PLoS Medicine (May 2021)

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

  • Jeanne Tie,
  • Yuxuan Wang,
  • Joshua Cohen,
  • Lu Li,
  • Wei Hong,
  • Michael Christie,
  • Hui Li Wong,
  • Suzanne Kosmider,
  • Rachel Wong,
  • Benjamin Thomson,
  • Julian Choi,
  • Adrian Fox,
  • Kathryn Field,
  • Matthew Burge,
  • Jenny Shannon,
  • Dusan Kotasek,
  • Niall C Tebbutt,
  • Christos Karapetis,
  • Craig Underhill,
  • Andrew Haydon,
  • Joy Schaeffer,
  • Janine Ptak,
  • Cristian Tomasetti,
  • Nicholas Papadopoulos,
  • Kenneth W Kinzler,
  • Bert Vogelstein,
  • Peter Gibbs

DOI
https://doi.org/10.1371/journal.pmed.1003620
Journal volume & issue
Vol. 18, no. 5
p. e1003620

Abstract

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BackgroundIn 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 findingsWe 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 ConclusionsWe 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.Trial registrationACTRN12612000345886.