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Patients resistant against PSMA-targeting α-radiation therapy often harbor mutations in DNA damage-repair-associated genes

Prostate-specific membrane antigen (PSMA)-targeting α-radiation therapy (TAT) is an emerging treatment modality for metastatic castration-resistant prostate cancer. There is a subgroup of patients with poor response despite sufficient expression of PSMA in their tumors. The aim of this work was to c...

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Main Authors: Kratochwil, Clemens (Author) , Giesel, Frederik L. (Author) , Heußel, Claus Peter (Author) , Kazdal, Daniel (Author) , Endris, Volker (Author) , Nientiedt, Cathleen (Author) , Bruchertseifer, Frank (Author) , Kippenberger, Maximilian (Author) , Rathke, Hendrik (Author) , Leichsenring, Jonas (Author) , Hohenfellner, Markus (Author) , Morgenstern, Alfred (Author) , Haberkorn, Uwe (Author) , Duensing, Stefan (Author) , Stenzinger, Albrecht (Author)
Format: Article (Journal)
Language:English
Published: 2020
In: Journal of nuclear medicine
Year: 2019, Volume: 61, Issue: 5, Pages: 683-688
ISSN:2159-662X
DOI:10.2967/jnumed.119.234559
Online Access:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.2967/jnumed.119.234559
Verlag, lizenzpflichtig, Volltext: http://jnm.snmjournals.org/content/61/5/683
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Author Notes:Clemens Kratochwil, Frederik L. Giesel, Claus-Peter Heussel, Daniel Kazdal, Volker Endris, Cathleen Nientiedt, Frank Bruchertseifer, Maximilian Kippenberger, Hendrik Rathke, Jonas Leichsenring, Markus Hohenfellner, Alfred Morgenstern, Uwe Haberkorn, Stefan Duensing, Albrecht Stenzinger
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Summary:Prostate-specific membrane antigen (PSMA)-targeting α-radiation therapy (TAT) is an emerging treatment modality for metastatic castration-resistant prostate cancer. There is a subgroup of patients with poor response despite sufficient expression of PSMA in their tumors. The aim of this work was to characterize PSMA-TAT-nonresponding lesions by targeted next-generation sequencing. Methods: Of 60 patients treated with 225Ac-PSMA-617, we identified 10 patients who presented with a poor response despite sufficient tumor uptake in PSMA PET/CT. We were able to perform CT-guided biopsies with histologic validation of the nonresponding lesions in 7 of these nonresponding patients. Specimens were analyzed by targeted next-generation sequencing interrogating 37 DNA damage-repair-associated genes. Results: In the 7 tumor samples analyzed, we found a total of 15 whole-gene deletions, deleterious or presumably deleterious mutations affecting TP53 (n = 3), CHEK2 (n = 2), ATM (n = 2), and BRCA1, BRCA2, PALB2, MSH2, MSH6, NBN, FANCB, and PMS1 (n = 1 each). The average number of deleterious or presumably deleterious mutations was 2.2 (range, 0-6) per patient. In addition, several variants of unknown significance in ATM, BRCA1, MSH2, SLX4, ERCC, and various FANC genes were detected. Conclusion: Patients with resistance to PSMA-TAT despite PSMA positivity frequently harbor mutations in DNA damage-repair and checkpoint genes. Although the causal role of these alterations in the patient outcome remains to be determined, our findings encourage future studies combining PSMA-TAT and DNA damage-repair-targeting agents such as poly(ADP-ribose)-polymerase inhibitors.
Item Description:Published online Oct. 10,
Gesehen am 04.06.2020
Physical Description:Online Resource
ISSN:2159-662X
DOI:10.2967/jnumed.119.234559

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