Cell-free urine- and plasma DNA mutational analysis predicts neoadjuvant chemotherapy response and outcome in patients with muscle invasive bladder cancer

Emil Christensen; Iver Nordentoft; Karin Birkenkamp-Demtroder; Sara K Elbæk; Sia V Lindskrog; Ann Taber; Tine G Andreasen; Trine Strandgaard; Michael Knudsen; Philippe Lamy; Mads Agerbæk; Jørgen B Jensen; Lars Dyrskjøt

doi:10.1158/1078-0432.CCR-22-3250

Cell-free urine- and plasma DNA mutational analysis predicts neoadjuvant chemotherapy response and outcome in patients with muscle invasive bladder cancer

Emil Christensen, Iver Nordentoft, Karin Birkenkamp-Demtroder, Sara K Elbæk, Sia V Lindskrog, Ann Taber, Tine G Andreasen, Trine Strandgaard, Michael Knudsen, Philippe Lamy, Mads Agerbæk, Jørgen B Jensen, Lars Dyrskjøt^*

^*Corresponding author for this work

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Abstract

Purpose: To investigate the use of plasma and urine DNA mutation analysis for predicting neoadjuvant chemotherapy (NAC) response and oncological outcome in patients with muscle-invasive bladder cancer. Experimental Design: Whole-exome sequencing of tumor and germline DNA was performed for 92 patients treated with NAC followed by radical cystectomy (RC). A custom NGS-panel capturing approximately 50 mutations per patient was designed and used to track mutated tumor DNA in plasma and urine. A total of 447 plasma samples, 281 urine supernatants, and 123 urine pellets collected before, during, and after treatment were analyzed. Patients were enrolled from 2013 to 2019, with a median follow-up time of 41.3 months after RC. Results: We identified tumor DNA before NAC in 89% of urine supernatants, 85% of urine pellets, and 43% of plasma samples. Tumor DNA levels were higher in urine supernatants and urine pellets compared with plasma samples (P < 0.001). In plasma, detection of circulating tumor DNA (ctDNA) before NAC was associated with a lower NAC response rate (P < 0.001). Detection of tumor DNA after NAC was associated with lower response rates in plasma, urine supernatant, and urine pellet (P < 0.001, P ¼ 0.03, P ¼ 0.002). Tumor DNA dynamics during NAC was predictive of NAC response and outcome in urine supernatant and plasma (P ¼ 0.006 and P ¼ 0.002). A combined measure from plasma and urine supernatant tumor DNA dynamics stratified patients by outcome (P ¼ 0.003). Conclusions: Analysis of tumor DNA in plasma and urine samples both separately and combined has a potential to predict treatment response and outcome.

Original language	English
Journal	Clinical Cancer Research
Volume	29
Issue	8
Pages (from-to)	1582–1591
Number of pages	10
ISSN	1078-0432
DOIs	https://doi.org/10.1158/1078-0432.CCR-22-3250
Publication status	Published - 15 Apr 2023

Keywords

Chemotherapy, Adjuvant
Cystectomy
DNA Mutational Analysis
Humans
Muscles/pathology
Neoadjuvant Therapy/adverse effects
Neoplasm Invasiveness/pathology
Retrospective Studies
Urinary Bladder Neoplasms/drug therapy

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Christensen, E., Nordentoft, I., Birkenkamp-Demtroder, K., Elbæk, S. K., Lindskrog, S. V., Taber, A., Andreasen, T. G., Strandgaard, T., Knudsen, M., Lamy, P., Agerbæk, M., Jensen, J. B., & Dyrskjøt, L. (2023). Cell-free urine- and plasma DNA mutational analysis predicts neoadjuvant chemotherapy response and outcome in patients with muscle invasive bladder cancer. Clinical Cancer Research, 29(8), 1582–1591. https://doi.org/10.1158/1078-0432.CCR-22-3250

@article{fbdb49df91c245a598ae1c5ef2305340,

title = "Cell-free urine- and plasma DNA mutational analysis predicts neoadjuvant chemotherapy response and outcome in patients with muscle invasive bladder cancer",

abstract = "Purpose: To investigate the use of plasma and urine DNA mutation analysis for predicting neoadjuvant chemotherapy (NAC) response and oncological outcome in patients with muscle-invasive bladder cancer. Experimental Design: Whole-exome sequencing of tumor and germline DNA was performed for 92 patients treated with NAC followed by radical cystectomy (RC). A custom NGS-panel capturing approximately 50 mutations per patient was designed and used to track mutated tumor DNA in plasma and urine. A total of 447 plasma samples, 281 urine supernatants, and 123 urine pellets collected before, during, and after treatment were analyzed. Patients were enrolled from 2013 to 2019, with a median follow-up time of 41.3 months after RC. Results: We identified tumor DNA before NAC in 89% of urine supernatants, 85% of urine pellets, and 43% of plasma samples. Tumor DNA levels were higher in urine supernatants and urine pellets compared with plasma samples (P < 0.001). In plasma, detection of circulating tumor DNA (ctDNA) before NAC was associated with a lower NAC response rate (P < 0.001). Detection of tumor DNA after NAC was associated with lower response rates in plasma, urine supernatant, and urine pellet (P < 0.001, P ¼ 0.03, P ¼ 0.002). Tumor DNA dynamics during NAC was predictive of NAC response and outcome in urine supernatant and plasma (P ¼ 0.006 and P ¼ 0.002). A combined measure from plasma and urine supernatant tumor DNA dynamics stratified patients by outcome (P ¼ 0.003). Conclusions: Analysis of tumor DNA in plasma and urine samples both separately and combined has a potential to predict treatment response and outcome.",

keywords = "Chemotherapy, Adjuvant, Cystectomy, DNA Mutational Analysis, Humans, Muscles/pathology, Neoadjuvant Therapy/adverse effects, Neoplasm Invasiveness/pathology, Retrospective Studies, Urinary Bladder Neoplasms/drug therapy",

author = "Emil Christensen and Iver Nordentoft and Karin Birkenkamp-Demtroder and Elb{\ae}k, {Sara K} and Lindskrog, {Sia V} and Ann Taber and Andreasen, {Tine G} and Trine Strandgaard and Michael Knudsen and Philippe Lamy and Mads Agerb{\ae}k and Jensen, {J{\o}rgen B} and Lars Dyrskj{\o}t",

year = "2023",

month = apr,

day = "15",

doi = "10.1158/1078-0432.CCR-22-3250",

language = "English",

volume = "29",

pages = "1582–1591",

journal = "Clinical Cancer Research",

issn = "1078-0432",

publisher = "American Association for Cancer Research Inc.",

number = "8",

}

Christensen, E, Nordentoft, I, Birkenkamp-Demtroder, K, Elbæk, SK, Lindskrog, SV, Taber, A, Andreasen, TG , Strandgaard, T , Knudsen, M , Lamy, P, Agerbæk, M, Jensen, JB & Dyrskjøt, L 2023, 'Cell-free urine- and plasma DNA mutational analysis predicts neoadjuvant chemotherapy response and outcome in patients with muscle invasive bladder cancer', Clinical Cancer Research, vol. 29, no. 8, pp. 1582–1591. https://doi.org/10.1158/1078-0432.CCR-22-3250

Cell-free urine- and plasma DNA mutational analysis predicts neoadjuvant chemotherapy response and outcome in patients with muscle invasive bladder cancer. / Christensen, Emil; Nordentoft, Iver; Birkenkamp-Demtroder, Karin et al.
In: Clinical Cancer Research, Vol. 29, No. 8, 15.04.2023, p. 1582–1591.

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

TY - JOUR

T1 - Cell-free urine- and plasma DNA mutational analysis predicts neoadjuvant chemotherapy response and outcome in patients with muscle invasive bladder cancer

AU - Christensen, Emil

AU - Nordentoft, Iver

AU - Birkenkamp-Demtroder, Karin

AU - Elbæk, Sara K

AU - Lindskrog, Sia V

AU - Taber, Ann

AU - Andreasen, Tine G

AU - Strandgaard, Trine

AU - Knudsen, Michael

AU - Lamy, Philippe

AU - Agerbæk, Mads

AU - Jensen, Jørgen B

AU - Dyrskjøt, Lars

PY - 2023/4/15

Y1 - 2023/4/15

N2 - Purpose: To investigate the use of plasma and urine DNA mutation analysis for predicting neoadjuvant chemotherapy (NAC) response and oncological outcome in patients with muscle-invasive bladder cancer. Experimental Design: Whole-exome sequencing of tumor and germline DNA was performed for 92 patients treated with NAC followed by radical cystectomy (RC). A custom NGS-panel capturing approximately 50 mutations per patient was designed and used to track mutated tumor DNA in plasma and urine. A total of 447 plasma samples, 281 urine supernatants, and 123 urine pellets collected before, during, and after treatment were analyzed. Patients were enrolled from 2013 to 2019, with a median follow-up time of 41.3 months after RC. Results: We identified tumor DNA before NAC in 89% of urine supernatants, 85% of urine pellets, and 43% of plasma samples. Tumor DNA levels were higher in urine supernatants and urine pellets compared with plasma samples (P < 0.001). In plasma, detection of circulating tumor DNA (ctDNA) before NAC was associated with a lower NAC response rate (P < 0.001). Detection of tumor DNA after NAC was associated with lower response rates in plasma, urine supernatant, and urine pellet (P < 0.001, P ¼ 0.03, P ¼ 0.002). Tumor DNA dynamics during NAC was predictive of NAC response and outcome in urine supernatant and plasma (P ¼ 0.006 and P ¼ 0.002). A combined measure from plasma and urine supernatant tumor DNA dynamics stratified patients by outcome (P ¼ 0.003). Conclusions: Analysis of tumor DNA in plasma and urine samples both separately and combined has a potential to predict treatment response and outcome.

AB - Purpose: To investigate the use of plasma and urine DNA mutation analysis for predicting neoadjuvant chemotherapy (NAC) response and oncological outcome in patients with muscle-invasive bladder cancer. Experimental Design: Whole-exome sequencing of tumor and germline DNA was performed for 92 patients treated with NAC followed by radical cystectomy (RC). A custom NGS-panel capturing approximately 50 mutations per patient was designed and used to track mutated tumor DNA in plasma and urine. A total of 447 plasma samples, 281 urine supernatants, and 123 urine pellets collected before, during, and after treatment were analyzed. Patients were enrolled from 2013 to 2019, with a median follow-up time of 41.3 months after RC. Results: We identified tumor DNA before NAC in 89% of urine supernatants, 85% of urine pellets, and 43% of plasma samples. Tumor DNA levels were higher in urine supernatants and urine pellets compared with plasma samples (P < 0.001). In plasma, detection of circulating tumor DNA (ctDNA) before NAC was associated with a lower NAC response rate (P < 0.001). Detection of tumor DNA after NAC was associated with lower response rates in plasma, urine supernatant, and urine pellet (P < 0.001, P ¼ 0.03, P ¼ 0.002). Tumor DNA dynamics during NAC was predictive of NAC response and outcome in urine supernatant and plasma (P ¼ 0.006 and P ¼ 0.002). A combined measure from plasma and urine supernatant tumor DNA dynamics stratified patients by outcome (P ¼ 0.003). Conclusions: Analysis of tumor DNA in plasma and urine samples both separately and combined has a potential to predict treatment response and outcome.

KW - Chemotherapy, Adjuvant

KW - Cystectomy

KW - DNA Mutational Analysis

KW - Humans

KW - Muscles/pathology

KW - Neoadjuvant Therapy/adverse effects

KW - Neoplasm Invasiveness/pathology

KW - Retrospective Studies

KW - Urinary Bladder Neoplasms/drug therapy

UR - http://www.scopus.com/inward/record.url?scp=85152599852&partnerID=8YFLogxK

U2 - 10.1158/1078-0432.CCR-22-3250

DO - 10.1158/1078-0432.CCR-22-3250

M3 - Journal article

C2 - 36780195

SN - 1078-0432

VL - 29

SP - 1582

EP - 1591

JO - Clinical Cancer Research

JF - Clinical Cancer Research

IS - 8

ER -

Cell-free urine- and plasma DNA mutational analysis predicts neoadjuvant chemotherapy response and outcome in patients with muscle invasive bladder cancer

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