Circulating tumor DNA in stage III colorectal cancer, beyond minimal residual disease detection, towards assessment of adjuvant therapy efficacy and clinical behavior of recurrences: Serial postoperative ctDNA monitoring of CRC recurrence

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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 stage III colorectal cancer patients treated with curative intent at Danish and Spanish hospitals between 2014-2019. To quantify ctDNA in plasma samples (n=1204), 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%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 (27% ctDNA-increase/month) and fast (137% 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 three months detected recurrence with a median lead-time of 9.8 months compared to 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.

Translated title of the contributionCirkulerende tumor DNA i stadie III colorectal cancer, videre end opsporing af minimal residual sygdom, mod evaluering af terapeutisk effekt af adjuverende behandling og klinisk præsentation af tilbagefald: Seriel postoperativ ctDNA monitorering af tilbagefald af tarmkræft
Original languageEnglish
JournalClinical Cancer Research
ISSN1078-0432
DOIs
Publication statusE-pub ahead of print - 8 Oct 2021

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