Previous interim analysis of the GALAXY study, an observational arm of the ongoing, prospective, multicentre CIRCULATE-Japan study, which included 1039 patients with a median follow-up of 16.7 months, established a significant association between post-surgical circulating tumour DNA (ctDNA) positivity and elevated recurrence risk in patients with resected colorectal cancer (CRC). However, the follow-up duration was insufficient to evaluate the impact of molecular residual disease status on overall survival (OS).
In updated analysis with 2240 patients and 23 month median follow-up, the study researchers demonstrate that ctDNA-based molecular residual disease detection is a powerful prognostic biomarker for OS, as well as disease-free survival (DFS) in patients with resected CRC. The findings were presented at ESMO Congress 2024 along with simultaneous publication by Dr. Takayuki Yoshino of the Department of Gastrointestinal Oncology, National Cancer Center Hospital East in Kashiwa and Kindai University Faculty of Medicine in Osaka-Sayama, Japan, Dr. Eiji Oki of the Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University in Fukuoka, Japan and colleagues on 16 September 2024 in the Nature Medicine.
In initial report involving 1039 patients, the researchers showed a significant correlation between post-surgical ctDNA positivity and elevated recurrence risk, compared to other high-risk clinicopathological features, and a larger benefit from adjuvant chemotherapy in patients with molecular residual disease positivity. In particular, the patients were followed for a median of 16.7 months (range, 0.5–24.8 months).
Now the researchers report updated results from the GALAXY study in an expanded cohort of 2240 patients with stage II–III resectable colon cancer or stage IV CRC with extended follow-up of median 23 months (range, 2–49 months). They aimed to comprehensively evaluate the prognostic and predictive value of post-surgical ctDNA detection and its association with DFS and OS. They further investigated whether ctDNA molecular residual disease positivity predicts outcomes based on actionable biomarker stratification and whether ctDNA clearance in response to adjuvant chemotherapy informs treatment efficacy.
Findings from this updated analysis reinforces the prognostic value of ctDNA positivity during the molecular residual disease window with significantly inferior DFS (hazard ratio [HR] 11.99, p < 0.0001) and OS (HR 9.68, p < 0.0001). In patients who experienced recurrence, ctDNA positivity correlated with shorter OS (HR 2.71, p < 0.0001).
The significantly shorter DFS in molecular residual disease positive patients was consistent across actionable biomarker subsets. Sustained ctDNA clearance in response to adjuvant chemotherapy was an indicator of favourable DFS and OS compared to transient clearance with 24 month DFS rate of 89.0% versus 3.3% and 24 month OS rate of 100.0% versus 82.3%. True spontaneous clearance rate with no clinical recurrence was 1.9%.
In the present analysis, ctDNA positivity emerged as the most significant prognostic factor associated with poor OS, outperforming other well established clinicopathological features. Furthermore, among patients with radiological recurrence, presence of ctDNA positivity significantly correlated with higher mortality compared to ctDNA negativity, regardless of recurrence sites, and with fewer opportunities for curative metastasectomy. These findings underscore the urgent need for novel therapeutic approaches for this population, both in the adjuvant setting and after clinical recurrence.
This updated analysis also strongly validates previous finding that observation alone may be sufficient for favourable outcomes among molecular residual disease negative patients, whereas molecular residual disease positive patients derive significant benefit from adjuvant chemotherapy. Although T4N0 demonstrated slightly inferior outcomes compared to the T3N0 counterparts, adjuvant chemotherapy did not show any survival benefit after adjusting for age, sex and performance status to mitigate residual bias. This finding provides further support for the randomised, phase III VEGA study in the CIRCULATE-Japan platform, which is currently assessing the non-inferiority of observation alone compared to standard adjuvant chemotherapy in patients with high-risk stage II or low-risk pathological stage III CRC who are confirmed to be ctDNA negative 4 weeks after surgery.
The analysis of ctDNA clearance patterns demonstrated that sustained ctDNA clearance in response to adjuvant chemotherapy was a better indicator of treatment efficacy and favourable outcomes compared to transient clearance. The incorporation of ctDNA clearance assessment into clinical trials has the potential to streamline and assist with efficient drug development. The authors wrote that the results from ongoing randomised controlled trials evaluating the efficacy of novel therapeutic strategies in ctDNA positive patients will be crucial to fully harness the potential of ctDNA as a biomarker in the management of resected CRC.
CIRCULATE-Japan receives financial support from the Japan Agency for Medical Research and Development grants and the National Cancer Center Research and Development Fund.
References
Nakamura Y, Watanabe J, Akazawa N, et al. ctDNA-based molecular residual disease and survival in resectable colorectal cancer. Nature Medicine; Published online 16 September 2024. DOI: https://doi.org/10.1038/s41591-024-03254-6
553P - Nagata J, Nakamura Y, Watanabe J, et al. Association of ctDNA-based MRD detection and MRD clearance with short-term overall survival in patients with resectable colorectal cancer: Updated analysis of CIRCULATE-Japan GALAXY. Annals of Oncology 2024;35(Suppl 2):S457.