Whole-genome Mutational Analysis for Tumor-informed Detection of Circulating Tumor DNA in Patients with Urothelial Carcinoma

Iver Nordentoft; Sia Viborg Lindskrog; Karin Birkenkamp-Demtröder; Santiago Gonzalez; Maja Kuzman; Jurica Levatic; Dunja Glavas; Ryan Ptashkin; James Smadbeck; Danielle Afterman; Tomer Lauterman; Yarin Cohen; Zohar Donenhirsh; Iman Tavassoly; Ury Alon; Amanda Frydendahl; Mads Heilskov Rasmussen; Claus Lindbjerg Andersen; Philippe Lamy; Michael Knudsen; Paz Polak; Asaf Zviran; Boris Oklander; Mads Agerbæk; Jørgen Bjerggaard Jensen; Lars Dyrskjøt

doi:10.1016/j.eururo.2024.05.014

Whole-genome Mutational Analysis for Tumor-informed Detection of Circulating Tumor DNA in Patients with Urothelial Carcinoma

Iver Nordentoft^*, Sia Viborg Lindskrog, Karin Birkenkamp-Demtröder, Santiago Gonzalez, Maja Kuzman, Jurica Levatic, Dunja Glavas, Ryan Ptashkin, James Smadbeck, Danielle Afterman, Tomer Lauterman, Yarin Cohen, Zohar Donenhirsh, Iman Tavassoly, Ury Alon, Amanda Frydendahl, Mads Heilskov Rasmussen, Claus Lindbjerg Andersen, Philippe Lamy, Michael KnudsenPaz Polak, Asaf Zviran, Boris Oklander, Mads Agerbæk, Jørgen Bjerggaard Jensen, Lars Dyrskjøt^*

^*Corresponding author af dette arbejde

Publikation: Bidrag til tidsskrift/Konferencebidrag i tidsskrift /Bidrag til avis › Tidsskriftartikel › Forskning › peer review

8 Citationer (Scopus)

Abstract

Background and objective: Circulating tumor DNA (ctDNA) can be used for sensitive detection of minimal residual disease (MRD). However, the probability of detecting ctDNA in settings of low tumor burden is limited by the number of mutations analyzed and the plasma volume available. We used a whole-genome sequencing (WGS) approach for ctDNA detection in patients with urothelial carcinoma. Methods: We used a tumor-informed WGS approach for ctDNA-based detection of MRD and evaluation of treatment responses. We analyzed 916 longitudinally collected plasma samples from 112 patients with localized muscle-invasive bladder cancer who received neoadjuvant chemotherapy (NAC) before radical cystectomy. Recurrence-free survival (primary endpoint), overall survival, and ctDNA dynamics during NAC were assessed. Key findings and limitations: We found that WGS-based ctDNA detection is prognostic for patient outcomes with a median lead time of 131 d over radiographic imaging. WGS-based ctDNA assessment after radical cystectomy identified recurrence with sensitivity of 91% and specificity of 92%. In addition, genomic characterization of post-treatment plasma samples with a high ctDNA level revealed acquisition of platinum therapy–associated mutational signatures and copy number variations not present in the primary tumors. The sequencing depth is a limitation for studying tumor evolution. Conclusions and clinical implications: Our results support the use of WGS for ultrasensitive ctDNA detection and highlight the possibility of plasma-based tracking of tumor evolution. WGS-based ctDNA detection represents a promising option for clinical use owing to the low volume of plasma needed and the ease of performing WGS, eliminating the need for personalized assay design.

Originalsprog	Engelsk
Tidsskrift	European Urology
Vol/bind	86
Nummer	4
Sider (fra-til)	301-311
Antal sider	11
ISSN	1828-6569
DOI	https://doi.org/10.1016/j.eururo.2024.05.014
Status	Udgivet - okt. 2024

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10.1016/j.eururo.2024.05.014Licens: CC BY

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Nordentoft, I., Lindskrog, S. V., Birkenkamp-Demtröder, K., Gonzalez, S., Kuzman, M., Levatic, J., Glavas, D., Ptashkin, R., Smadbeck, J., Afterman, D., Lauterman, T., Cohen, Y., Donenhirsh, Z., Tavassoly, I., Alon, U., Frydendahl, A., Rasmussen, M. H., Andersen, C. L., Lamy, P., ... Dyrskjøt, L. (2024). Whole-genome Mutational Analysis for Tumor-informed Detection of Circulating Tumor DNA in Patients with Urothelial Carcinoma. European Urology, 86(4), 301-311. https://doi.org/10.1016/j.eururo.2024.05.014

@article{f480e6d67a47486fa9ccf6c91883ef41,

title = "Whole-genome Mutational Analysis for Tumor-informed Detection of Circulating Tumor DNA in Patients with Urothelial Carcinoma",

abstract = "Background and objective: Circulating tumor DNA (ctDNA) can be used for sensitive detection of minimal residual disease (MRD). However, the probability of detecting ctDNA in settings of low tumor burden is limited by the number of mutations analyzed and the plasma volume available. We used a whole-genome sequencing (WGS) approach for ctDNA detection in patients with urothelial carcinoma. Methods: We used a tumor-informed WGS approach for ctDNA-based detection of MRD and evaluation of treatment responses. We analyzed 916 longitudinally collected plasma samples from 112 patients with localized muscle-invasive bladder cancer who received neoadjuvant chemotherapy (NAC) before radical cystectomy. Recurrence-free survival (primary endpoint), overall survival, and ctDNA dynamics during NAC were assessed. Key findings and limitations: We found that WGS-based ctDNA detection is prognostic for patient outcomes with a median lead time of 131 d over radiographic imaging. WGS-based ctDNA assessment after radical cystectomy identified recurrence with sensitivity of 91% and specificity of 92%. In addition, genomic characterization of post-treatment plasma samples with a high ctDNA level revealed acquisition of platinum therapy–associated mutational signatures and copy number variations not present in the primary tumors. The sequencing depth is a limitation for studying tumor evolution. Conclusions and clinical implications: Our results support the use of WGS for ultrasensitive ctDNA detection and highlight the possibility of plasma-based tracking of tumor evolution. WGS-based ctDNA detection represents a promising option for clinical use owing to the low volume of plasma needed and the ease of performing WGS, eliminating the need for personalized assay design.",

keywords = "Bladder cancer, Circulating tumor DNA, Liquid biopsies, Muscle-invasive bladder cancer, Tumor evolution, Urothelial carcinoma, Whole-genome sequencing",

author = "Iver Nordentoft and Lindskrog, {Sia Viborg} and Karin Birkenkamp-Demtr{\"o}der and Santiago Gonzalez and Maja Kuzman and Jurica Levatic and Dunja Glavas and Ryan Ptashkin and James Smadbeck and Danielle Afterman and Tomer Lauterman and Yarin Cohen and Zohar Donenhirsh and Iman Tavassoly and Ury Alon and Amanda Frydendahl and Rasmussen, {Mads Heilskov} and Andersen, {Claus Lindbjerg} and Philippe Lamy and Michael Knudsen and Paz Polak and Asaf Zviran and Boris Oklander and Mads Agerb{\ae}k and Jensen, {J{\o}rgen Bjerggaard} and Lars Dyrskj{\o}t",

year = "2024",

month = oct,

doi = "10.1016/j.eururo.2024.05.014",

language = "English",

volume = "86",

pages = "301--311",

journal = "European Urology",

issn = "1828-6569",

publisher = "EdizioniEdra",

number = "4",

}

Nordentoft, I , Lindskrog, SV, Birkenkamp-Demtröder, K, Gonzalez, S, Kuzman, M, Levatic, J, Glavas, D, Ptashkin, R, Smadbeck, J, Afterman, D, Lauterman, T, Cohen, Y, Donenhirsh, Z, Tavassoly, I, Alon, U, Frydendahl, A , Rasmussen, MH , Andersen, CL , Lamy, P , Knudsen, M, Polak, P, Zviran, A, Oklander, B, Agerbæk, M, Jensen, JB & Dyrskjøt, L 2024, 'Whole-genome Mutational Analysis for Tumor-informed Detection of Circulating Tumor DNA in Patients with Urothelial Carcinoma', European Urology, bind 86, nr. 4, s. 301-311. https://doi.org/10.1016/j.eururo.2024.05.014

Whole-genome Mutational Analysis for Tumor-informed Detection of Circulating Tumor DNA in Patients with Urothelial Carcinoma. / Nordentoft, Iver ; Lindskrog, Sia Viborg; Birkenkamp-Demtröder, Karin et al.
I: European Urology, Bind 86, Nr. 4, 10.2024, s. 301-311.

Publikation: Bidrag til tidsskrift/Konferencebidrag i tidsskrift /Bidrag til avis › Tidsskriftartikel › Forskning › peer review

TY - JOUR

T1 - Whole-genome Mutational Analysis for Tumor-informed Detection of Circulating Tumor DNA in Patients with Urothelial Carcinoma

AU - Nordentoft, Iver

AU - Lindskrog, Sia Viborg

AU - Birkenkamp-Demtröder, Karin

AU - Gonzalez, Santiago

AU - Kuzman, Maja

AU - Levatic, Jurica

AU - Glavas, Dunja

AU - Ptashkin, Ryan

AU - Smadbeck, James

AU - Afterman, Danielle

AU - Lauterman, Tomer

AU - Cohen, Yarin

AU - Donenhirsh, Zohar

AU - Tavassoly, Iman

AU - Alon, Ury

AU - Frydendahl, Amanda

AU - Rasmussen, Mads Heilskov

AU - Andersen, Claus Lindbjerg

AU - Lamy, Philippe

AU - Knudsen, Michael

AU - Polak, Paz

AU - Zviran, Asaf

AU - Oklander, Boris

AU - Agerbæk, Mads

AU - Jensen, Jørgen Bjerggaard

AU - Dyrskjøt, Lars

PY - 2024/10

Y1 - 2024/10

N2 - Background and objective: Circulating tumor DNA (ctDNA) can be used for sensitive detection of minimal residual disease (MRD). However, the probability of detecting ctDNA in settings of low tumor burden is limited by the number of mutations analyzed and the plasma volume available. We used a whole-genome sequencing (WGS) approach for ctDNA detection in patients with urothelial carcinoma. Methods: We used a tumor-informed WGS approach for ctDNA-based detection of MRD and evaluation of treatment responses. We analyzed 916 longitudinally collected plasma samples from 112 patients with localized muscle-invasive bladder cancer who received neoadjuvant chemotherapy (NAC) before radical cystectomy. Recurrence-free survival (primary endpoint), overall survival, and ctDNA dynamics during NAC were assessed. Key findings and limitations: We found that WGS-based ctDNA detection is prognostic for patient outcomes with a median lead time of 131 d over radiographic imaging. WGS-based ctDNA assessment after radical cystectomy identified recurrence with sensitivity of 91% and specificity of 92%. In addition, genomic characterization of post-treatment plasma samples with a high ctDNA level revealed acquisition of platinum therapy–associated mutational signatures and copy number variations not present in the primary tumors. The sequencing depth is a limitation for studying tumor evolution. Conclusions and clinical implications: Our results support the use of WGS for ultrasensitive ctDNA detection and highlight the possibility of plasma-based tracking of tumor evolution. WGS-based ctDNA detection represents a promising option for clinical use owing to the low volume of plasma needed and the ease of performing WGS, eliminating the need for personalized assay design.

AB - Background and objective: Circulating tumor DNA (ctDNA) can be used for sensitive detection of minimal residual disease (MRD). However, the probability of detecting ctDNA in settings of low tumor burden is limited by the number of mutations analyzed and the plasma volume available. We used a whole-genome sequencing (WGS) approach for ctDNA detection in patients with urothelial carcinoma. Methods: We used a tumor-informed WGS approach for ctDNA-based detection of MRD and evaluation of treatment responses. We analyzed 916 longitudinally collected plasma samples from 112 patients with localized muscle-invasive bladder cancer who received neoadjuvant chemotherapy (NAC) before radical cystectomy. Recurrence-free survival (primary endpoint), overall survival, and ctDNA dynamics during NAC were assessed. Key findings and limitations: We found that WGS-based ctDNA detection is prognostic for patient outcomes with a median lead time of 131 d over radiographic imaging. WGS-based ctDNA assessment after radical cystectomy identified recurrence with sensitivity of 91% and specificity of 92%. In addition, genomic characterization of post-treatment plasma samples with a high ctDNA level revealed acquisition of platinum therapy–associated mutational signatures and copy number variations not present in the primary tumors. The sequencing depth is a limitation for studying tumor evolution. Conclusions and clinical implications: Our results support the use of WGS for ultrasensitive ctDNA detection and highlight the possibility of plasma-based tracking of tumor evolution. WGS-based ctDNA detection represents a promising option for clinical use owing to the low volume of plasma needed and the ease of performing WGS, eliminating the need for personalized assay design.

KW - Bladder cancer

KW - Circulating tumor DNA

KW - Liquid biopsies

KW - Muscle-invasive bladder cancer

KW - Tumor evolution

KW - Urothelial carcinoma

KW - Whole-genome sequencing

UR - http://www.scopus.com/inward/record.url?scp=85194569973&partnerID=8YFLogxK

U2 - 10.1016/j.eururo.2024.05.014

DO - 10.1016/j.eururo.2024.05.014

M3 - Journal article

C2 - 38811314

SN - 1828-6569

VL - 86

SP - 301

EP - 311

JO - European Urology

JF - European Urology

IS - 4

ER -

Whole-genome Mutational Analysis for Tumor-informed Detection of Circulating Tumor DNA in Patients with Urothelial Carcinoma

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