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Development and Validation of Postoperative Circulating Tumor DNA Combined with Clinicopathological Risk Factors for Recurrence Prediction in Patients with Stages I-III Colorectal Cancer
27 Pages Posted: 20 Sep 2022
More...Abstract
Purpose: To improve recurrence risk prediction by combining circulating tumor DNA (ctDNA) with clinico pathological risk factors in stage I-III colorectal cancer (CRC).
Methods: Two independent cohorts, both consisting of early-stage CRC patients who underwent curative surgery, were included: (i) the discovery cohort (N=124) with tumor tissues and postoperative plasmas for ctDNA determination; and (ii) the external validation cohort (N=125) with available ctDNA results.
Results: In the discovery cohort, 17 of 108 (15.7%) patients had detectable ctDNA. ctDNA-positive patients had a significantly high recurrence rate (76.5% vs. 16.5%, P<0.001) and short recurrence-free survival (RFS; P<0.001) versus ctDNA-negative patients. In addition to ctDNA status, the univariate Cox model identified pathologic stage, lymphovascular invasion, nerve invasion, and preoperative carcinoembryonic antigen level associated with RFS. We combined the ctDNA and clinico pathological risk factors (CTCP) to construct a model for recurrence prediction. A significantly higher recurrence rate (64.7% vs. 8.1%, P<0.001) and worse RFS (P<0.001) were seen in the high-risk patients classified by the CTCP model versus those in the low-risk patients. Receiver operating characteristic analysis demonstrated that the CTCP model outperformed ctDNA alone at recurrence prediction, which increased the sensitivity of 2-year RFS from 49.6% by ctDNA alone to 87.5%. Harrell's concordance index, calibration curve, and decision curve analysis also suggested that the CTCP model had good discrimination, consistency, and clinical utility. These results were reproduced in the validation cohort.
Conclusion: Combining postoperative ctDNA and clinical risk may better predict recurrence than ctDNA alone for developing a personalized postoperative management strategy for CRC.
Funding Information: This work was supported by Capital's Funds for Health Improvement and Research (CFH 2020-1-6041) and the National Natural Science Foundation (82073223).
Declaration of Interests: Hui Chen, Zheping Yuan, Jinping Cai, Shiqing Chen, Xiaochen Zhao, and Yuezong Bai are employees of the 3D Medicines Inc. Other authors declare no potential conflicts of interest.
Ethics Approval Statement: The Ethics Committee of Peking University Shougang Hospital approved the protocols (approval ID: IRBK-2020-045- 01), which complied with the principles of the Declaration of Helsinki.
Keywords: colorectal cancer, circulating tumor DNA, clinicopathological risk factors, recurrence
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