor for recurrence in multivariate analysis. The study findings are published by Dr. Eiji Oko of the Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University in Fukuoka, Japan and colleagues on 16 January 2023 in the Nature Medicine.
ctDNA is a minimally invasive biomarker that can aid in the measurement of disease status across several settings, including postcurative surgery or treatment for detection of molecular residual disease, during surveillance, and throughout the course of therapy for treatment response monitoring. Despite standard-of-care treatment, more than 30% of patients with resectable colorectal cancer relapse. The value of tumour-informed ctDNA analysis has been evaluated in several retrospective and prospective studies in patients with early-stage colorectal cancer. Among patients with early-stage CRC, ctDNA positivity after curative-intent surgery has been associated with higher rates of disease recurrence.
The GALAXY study, which is a part of the CIRCULATE-Japan project, is a large prospective, observational study that monitors ctDNA status for patients with clinical stage II to IV or recurrent colorectal cancer following curative-intent surgery. In this analysis, the study team report on postsurgical ctDNA positivity and its associations with patient outcomes and its implications for selection of adjuvant chemotherapy, and the association between ctDNA dynamics and prognosis.
Of the 1039 patients included in the ctDNA analysis, 187 (18.0%) were ctDNA-positive 4 weeks after surgery, and 852 (82.0%) were ctDNA-negative. To evaluate ctDNA dynamics from 4 weeks to 12 weeks, 45 patients who experienced recurrence within 12 weeks or 157 who did not have ctDNA status available 12 weeks after surgery were excluded, and the remaining 838 patients were analyzed. For clearance analysis, among 187 patients who were ctDNA positive 4 weeks after surgery, those 5 with no available ctDNA status 12 weeks after surgery were excluded, and the remaining 182 were analyzed. There were significant differences in sex, primary location, pathological stage, RAS and BRAF status, and MSI status between the ctDNA-positive and ctDNA-negative groups.
With a median follow-up of 16.74 months (range, 0.49–24.83 months), postsurgical ctDNA positivity at 4 weeks after surgery was associated with higher recurrence risk (hazard ratio (HR) 10.0; p < 0.0001) and was the most significant prognostic factor associated with recurrence risk in patients with stage II or III colorectal cancer (HR 10.82; p < 0.001). Furthermore, postsurgical ctDNA positivity identified patients with stage II or III colorectal cancer who derived benefit from adjuvant chemotherapy (HR 6.59; p < 0.0001).
The authors also reported that in this study, the tumour-informed, personalised ctDNA assay detected ctDNA before surgery in 91.3% (934 out of 1,023) of patients overall; specifically, in 94.5% (291 out of 308) of patients with pathological stage II disease, 97.2% (380 out of 391) of patients with stage III disease, and 84.2% (192 out of 228) of patients with stage IV oligometastatic or recurrent disease. The lower presurgical ctDNA detection rate for patients with clinical stage IV or recurrent colorectal cancer is probably due to prior chemotherapy and other factors, suggesting that neoadjuvant chemotherapy may obscure molecular disease in these patients (77.1% with prior chemotherapy versus 85.6% without chemotherapy).
In total, 55.7% of genes selected for the tumour-informed ctDNA assay were found to be unique to each patient. This highlights the importance of personalised ctDNA analysis based on patient-specific somatic tumour mutations.
The authors concluded that the results of their study, a large and comprehensive prospective analysis of ctDNA in resectable colorectal cancer, support the use of ctDNA testing to identify patients who are at increased risk of recurrence and are likely to benefit from adjuvant chemotherapy. Currently, adjuvant chemotherapy for patients with colorectal cancer after surgery is considered according to clinicopathological risk factors, including pathological TNM staging, lymphovascular invasion, clinical obstruction and perforation, particularly for patients with stage II disease. The authors believe that their results can help to refine staging criteria in the future by incorporating postsurgical ctDNA status into traditional TNM staging criteria.
CIRCULATE-Japan receives financial support from the Japan Agency for Medical Research and Development.
Kotani D, Oki E, Nakamura Y, et al. Molecular residual disease and efficacy of adjuvant chemotherapy in patients with colorectal cancer. Nature Medicine; Published online 16 January 2023. DOI: https://doi.org/10.1038/s41591-022-02115-4