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

IF 8.6 1区医学 Q1 RADIOLOGY, NUCLEAR MEDICINE & MEDICAL IMAGING

European Journal of Nuclear Medicine and Molecular Imaging Pub Date : 2025-04-22 DOI:10.1007/s00259-025-07280-5

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

{"title":"Genomic instability is associated with response to [¹⁷⁷Lu]Lu-PSMA-I&T radioligand therapy: an exploratory, preliminary liquid biopsy analysis","authors":"Kilian Kluge, David Haberl, Alexander Haug, Lukas Kenner, Gero Kramer, Shahrokh Shariat, Katarina Kumpf, Marcus Hacker","doi":"10.1007/s00259-025-07280-5","DOIUrl":null,"url":null,"abstract":"<h3 data-test=\"abstract-sub-heading\">Background</h3><p>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.</p><h3 data-test=\"abstract-sub-heading\">Methods</h3><p>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.</p><h3 data-test=\"abstract-sub-heading\">Results</h3><p>Non-responders exhibited higher degrees of cfDNA CNV burden (<i>P</i> = 0.048) and higher ctDNA levels (<i>P =</i> 0.036) than responders. Both markers allowed for the differentiation of responses (AUC: 0.792, 0.806) and 1YOS (AUC: 0.778, 0.847).</p><h3 data-test=\"abstract-sub-heading\">Conclusion</h3><p>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.</p><h3 data-test=\"abstract-sub-heading\">Graphical Abstract</h3>","PeriodicalId":11909,"journal":{"name":"European Journal of Nuclear Medicine and Molecular Imaging","volume":"17 1","pages":""},"PeriodicalIF":8.6000,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"European Journal of Nuclear Medicine and Molecular Imaging","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1007/s00259-025-07280-5","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"RADIOLOGY, NUCLEAR MEDICINE & MEDICAL IMAGING","Score":null,"Total":0}

引用次数: 0

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.

Graphical Abstract

查看原文本刊更多论文

基因组不稳定性与[¹⁷⁷Lu]Lu-PSMA-I&T放射性配体疗法的反应有关：一项探索性的初步液体活检分析

PSMA靶向放射配体治疗（PSMA RLT）是转移性去势抵抗性前列腺癌的一种有效且安全的选择，但反应亚型及其生物标志物尚未完全定义。方法收集17例接受[¹⁷Lu]Lu- psma - i &；T治疗的患者的血浆样本进行游离DNA （cfDNA）分析。对CfDNA进行全基因组测序，以建立拷贝数变异（CNV）谱和循环肿瘤DNA （ctDNA）水平，并比较前列腺特异性抗原（PSA）应答组和1年总生存期（1YOS）组之间的差异。结果无应答者的cfDNA CNV负荷程度（P = 0.048）和ctDNA水平（P = 0.036）均高于应答者。这两种标记都允许分化反应（AUC: 0.792, 0.806）和1yo （AUC: 0.778, 0.847）。结论：无反应患者表现出更高水平的cfDNA基因组不稳定性和ctDNA水平，因此，除了靶向方法之外，全基因组CNV谱分析研究更有必要进行机械放射生物学研究，以及它们作为PSMA rlt反应性生物标志物的价值。图形抽象

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文求助全文

来源期刊

European Journal of Nuclear Medicine and Molecular Imaging 医学-核医学

CiteScore

15.60

自引率

9.90%

发文量

392

审稿时长

3 months

期刊介绍： The European Journal of Nuclear Medicine and Molecular Imaging serves as a platform for the exchange of clinical and scientific information within nuclear medicine and related professions. It welcomes international submissions from professionals involved in the functional, metabolic, and molecular investigation of diseases. The journal's coverage spans physics, dosimetry, radiation biology, radiochemistry, and pharmacy, providing high-quality peer review by experts in the field. Known for highly cited and downloaded articles, it ensures global visibility for research work and is part of the EJNMMI journal family.