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

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
Journal	European Journal of Nuclear Medicine and Molecular Imaging
DOIs	https://doi.org/10.1007/s00259-025-07280-5
Publication status	E-pub ahead of print - 22 Apr 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. Advance online publication. https://doi.org/10.1007/s00259-025-07280-5

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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 = apr,

day = "22",

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

language = "English",

journal = "European Journal of Nuclear Medicine and Molecular Imaging",

issn = "1619-7070",

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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 - 2025/4/22

Y1 - 2025/4/22

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.

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U2 - 10.1007/s00259-025-07280-5

DO - 10.1007/s00259-025-07280-5

M3 - Letter/short communication

C2 - 40261406

SN - 1619-7070

JO - European Journal of Nuclear Medicine and Molecular Imaging

JF - European Journal of Nuclear Medicine and Molecular Imaging

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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