TY - JOUR
T1 - Circulating Tumor DNA in Stage III Colorectal Cancer, beyond Minimal Residual Disease Detection, toward Assessment of Adjuvant Therapy Efficacy and Clinical Behavior of Recurrences
AU - Henriksen, Tenna Vesterman
AU - Tarazona, Noelia
AU - Frydendahl, Amanda
AU - Reinert, Thomas
AU - Gimeno-Valiente, Francisco
AU - Carbonell-Asins, Juan Antonio
AU - Sharma, Shruti
AU - Renner, Derrick
AU - Hafez, Dina
AU - Roda, Desamparados
AU - Huerta, Marisol
AU - Roselló, Susana
AU - Madsen, Anders Husted
AU - Løve, Uffe S.
AU - Andersen, Per Vadgaard
AU - Thorlacius-Ussing, Ole
AU - Iversen, Lene Hjerrild
AU - Gotschalck, Kåre Andersson
AU - Sethi, Himanshu
AU - Aleshin, Alexey
AU - Cervantes, Andres
AU - Andersen, Claus Lindbjerg
N1 - ©2021 The Authors; Published by the American Association for Cancer Research.
PY - 2022/2
Y1 - 2022/2
N2 - 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 ctDNAanalysis 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.
AB - 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 ctDNAanalysis 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.
UR - http://www.scopus.com/inward/record.url?scp=85123834862&partnerID=8YFLogxK
U2 - 10.1158/1078-0432.CCR-21-2404
DO - 10.1158/1078-0432.CCR-21-2404
M3 - Journal article
C2 - 34625408
SN - 1078-0432
VL - 28
SP - 507
EP - 517
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 3
ER -