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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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Hauptverfasser: Kratochwil, Clemens (VerfasserIn) , Giesel, Frederik L. (VerfasserIn) , Heußel, Claus Peter (VerfasserIn) , Kazdal, Daniel (VerfasserIn) , Endris, Volker (VerfasserIn) , Nientiedt, Cathleen (VerfasserIn) , Bruchertseifer, Frank (VerfasserIn) , Kippenberger, Maximilian (VerfasserIn) , Rathke, Hendrik (VerfasserIn) , Leichsenring, Jonas (VerfasserIn) , Hohenfellner, Markus (VerfasserIn) , Morgenstern, Alfred (VerfasserIn) , Haberkorn, Uwe (VerfasserIn) , Duensing, Stefan (VerfasserIn) , Stenzinger, Albrecht (VerfasserIn)
Dokumenttyp: Article (Journal)
Sprache:Englisch
Veröffentlicht: 2020
In: Journal of nuclear medicine
Year: 2019, Jahrgang: 61, Heft: 5, Pages: 683-688
ISSN:2159-662X
DOI:10.2967/jnumed.119.234559
Online-Zugang:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.2967/jnumed.119.234559
Verlag, lizenzpflichtig, Volltext: http://jnm.snmjournals.org/content/61/5/683
Volltext
Verfasserangaben: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
Beschreibung
Zusammenfassung: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.
Beschreibung:Published online Oct. 10,
Gesehen am 04.06.2020
Beschreibung:Online Resource
ISSN:2159-662X
DOI:10.2967/jnumed.119.234559

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