Analysis of Plasma Cell-Free DNA by Ultradeep Sequencing in Patients With Stages I to III Colorectal Cancer

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaperJournal articleResearchpeer-review

  • Thomas Reinert
  • Tenna Vesterman Henriksen
  • Emil Christensen
  • Shruti Sharma, Natera Inc, San Carlos, California.
  • ,
  • Raheleh Salari, Natera Inc, San Carlos, California.
  • ,
  • Himanshu Sethi, Natera Inc, San Carlos, California.
  • ,
  • Michael Knudsen, Department of Molecular Medicine, Aarhus University Hospital, 8000 Aarhus, Denmark.
  • ,
  • Iver Nordentoft
  • Hsin-Ta Wu, Natera Inc, San Carlos, California.
  • ,
  • Antony S Tin, Natera Inc, San Carlos, California.
  • ,
  • Mads Heilskov Rasmussen
  • Søren Vang
  • Svetlana Shchegrova, Natera Inc, San Carlos, California.
  • ,
  • Amanda Frydendahl Boll Johansen
  • Ramya Srinivasan, Natera Inc, San Carlos, California.
  • ,
  • Zoe Assaf, Natera Inc, San Carlos, California.
  • ,
  • Mustafa Balcioglu, Natera Inc, San Carlos, California.
  • ,
  • Alexander Olson, Natera Inc, San Carlos, California.
  • ,
  • Scott Dashner, Natera Inc, San Carlos, California.
  • ,
  • Dina Hafez, Natera Inc, San Carlos, California.
  • ,
  • Samantha Navarro, Natera Inc, San Carlos, California.
  • ,
  • Shruti Goel, Natera Inc, San Carlos, California.
  • ,
  • Matthew Rabinowitz, Natera Inc, San Carlos, California.
  • ,
  • Paul Billings, Natera Inc, San Carlos, California.
  • ,
  • Styrmir Sigurjonsson, Natera Inc, San Carlos, California.
  • ,
  • Lars Dyrskjøt
  • Ryan Swenerton, Natera Inc, San Carlos, California.
  • ,
  • Alexey Aleshin, Natera Inc, San Carlos, California.
  • ,
  • Søren Laurberg
  • Anders Husted Madsen
  • Anne-Sofie Kannerup
  • Katrine Stribolt, Department of Pathology, Randers Regional Hospital, Østervangsvej 48, 8930, Randers NØ, Denmark.
  • ,
  • Søren Palmelund Krag, Department of Pathology, Aarhus University Hospital, University of Aarhus, Aarhus, Denmark.
  • ,
  • Lene H Iversen
  • Kåre Gotschalck Sunesen, Department of Surgery, Randers Hospital, Randers
  • ,
  • Cheng-Ho Jimmy Lin, Natera Inc, San Carlos, California.
  • ,
  • Bernhard G Zimmermann, Natera Inc, San Carlos, California.
  • ,
  • Claus Lindbjerg Andersen

Importance: Novel sensitive methods for detection and monitoring of residual disease can improve postoperative risk stratification with implications for patient selection for adjuvant chemotherapy (ACT), ACT duration, intensity of radiologic surveillance, and, ultimately, outcome for patients with colorectal cancer (CRC).

Objective: To investigate the association of circulating tumor DNA (ctDNA) with recurrence using longitudinal data from ultradeep sequencing of plasma cell-free DNA in patients with CRC before and after surgery, during and after ACT, and during surveillance.

Design, Setting, and Participants: In this prospective, multicenter cohort study, ctDNA was quantified in the preoperative and postoperative settings of stages I to III CRC by personalized multiplex, polymerase chain reaction-based, next-generation sequencing. The study enrolled 130 patients at the surgical departments of Aarhus University Hospital, Randers Hospital, and Herning Hospital in Denmark from May 1, 2014, to January 31, 2017. Plasma samples (n = 829) were collected before surgery, postoperatively at day 30, and every third month for up to 3 years.

Main Outcomes and Measures: Outcomes were ctDNA measurement, clinical recurrence, and recurrence-free survival.

Results: A total of 130 patients with stages I to III CRC (mean [SD] age, 67.9 [10.1] years; 74 [56.9%] male) were enrolled in the study; 5 patients discontinued participation, leaving 125 patients for analysis. Preoperatively, ctDNA was detectable in 84 of 94 patients (89.4%). After definitive treatment, longitudinal ctDNA analysis identified 14 of 16 relapses (87.5%). At postoperative day 30, ctDNA-positive patients were 7 times more likely to relapse than ctDNA-negative patients (hazard ratio [HR], 7.2; 95% CI, 2.7-19.0; P < .001). Similarly, shortly after ACT ctDNA-positive patients were 17 times (HR, 17.5; 95% CI, 5.4-56.5; P < .001) more likely to relapse. All 7 patients who were ctDNA positive after ACT experienced relapse. Monitoring during and after ACT indicated that 3 of the 10 ctDNA-positive patients (30.0%) were cleared by ACT. During surveillance after definitive therapy, ctDNA-positive patients were more than 40 times more likely to experience disease recurrence than ctDNA-negative patients (HR, 43.5; 95% CI, 9.8-193.5 P < .001). In all multivariate analyses, ctDNA status was independently associated with relapse after adjusting for known clinicopathologic risk factors. Serial ctDNA analyses revealed disease recurrence up to 16.5 months ahead of standard-of-care radiologic imaging (mean, 8.7 months; range, 0.8-16.5 months). Actionable mutations were identified in 81.8% of the ctDNA-positive relapse samples.

Conclusions and Relevance: Circulating tumor DNA analysis can potentially change the postoperative management of CRC by enabling risk stratification, ACT monitoring, and early relapse detection.

Original languageEnglish
JournalJAMA Oncology
ISSN2374-2437
DOIs
Publication statusE-pub ahead of print - 9 May 2019
Externally publishedYes

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