La Trobe
1169716_Tie,J_2021.pdf (1.8 MB)

Circulating tumor DNA dynamics and recurrence risk in patients undergoing curative intent resection of colorectal cancer liver metastases: A prospective cohort study

Download (1.8 MB)
journal contribution
posted on 2021-07-06, 03:57 authored by J Tie, Y Wang, J Cohen, L Li, W Hong, M Christie, HL Wong, S Kosmider, R Wong, B Thomson, J Choi, A Fox, K Field, M Burge, J Shannon, D Kotasek, NC Tebbutt, C Karapetis, C Underhill, A Haydon, J Schaeffer, J Ptak, C Tomasetti, N Papadopoulos, KW Kinzler, B Vogelstein, P Gibbs
In patients with resectable colorectal liver metastases (CRLM), the role of pre-and postoperative systemic therapy continues to be debated. Previous studies have shown that circulating tumor DNA (ctDNA) analysis, as a marker of minimal residual disease, is a powerful prognostic factor in patients with nonmetastatic colorectal cancer (CRC). Serial analysis of ctDNA in patients with resectable CRLM could inform the optimal use of perioperative chemotherapy. Here, we performed a validation study to confirm the prognostic impact of postoperative ctDNA in resectable CRLM observed in a previous discovery study. Methods and findings We prospectively collected plasma samples from patients with resectable CRLM, including presurgical and postsurgical samples, serial samples during any pre-or postoperative chemotherapy, and serial samples in follow-up. Via targeted sequencing of 15 genes commonly mutated in CRC, we identified at least 1 somatic mutation in each patient's tumor. We then designed a personalized assay to assess 1 mutation in plasma samples using the Safe-SeqS assay. A total of 380 plasma samples from 54 patients recruited from July 2011 to Dec 2014 were included in our analysis. Twenty-Three (43%) patients received neoadjuvant chemotherapy, and 42 patients (78%) received adjuvant chemotherapy after surgery. Median follow-up was 51 months (interquartile range, 31 to 60 months). At least 1 somatic mutation was identified in all patients' tumor tissue. ctDNA was detectable in 46/54 (85%) patients prior to any treatment and 12/49 (24%) patients after surgery. There was a median 40.93-fold (19.10 to 87.73, P 0.001) decrease in ctDNA mutant allele fraction with neoadjuvant chemotherapy, but ctDNA clearance during neoadjuvant chemotherapy was not associated with a better recurrence-free survival (RFS). Patients with detectable postoperative ctDNA experienced a significantly lower RFS (HR 6.3; 95% CI 2.58 to 15.2; P 0.001) and overall survival (HR 4.2; 95% CI 1.5 to 11.8; P 0.001) compared to patients with undetectable ctDNA. For the 11 patients with detectable postoperative ctDNA who had serial ctDNA sampling during adjuvant chemotherapy, ctDNA clearance was observed in 3 patients, 2 of whom remained disease-free. All 8 patients with persistently detectable ctDNA after adjuvant chemotherapy have recurred. End-of-Treatment (surgery +/? adjuvant chemotherapy) ctDNA detection was associated with a 5-year RFS of 0% compared to 75.6% for patients with an undetectable end-of-Treatment ctDNA (HR 14.9; 95% CI 4.94 to 44.7; P 0.001). Key limitations of the study include the small sample size and the potential for falsepositive findings with multiple hypothesis testing. Conclusions We confirmed the prognostic impact of postsurgery and posttreatment ctDNA in patients with resected CRLM. The potential utility of serial ctDNA analysis during adjuvant chemotherapy as an early marker of treatment efficacy was also demonstrated. Further studies are required to define how to optimally integrate ctDNA analyses into decision-making regarding the use and timing of adjuvant therapy for resectable CRLM.


This work was supported by Victorian Cancer Agency (CRF14007 to JT), the Virginia and D.K. Ludwig Fund for Cancer Research (PG), the National Institutes of Health (P50-CA062924, CA06973, CA176828, and CA210170 to BV) and the John Templeton Foundation (CT). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.


Publication Date



PLoS Medicine





Article Number

ARTN e1003620







Rights Statement

The Author reserves all moral rights over the deposited text and must be credited if any re-use occurs. Documents deposited in OPAL are the Open Access versions of outputs published elsewhere. Changes resulting from the publishing process may therefore not be reflected in this document. The final published version may be obtained via the publisher’s DOI. Please note that additional copyright and access restrictions may apply to the published version.

Usage metrics

    Journal Articles


    No categories selected



    Ref. manager