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

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Analysis of Plasma Cell-Free DNA by Ultradeep Sequencing in Patients With Stages I to III Colorectal Cancer. / Reinert, Thomas; Henriksen, Tenna Vesterman; Christensen, Emil; Sharma, Shruti; Salari, Raheleh; Sethi, Himanshu; Knudsen, Michael; Nordentoft, Iver; Wu, Hsin-Ta; Tin, Antony S; Heilskov Rasmussen, Mads; Vang, Søren; Shchegrova, Svetlana; Frydendahl Boll Johansen, Amanda; Srinivasan, Ramya; Assaf, Zoe; Balcioglu, Mustafa; Olson, Alexander; Dashner, Scott; Hafez, Dina; Navarro, Samantha; Goel, Shruti; Rabinowitz, Matthew; Billings, Paul; Sigurjonsson, Styrmir; Dyrskjøt, Lars; Swenerton, Ryan; Aleshin, Alexey; Laurberg, Søren; Husted Madsen, Anders; Kannerup, Anne-Sofie; Stribolt, Katrine; Palmelund Krag, Søren; Iversen, Lene H; Gotschalck Sunesen, Kåre; Lin, Cheng-Ho Jimmy; Zimmermann, Bernhard G; Lindbjerg Andersen, Claus.

I: JAMA Oncology, Bind 5, Nr. 8, 01.08.2019, s. 1124-1131.

Publikation: Bidrag til tidsskrift/Konferencebidrag i tidsskrift /Bidrag til avisTidsskriftartikelForskningpeer review

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Reinert, T, Henriksen, TV, Christensen, E, Sharma, S, Salari, R, Sethi, H, Knudsen, M, Nordentoft, I, Wu, H-T, Tin, AS, Heilskov Rasmussen, M, Vang, S, Shchegrova, S, Frydendahl Boll Johansen, A, Srinivasan, R, Assaf, Z, Balcioglu, M, Olson, A, Dashner, S, Hafez, D, Navarro, S, Goel, S, Rabinowitz, M, Billings, P, Sigurjonsson, S, Dyrskjøt, L, Swenerton, R, Aleshin, A, Laurberg, S, Husted Madsen, A, Kannerup, A-S, Stribolt, K, Palmelund Krag, S, Iversen, LH, Gotschalck Sunesen, K, Lin, C-HJ, Zimmermann, BG & Lindbjerg Andersen, C 2019, 'Analysis of Plasma Cell-Free DNA by Ultradeep Sequencing in Patients With Stages I to III Colorectal Cancer', JAMA Oncology, bind 5, nr. 8, s. 1124-1131. https://doi.org/10.1001/jamaoncol.2019.0528

APA

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Reinert T, Henriksen TV, Christensen E, Sharma S, Salari R, Sethi H, Knudsen M, Nordentoft I, Wu H-T, Tin AS, Heilskov Rasmussen M, Vang S, Shchegrova S, Frydendahl Boll Johansen A, Srinivasan R, Assaf Z, Balcioglu M, Olson A, Dashner S, Hafez D, Navarro S, Goel S, Rabinowitz M, Billings P, Sigurjonsson S, Dyrskjøt L, Swenerton R, Aleshin A, Laurberg S, Husted Madsen A, Kannerup A-S, Stribolt K, Palmelund Krag S, Iversen LH, Gotschalck Sunesen K, Lin C-HJ, Zimmermann BG, Lindbjerg Andersen C. 2019. Analysis of Plasma Cell-Free DNA by Ultradeep Sequencing in Patients With Stages I to III Colorectal Cancer. JAMA Oncology. 5(8):1124-1131. https://doi.org/10.1001/jamaoncol.2019.0528

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Author

Reinert, Thomas ; Henriksen, Tenna Vesterman ; Christensen, Emil ; Sharma, Shruti ; Salari, Raheleh ; Sethi, Himanshu ; Knudsen, Michael ; Nordentoft, Iver ; Wu, Hsin-Ta ; Tin, Antony S ; Heilskov Rasmussen, Mads ; Vang, Søren ; Shchegrova, Svetlana ; Frydendahl Boll Johansen, Amanda ; Srinivasan, Ramya ; Assaf, Zoe ; Balcioglu, Mustafa ; Olson, Alexander ; Dashner, Scott ; Hafez, Dina ; Navarro, Samantha ; Goel, Shruti ; Rabinowitz, Matthew ; Billings, Paul ; Sigurjonsson, Styrmir ; Dyrskjøt, Lars ; Swenerton, Ryan ; Aleshin, Alexey ; Laurberg, Søren ; Husted Madsen, Anders ; Kannerup, Anne-Sofie ; Stribolt, Katrine ; Palmelund Krag, Søren ; Iversen, Lene H ; Gotschalck Sunesen, Kåre ; Lin, Cheng-Ho Jimmy ; Zimmermann, Bernhard G ; Lindbjerg Andersen, Claus. / Analysis of Plasma Cell-Free DNA by Ultradeep Sequencing in Patients With Stages I to III Colorectal Cancer. I: JAMA Oncology. 2019 ; Bind 5, Nr. 8. s. 1124-1131.

Bibtex

@article{61388ffafcf74e48962b06f335d2c982,
title = "Analysis of Plasma Cell-Free DNA by Ultradeep Sequencing in Patients With Stages I to III Colorectal Cancer",
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..",
keywords = "ADJUVANT CHEMOTHERAPY, COLON-CANCER, FLUOROURACIL, RECURRENCE, RISK, SURGERY, SURVEILLANCE, SURVIVAL",
author = "Thomas Reinert and Henriksen, {Tenna Vesterman} and Emil Christensen and Shruti Sharma and Raheleh Salari and Himanshu Sethi and Michael Knudsen and Iver Nordentoft and Hsin-Ta Wu and Tin, {Antony S} and {Heilskov Rasmussen}, Mads and S{\o}ren Vang and Svetlana Shchegrova and {Frydendahl Boll Johansen}, Amanda and Ramya Srinivasan and Zoe Assaf and Mustafa Balcioglu and Alexander Olson and Scott Dashner and Dina Hafez and Samantha Navarro and Shruti Goel and Matthew Rabinowitz and Paul Billings and Styrmir Sigurjonsson and Lars Dyrskj{\o}t and Ryan Swenerton and Alexey Aleshin and S{\o}ren Laurberg and {Husted Madsen}, Anders and Anne-Sofie Kannerup and Katrine Stribolt and {Palmelund Krag}, S{\o}ren and Iversen, {Lene H} and {Gotschalck Sunesen}, K{\aa}re and Lin, {Cheng-Ho Jimmy} and Zimmermann, {Bernhard G} and {Lindbjerg Andersen}, Claus",
year = "2019",
month = aug,
day = "1",
doi = "10.1001/jamaoncol.2019.0528",
language = "English",
volume = "5",
pages = "1124--1131",
journal = "JAMA Oncology",
issn = "2374-2437",
publisher = "American Medical Association",
number = "8",

}

RIS

TY - JOUR

T1 - Analysis of Plasma Cell-Free DNA by Ultradeep Sequencing in Patients With Stages I to III Colorectal Cancer

AU - Reinert, Thomas

AU - Henriksen, Tenna Vesterman

AU - Christensen, Emil

AU - Sharma, Shruti

AU - Salari, Raheleh

AU - Sethi, Himanshu

AU - Knudsen, Michael

AU - Nordentoft, Iver

AU - Wu, Hsin-Ta

AU - Tin, Antony S

AU - Heilskov Rasmussen, Mads

AU - Vang, Søren

AU - Shchegrova, Svetlana

AU - Frydendahl Boll Johansen, Amanda

AU - Srinivasan, Ramya

AU - Assaf, Zoe

AU - Balcioglu, Mustafa

AU - Olson, Alexander

AU - Dashner, Scott

AU - Hafez, Dina

AU - Navarro, Samantha

AU - Goel, Shruti

AU - Rabinowitz, Matthew

AU - Billings, Paul

AU - Sigurjonsson, Styrmir

AU - Dyrskjøt, Lars

AU - Swenerton, Ryan

AU - Aleshin, Alexey

AU - Laurberg, Søren

AU - Husted Madsen, Anders

AU - Kannerup, Anne-Sofie

AU - Stribolt, Katrine

AU - Palmelund Krag, Søren

AU - Iversen, Lene H

AU - Gotschalck Sunesen, Kåre

AU - Lin, Cheng-Ho Jimmy

AU - Zimmermann, Bernhard G

AU - Lindbjerg Andersen, Claus

PY - 2019/8/1

Y1 - 2019/8/1

N2 - 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..

AB - 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..

KW - ADJUVANT CHEMOTHERAPY

KW - COLON-CANCER

KW - FLUOROURACIL

KW - RECURRENCE

KW - RISK

KW - SURGERY

KW - SURVEILLANCE

KW - SURVIVAL

U2 - 10.1001/jamaoncol.2019.0528

DO - 10.1001/jamaoncol.2019.0528

M3 - Journal article

C2 - 31070691

VL - 5

SP - 1124

EP - 1131

JO - JAMA Oncology

JF - JAMA Oncology

SN - 2374-2437

IS - 8

ER -