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Background <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> Methods <p>Plasma samples for cell-free DNA (cfDNA) analysis were collected from 17 patients undergoing [¹⁷⁷Lu]Lu-PSMA-I&amp;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> Results <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> Conclusion <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> Graphical Abstract <p></p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年4月22日

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

摘要

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