Circulating Tumor DNA Analysis in Advanced Urothelial Carcinoma: Insights from Biological Analysis and Extended Clinical Follow-up

Sia Viborg Lindskrog; Karin Birkenkamp-Demtröder; Iver Kristiansen Nordentoft; George  Laliotis; Philippe Lamy; Emil Christensen; Derrick Renner; Tine Ginnerup Andreasen; Naja Lange; Shruti Sharma; Adam C. ElNaggar; Minetta C. Liu; Himanshu Sethi; Alexey Aleshin; Mads Agerbæk; Jørgen Bjerggaard Jensen; Lars Dyrskjøt

doi:10.1158/1078-0432.CCR-23-1860

Circulating Tumor DNA Analysis in Advanced Urothelial Carcinoma: Insights from Biological Analysis and Extended Clinical Follow-up

Sia Viborg Lindskrog, Karin Birkenkamp-Demtröder, Iver Kristiansen Nordentoft, George Laliotis, Philippe Lamy, Emil Christensen, Derrick Renner, Tine Ginnerup Andreasen, Naja Lange, Shruti Sharma, Adam C. ElNaggar, Minetta C. Liu, Himanshu Sethi, Alexey Aleshin, Mads Agerbæk, Jørgen Bjerggaard Jensen, Lars Dyrskjøt^*

^*Corresponding author for this work

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

22 Citations (Scopus)

13 Downloads (Pure)

Abstract

Purpose: To investigate whether circulating tumor DNA (ctDNA) assessment in patients with muscle-invasive bladder cancer predicts treatment response and provides early detection of metastatic disease. Experimental Design: We present full follow-up results (median follow-up: 68 months) from a previously described cohort of 68 neoadjuvant chemotherapy (NAC)-treated patients who underwent longitudinal ctDNA testing (712 plasma samples). In addition, we performed ctDNA evaluation of 153 plasma samples collected before and after radical cystectomy (RC) in a separate cohort of 102 NAC-naïve patients (median follow-up: 72 months). Total RNA sequencing of tumors was performed to investigate biological characteristics of ctDNA shedding tumors. Results: Assessment of ctDNA after RC identified metastatic relapse with a sensitivity of 94% and specificity of 98% using the expanded follow-up data for the NAC-treated patients. ctDNA dynamics during NAC was independently associated with patient outcomes when adjusted for pathologic downstaging (HR = 4.7; P = 0.029). For the NAC-naïve patients, ctDNA was a prognostic predictor before (HR = 3.4; P = 0.0005) and after RC (HR = 17.8; P=0.0002). No statistically significant difference in recurrence-free survival for patients without detectable ctDNA at diagnosis was observed between the cohorts. Baseline ctDNA positivity was associated with the Basal/Squamous (Ba/Sq) subtype and enrichment of epithelial-to-mesenchymal transition and cell cycle-associated gene sets. Conclusions: ctDNA is prognostic in NAC-treated and NACnaïve patients with more than 5 years follow-up and outperforms pathologic downstaging in predicting treatment efficacy. Patients without detectable ctDNA at diagnosis may benefit significantly less from NAC, but additional studies are needed.

Original language	English
Journal	Clinical Cancer Research
Volume	29
Issue	23
Pages (from-to)	4797-4807
Number of pages	11
ISSN	1078-0432
DOIs	https://doi.org/10.1158/1078-0432.CCR-23-1860
Publication status	Published - Dec 2023

Access to Document

10.1158/1078-0432.CCR-23-1860Licence: CC BY-NC-ND

4797Final published version, 574 KBLicence: CC BY-NC-ND

Cite this

Lindskrog, S. V., Birkenkamp-Demtröder, K., Nordentoft, I. K., Laliotis, G., Lamy, P., Christensen, E., Renner, D., Andreasen, T. G., Lange, N., Sharma, S., ElNaggar, A. C., Liu, M. C., Sethi, H., Aleshin, A., Agerbæk, M., Jensen, J. B., & Dyrskjøt, L. (2023). Circulating Tumor DNA Analysis in Advanced Urothelial Carcinoma: Insights from Biological Analysis and Extended Clinical Follow-up. Clinical Cancer Research, 29(23), 4797-4807. https://doi.org/10.1158/1078-0432.CCR-23-1860

@article{d351ea2bc961421c868fd55c8493aff3,

title = "Circulating Tumor DNA Analysis in Advanced Urothelial Carcinoma: Insights from Biological Analysis and Extended Clinical Follow-up",

abstract = "Purpose: To investigate whether circulating tumor DNA (ctDNA) assessment in patients with muscle-invasive bladder cancer predicts treatment response and provides early detection of metastatic disease. Experimental Design: We present full follow-up results (median follow-up: 68 months) from a previously described cohort of 68 neoadjuvant chemotherapy (NAC)-treated patients who underwent longitudinal ctDNA testing (712 plasma samples). In addition, we performed ctDNA evaluation of 153 plasma samples collected before and after radical cystectomy (RC) in a separate cohort of 102 NAC-na{\"i}ve patients (median follow-up: 72 months). Total RNA sequencing of tumors was performed to investigate biological characteristics of ctDNA shedding tumors. Results: Assessment of ctDNA after RC identified metastatic relapse with a sensitivity of 94% and specificity of 98% using the expanded follow-up data for the NAC-treated patients. ctDNA dynamics during NAC was independently associated with patient outcomes when adjusted for pathologic downstaging (HR = 4.7; P = 0.029). For the NAC-na{\"i}ve patients, ctDNA was a prognostic predictor before (HR = 3.4; P = 0.0005) and after RC (HR = 17.8; P=0.0002). No statistically significant difference in recurrence-free survival for patients without detectable ctDNA at diagnosis was observed between the cohorts. Baseline ctDNA positivity was associated with the Basal/Squamous (Ba/Sq) subtype and enrichment of epithelial-to-mesenchymal transition and cell cycle-associated gene sets. Conclusions: ctDNA is prognostic in NAC-treated and NACna{\"i}ve patients with more than 5 years follow-up and outperforms pathologic downstaging in predicting treatment efficacy. Patients without detectable ctDNA at diagnosis may benefit significantly less from NAC, but additional studies are needed.",

author = "Lindskrog, {Sia Viborg} and Karin Birkenkamp-Demtr{\"o}der and Nordentoft, {Iver Kristiansen} and George Laliotis and Philippe Lamy and Emil Christensen and Derrick Renner and Andreasen, {Tine Ginnerup} and Naja Lange and Shruti Sharma and ElNaggar, {Adam C.} and Liu, {Minetta C.} and Himanshu Sethi and Alexey Aleshin and Mads Agerb{\ae}k and Jensen, {J{\o}rgen Bjerggaard} and Lars Dyrskj{\o}t",

year = "2023",

month = dec,

doi = "10.1158/1078-0432.CCR-23-1860",

language = "English",

volume = "29",

pages = "4797--4807",

journal = "Clinical Cancer Research",

issn = "1078-0432",

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

number = "23",

}

Lindskrog, SV, Birkenkamp-Demtröder, K, Nordentoft, IK, Laliotis, G, Lamy, P, Christensen, E, Renner, D, Andreasen, TG , Lange, N, Sharma, S, ElNaggar, AC, Liu, MC, Sethi, H, Aleshin, A, Agerbæk, M, Jensen, JB & Dyrskjøt, L 2023, 'Circulating Tumor DNA Analysis in Advanced Urothelial Carcinoma: Insights from Biological Analysis and Extended Clinical Follow-up', Clinical Cancer Research, vol. 29, no. 23, pp. 4797-4807. https://doi.org/10.1158/1078-0432.CCR-23-1860

Circulating Tumor DNA Analysis in Advanced Urothelial Carcinoma: Insights from Biological Analysis and Extended Clinical Follow-up. / Lindskrog, Sia Viborg; Birkenkamp-Demtröder, Karin; Nordentoft, Iver Kristiansen et al.
In: Clinical Cancer Research, Vol. 29, No. 23, 12.2023, p. 4797-4807.

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

TY - JOUR

T1 - Circulating Tumor DNA Analysis in Advanced Urothelial Carcinoma: Insights from Biological Analysis and Extended Clinical Follow-up

AU - Lindskrog, Sia Viborg

AU - Birkenkamp-Demtröder, Karin

AU - Nordentoft, Iver Kristiansen

AU - Laliotis, George

AU - Lamy, Philippe

AU - Christensen, Emil

AU - Renner, Derrick

AU - Andreasen, Tine Ginnerup

AU - Lange, Naja

AU - Sharma, Shruti

AU - ElNaggar, Adam C.

AU - Liu, Minetta C.

AU - Sethi, Himanshu

AU - Aleshin, Alexey

AU - Agerbæk, Mads

AU - Jensen, Jørgen Bjerggaard

AU - Dyrskjøt, Lars

PY - 2023/12

Y1 - 2023/12

N2 - Purpose: To investigate whether circulating tumor DNA (ctDNA) assessment in patients with muscle-invasive bladder cancer predicts treatment response and provides early detection of metastatic disease. Experimental Design: We present full follow-up results (median follow-up: 68 months) from a previously described cohort of 68 neoadjuvant chemotherapy (NAC)-treated patients who underwent longitudinal ctDNA testing (712 plasma samples). In addition, we performed ctDNA evaluation of 153 plasma samples collected before and after radical cystectomy (RC) in a separate cohort of 102 NAC-naïve patients (median follow-up: 72 months). Total RNA sequencing of tumors was performed to investigate biological characteristics of ctDNA shedding tumors. Results: Assessment of ctDNA after RC identified metastatic relapse with a sensitivity of 94% and specificity of 98% using the expanded follow-up data for the NAC-treated patients. ctDNA dynamics during NAC was independently associated with patient outcomes when adjusted for pathologic downstaging (HR = 4.7; P = 0.029). For the NAC-naïve patients, ctDNA was a prognostic predictor before (HR = 3.4; P = 0.0005) and after RC (HR = 17.8; P=0.0002). No statistically significant difference in recurrence-free survival for patients without detectable ctDNA at diagnosis was observed between the cohorts. Baseline ctDNA positivity was associated with the Basal/Squamous (Ba/Sq) subtype and enrichment of epithelial-to-mesenchymal transition and cell cycle-associated gene sets. Conclusions: ctDNA is prognostic in NAC-treated and NACnaïve patients with more than 5 years follow-up and outperforms pathologic downstaging in predicting treatment efficacy. Patients without detectable ctDNA at diagnosis may benefit significantly less from NAC, but additional studies are needed.

AB - Purpose: To investigate whether circulating tumor DNA (ctDNA) assessment in patients with muscle-invasive bladder cancer predicts treatment response and provides early detection of metastatic disease. Experimental Design: We present full follow-up results (median follow-up: 68 months) from a previously described cohort of 68 neoadjuvant chemotherapy (NAC)-treated patients who underwent longitudinal ctDNA testing (712 plasma samples). In addition, we performed ctDNA evaluation of 153 plasma samples collected before and after radical cystectomy (RC) in a separate cohort of 102 NAC-naïve patients (median follow-up: 72 months). Total RNA sequencing of tumors was performed to investigate biological characteristics of ctDNA shedding tumors. Results: Assessment of ctDNA after RC identified metastatic relapse with a sensitivity of 94% and specificity of 98% using the expanded follow-up data for the NAC-treated patients. ctDNA dynamics during NAC was independently associated with patient outcomes when adjusted for pathologic downstaging (HR = 4.7; P = 0.029). For the NAC-naïve patients, ctDNA was a prognostic predictor before (HR = 3.4; P = 0.0005) and after RC (HR = 17.8; P=0.0002). No statistically significant difference in recurrence-free survival for patients without detectable ctDNA at diagnosis was observed between the cohorts. Baseline ctDNA positivity was associated with the Basal/Squamous (Ba/Sq) subtype and enrichment of epithelial-to-mesenchymal transition and cell cycle-associated gene sets. Conclusions: ctDNA is prognostic in NAC-treated and NACnaïve patients with more than 5 years follow-up and outperforms pathologic downstaging in predicting treatment efficacy. Patients without detectable ctDNA at diagnosis may benefit significantly less from NAC, but additional studies are needed.

UR - http://www.scopus.com/inward/record.url?scp=85178519669&partnerID=8YFLogxK

U2 - 10.1158/1078-0432.CCR-23-1860

DO - 10.1158/1078-0432.CCR-23-1860

M3 - Journal article

C2 - 37782315

SN - 1078-0432

VL - 29

SP - 4797

EP - 4807

JO - Clinical Cancer Research

JF - Clinical Cancer Research

IS - 23

ER -

Circulating Tumor DNA Analysis in Advanced Urothelial Carcinoma: Insights from Biological Analysis and Extended Clinical Follow-up

Abstract

Access to Document

Other files and links

Fingerprint

Cite this