학술논문
Analysis of Plasma Cell-Free DNA by Ultradeep Sequencing in Patients With Stages I to III Colorectal Cancer.
Document Type
Academic Journal
Author
Reinert T; Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark.; Henriksen TV; Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark.; Christensen E; Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark.; Sharma S; Natera Inc, San Carlos, California.; Salari R; Natera Inc, San Carlos, California.; Sethi H; Natera Inc, San Carlos, California.; Knudsen M; Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark.; Nordentoft I; Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark.; Wu HT; Natera Inc, San Carlos, California.; Tin AS; Natera Inc, San Carlos, California.; Heilskov Rasmussen M; Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark.; Vang S; Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark.; Shchegrova S; Natera Inc, San Carlos, California.; Frydendahl Boll Johansen A; Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark.; Srinivasan R; Natera Inc, San Carlos, California.; Assaf Z; Natera Inc, San Carlos, California.; Balcioglu M; Natera Inc, San Carlos, California.; Olson A; Natera Inc, San Carlos, California.; Dashner S; Natera Inc, San Carlos, California.; Hafez D; Natera Inc, San Carlos, California.; Navarro S; Natera Inc, San Carlos, California.; Goel S; Natera Inc, San Carlos, California.; Rabinowitz M; Natera Inc, San Carlos, California.; Billings P; Natera Inc, San Carlos, California.; Sigurjonsson S; Natera Inc, San Carlos, California.; Dyrskjøt L; Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark.; Swenerton R; Natera Inc, San Carlos, California.; Aleshin A; Natera Inc, San Carlos, California.; Laurberg S; Department of Surgery, Aarhus University Hospital, Aarhus, Denmark.; Husted Madsen A; Department of Surgery, Regional Hospital Herning, Herning, Denmark.; Kannerup AS; Department of Surgery, Regional Hospital Randers, Randers, Denmark.; Stribolt K; Department of Pathology, Regional Hospital Randers, Randers, Denmark.; Palmelund Krag S; Department of Pathology, Aarhus University Hospital, Aarhus, Denmark.; Iversen LH; Department of Surgery, Aarhus University Hospital, Aarhus, Denmark.; Gotschalck Sunesen K; Department of Surgery, Regional Hospital Randers, Randers, Denmark.; Lin CJ; Natera Inc, San Carlos, California.; Zimmermann BG; Natera Inc, San Carlos, California.; Lindbjerg Andersen C; Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark.
Source
Publisher: American Medical Association Country of Publication: United States NLM ID: 101652861 Publication Model: Print Cited Medium: Internet ISSN: 2374-2445 (Electronic) Linking ISSN: 23742437 NLM ISO Abbreviation: JAMA Oncol Subsets: PubMed not MEDLINE; MEDLINE
Subject
Language
English
Abstract
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 108 of 122 patients (88.5%). 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.
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 108 of 122 patients (88.5%). 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.