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Title: Circulating tumor DNA dynamics and recurrence risk in patients undergoing curative intent resection of colorectal cancer liver metastases: A prospective cohort study.
Austin Authors: Tie, Jeanne;Wang, Yuxuan;Cohen, Joshua;Li, Lu;Hong, Wei;Christie, Michael;Wong, Hui Li;Kosmider, Suzanne;Wong, Rachel;Thomson, Benjamin;Choi, Julian;Fox, Adrian;Field, Kathryn;Burge, Matthew;Shannon, Jenny;Kotasek, Dusan;Tebbutt, Niall C ;Karapetis, Christos;Underhill, Craig;Haydon, Andrew;Schaeffer, Joy;Ptak, Janine;Tomasetti, Cristian;Papadopoulos, Nicholas;Kinzler, Kenneth W;Vogelstein, Bert;Gibbs, Peter
Affiliation: Olivia Newton-John Cancer Wellness and Research Centre
Flinders Medical Centre, Flinders University, Adelaide, Australia
Border Medical Oncology, Albury, Australia
The Alfred Hospital, Melbourne, Australia
Eastern Health Clinical School, Faculty of Medicine, Nursing and Health Sciences, Monash University, Melbourne, Australia
Eastern Health, Melbourne, Australia
Royal Melbourne Hospital, Melbourne, Australia
Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins Medicine, Baltimore, Maryland, United States of America
Peter MacCallum Cancer Centre, Melbourne, Australia
Western Health, Melbourne, Australia
The Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia
Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Australia
Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, United States of America
Royal Brisbane and Women's Hospital, Brisbane, Australia
Nepean Cancer Care Centre, Sydney, Australia
Icon Cancer Centre, Adelaide, Australia
Issue Date: 3-May-2021
Date: 2021-05-03
Publication information: PLoS Medicine 2021; 18(5): e1003620
Abstract: 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. 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 false-positive findings with multiple hypothesis testing. 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. ACTRN12612000345886.
DOI: 10.1371/journal.pmed.1003620
ORCID: 0000-0001-9244-2057
Journal: PLoS Medicine
PubMed URL: 33939694
Type: Journal Article
Appears in Collections:Journal articles

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