Journal
CLINICAL CANCER RESEARCH
Volume 28, Issue 3, Pages 507-517Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1078-0432.CCR-21-2404
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Funding
- Novo Nordisk Foundation [NNF17OC0025052]
- Danish Cancer Society [R133-A8520-00-S41, R146-A9466-16-S2, R231-A13845, R257-A14700]
- Dansk Kraeftforskningsfond [FID1839672]
- Krista and Viggo Petersen Foundation [6030/67]
- Aarhus University
- Instituto de Salud Carlos III [PI18/01909, PT17/0015/0049]
- [JR16/00040]
- [JR20/00005]
- [CM15/246]
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The study demonstrates the strong prognostic value of serial postoperative ctDNA analysis in predicting recurrence and assessing tumor growth rate. The novel combination of ctDNA detection and growth rate assessment provides unique opportunities for guiding treatment decisions.
Purpose: Sensitive methods for risk stratification, monitoring therapeutic efficacy, and early relapse detection may have a major impact on treatment decisions and patient management for stage III colorectal cancer patients. Beyond assessing the predictive power of postoperative ctDNA detection, we explored the added benefits of serial analysis: assessing adjuvant chemotherapy (ACT) efficacy, early relapse detection, and ctDNA growth rates. Experimental Design: We recruited 168 patients with stage III colorectal cancer treated with curative intent at Danish and Spanish hospitals between 2014 and 2019. To quantify ctDNA in plasma samples (n = 1,204), 16 patient-specific somatic single-nucleotide variants were profiled using multiplex-PCR, next-generation sequencing. Results: Detection of ctDNA was a strong recurrence predictor postoperatively [HR = 7.0; 95% confidence interval (CI), 3.7-13.5; P < 0.001] and directly after ACT (HR = 50.76; 95% CI, 15.4-167; P < 0.001). The recurrence rate of postoperative ctDNA-positive patients treated with ACT was 80% (16/20). Only patients who cleared ctDNA permanently during ACT did not relapse. Serial ctDNA assessment after the end of treatment was similarly predictive of recurrence (HR = 50.80; 95% CI, 14.9-172; P<0.001), and revealed two distinct rates of exponential ctDNA growth, slow (25% ctDNA-increase/month) and fast (143% ctDNA-increase/month; P < 0.001). The ctDNA growth rate was prognostic of survival (HR = 2.7; 95% CI, 1.1-6.7; P = 0.039). Serial ctDNA analysis every 3 months detected recurrence with a median lead-time of 9.8 months compared with standard-of-care computed tomography. Conclusions: Serial postoperative ctDNA analysis has a strong prognostic value and enables tumor growth rate assessment. The novel combination of ctDNA detection and growth rate assessment provides unique opportunities for guiding decision-making.
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