Genomic instability is associated with response to [¹⁷⁷Lu]Lu-PSMA-I&T radioligand therapy: an exploratory, preliminary liquid biopsy analysis

Kilian Kluge; David Haberl; Alexander Haug; Lukas Kenner; Gero Kramer; Shahrokh Shariat; Katarina Kumpf; Marcus Hacker

doi:10.1007/s00259-025-07280-5

Genomic instability is associated with response to [¹⁷⁷Lu]Lu-PSMA-I&T radioligand therapy: an exploratory, preliminary liquid biopsy analysis

Kilian Kluge, David Haberl, Alexander Haug, Lukas Kenner, Gero Kramer, Shahrokh Shariat, Katarina Kumpf, Marcus Hacker

Division of Urology (University Hospital Krems)

Research output: Journal article (peer-reviewed) › Letter/short communication

1 Citation (Scopus)

Abstract

BACKGROUND: PSMA-targeted radioligand therapies (PSMA RLT) are an effective and safe option for metastatic castration-resistant prostate cancer, but responsive subtypes and their biomarkers are not fully defined.

METHODS: Plasma samples for cell-free DNA (cfDNA) analysis were collected from 17 patients undergoing [¹⁷⁷Lu]Lu-PSMA-I&T. CfDNA underwent whole-genome sequencing to establish copy number variation (CNV) profiles and circulating-tumor DNA (ctDNA) levels and compared between prostate-specific antigen (PSA) response- and 1-year overall survival (1YOS) groups.

RESULTS: Non-responders exhibited higher degrees of cfDNA CNV burden (P = 0.048) and higher ctDNA levels (P = 0.036) than responders. Both markers allowed for the differentiation of responses (AUC: 0.792, 0.806) and 1YOS (AUC: 0.778, 0.847).

CONCLUSION: Unresponsive patients exhibited higher levels of cfDNA genomic instability and ctDNA levels, warranting genome-wide CNV profiling studies next to targeted approaches for mechanistic radiobiological insights and their value as response biomarkers for PSMA RLTs.

Original language	English
Pages (from-to)	4151-4156
Number of pages	6
Journal	European Journal of Nuclear Medicine and Molecular Imaging
Volume	52
Issue number	11
Early online date	22 Apr 2025
DOIs	https://doi.org/10.1007/s00259-025-07280-5
Publication status	Published - Sept 2025

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Kluge, K., Haberl, D., Haug, A., Kenner, L., Kramer, G., Shariat, S., Kumpf, K., & Hacker, M. (2025). Genomic instability is associated with response to [¹⁷⁷Lu]Lu-PSMA-I&T radioligand therapy: an exploratory, preliminary liquid biopsy analysis. European Journal of Nuclear Medicine and Molecular Imaging, 52(11), 4151-4156. https://doi.org/10.1007/s00259-025-07280-5

@article{a0a4180197ba4dab9d30e60b896f847b,

title = "Genomic instability is associated with response to [¹⁷⁷Lu]Lu-PSMA-I\&T radioligand therapy: an exploratory, preliminary liquid biopsy analysis",

abstract = "BACKGROUND: PSMA-targeted radioligand therapies (PSMA RLT) are an effective and safe option for metastatic castration-resistant prostate cancer, but responsive subtypes and their biomarkers are not fully defined.METHODS: Plasma samples for cell-free DNA (cfDNA) analysis were collected from 17 patients undergoing [¹⁷⁷Lu]Lu-PSMA-I\&T. CfDNA underwent whole-genome sequencing to establish copy number variation (CNV) profiles and circulating-tumor DNA (ctDNA) levels and compared between prostate-specific antigen (PSA) response- and 1-year overall survival (1YOS) groups.RESULTS: Non-responders exhibited higher degrees of cfDNA CNV burden (P = 0.048) and higher ctDNA levels (P = 0.036) than responders. Both markers allowed for the differentiation of responses (AUC: 0.792, 0.806) and 1YOS (AUC: 0.778, 0.847).CONCLUSION: Unresponsive patients exhibited higher levels of cfDNA genomic instability and ctDNA levels, warranting genome-wide CNV profiling studies next to targeted approaches for mechanistic radiobiological insights and their value as response biomarkers for PSMA RLTs.",

author = "Kilian Kluge and David Haberl and Alexander Haug and Lukas Kenner and Gero Kramer and Shahrokh Shariat and Katarina Kumpf and Marcus Hacker",

note = "Publisher Copyright: {\textcopyright} The Author(s) 2025.",

year = "2025",

month = sep,

doi = "10.1007/s00259-025-07280-5",

language = "English",

volume = "52",

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Kluge, K, Haberl, D, Haug, A, Kenner, L, Kramer, G, Shariat, S, Kumpf, K & Hacker, M 2025, 'Genomic instability is associated with response to [¹⁷⁷Lu]Lu-PSMA-I&T radioligand therapy: an exploratory, preliminary liquid biopsy analysis', European Journal of Nuclear Medicine and Molecular Imaging, vol. 52, no. 11, pp. 4151-4156. https://doi.org/10.1007/s00259-025-07280-5

Genomic instability is associated with response to [¹⁷⁷Lu]Lu-PSMA-I&T radioligand therapy: an exploratory, preliminary liquid biopsy analysis. / Kluge, Kilian; Haberl, David; Haug, Alexander et al.
In: European Journal of Nuclear Medicine and Molecular Imaging, Vol. 52, No. 11, 09.2025, p. 4151-4156.

Research output: Journal article (peer-reviewed) › Letter/short communication

TY - JOUR

T1 - Genomic instability is associated with response to [¹⁷⁷Lu]Lu-PSMA-I&T radioligand therapy

T2 - an exploratory, preliminary liquid biopsy analysis

AU - Kluge, Kilian

AU - Haberl, David

AU - Haug, Alexander

AU - Kenner, Lukas

AU - Kramer, Gero

AU - Shariat, Shahrokh

AU - Kumpf, Katarina

AU - Hacker, Marcus

PY - 2025/9

Y1 - 2025/9

N2 - BACKGROUND: PSMA-targeted radioligand therapies (PSMA RLT) are an effective and safe option for metastatic castration-resistant prostate cancer, but responsive subtypes and their biomarkers are not fully defined.METHODS: Plasma samples for cell-free DNA (cfDNA) analysis were collected from 17 patients undergoing [¹⁷⁷Lu]Lu-PSMA-I&T. CfDNA underwent whole-genome sequencing to establish copy number variation (CNV) profiles and circulating-tumor DNA (ctDNA) levels and compared between prostate-specific antigen (PSA) response- and 1-year overall survival (1YOS) groups.RESULTS: Non-responders exhibited higher degrees of cfDNA CNV burden (P = 0.048) and higher ctDNA levels (P = 0.036) than responders. Both markers allowed for the differentiation of responses (AUC: 0.792, 0.806) and 1YOS (AUC: 0.778, 0.847).CONCLUSION: Unresponsive patients exhibited higher levels of cfDNA genomic instability and ctDNA levels, warranting genome-wide CNV profiling studies next to targeted approaches for mechanistic radiobiological insights and their value as response biomarkers for PSMA RLTs.

AB - BACKGROUND: PSMA-targeted radioligand therapies (PSMA RLT) are an effective and safe option for metastatic castration-resistant prostate cancer, but responsive subtypes and their biomarkers are not fully defined.METHODS: Plasma samples for cell-free DNA (cfDNA) analysis were collected from 17 patients undergoing [¹⁷⁷Lu]Lu-PSMA-I&T. CfDNA underwent whole-genome sequencing to establish copy number variation (CNV) profiles and circulating-tumor DNA (ctDNA) levels and compared between prostate-specific antigen (PSA) response- and 1-year overall survival (1YOS) groups.RESULTS: Non-responders exhibited higher degrees of cfDNA CNV burden (P = 0.048) and higher ctDNA levels (P = 0.036) than responders. Both markers allowed for the differentiation of responses (AUC: 0.792, 0.806) and 1YOS (AUC: 0.778, 0.847).CONCLUSION: Unresponsive patients exhibited higher levels of cfDNA genomic instability and ctDNA levels, warranting genome-wide CNV profiling studies next to targeted approaches for mechanistic radiobiological insights and their value as response biomarkers for PSMA RLTs.

UR - https://www.scopus.com/pages/publications/105003304948

U2 - 10.1007/s00259-025-07280-5

DO - 10.1007/s00259-025-07280-5

M3 - Letter/short communication

C2 - 40261406

SN - 1619-7070

VL - 52

SP - 4151

EP - 4156

JO - European Journal of Nuclear Medicine and Molecular Imaging

JF - European Journal of Nuclear Medicine and Molecular Imaging

IS - 11

ER -

Genomic instability is associated with response to [¹⁷⁷Lu]Lu-PSMA-I&T radioligand therapy: an exploratory, preliminary liquid biopsy analysis

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