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

• Verfasst von: Kratochwil, Clemens [VerfasserIn]
• Verfasst von: Giesel, Frederik L. [VerfasserIn]
• Verfasst von: Heußel, Claus Peter [VerfasserIn]
• Verfasst von: Kazdal, Daniel [VerfasserIn]
• Verfasst von: Endris, Volker [VerfasserIn]
• Verfasst von: Nientiedt, Cathleen [VerfasserIn]
• Verfasst von: Bruchertseifer, Frank [VerfasserIn]
• Verfasst von: Kippenberger, Maximilian [VerfasserIn]
• Verfasst von: Rathke, Hendrik [VerfasserIn]
• Verfasst von: Leichsenring, Jonas [VerfasserIn]
• Verfasst von: Hohenfellner, Markus [VerfasserIn]
• Verfasst von: Morgenstern, Alfred [VerfasserIn]
• Verfasst von: Haberkorn, Uwe [VerfasserIn]
• Verfasst von: Duensing, Stefan [VerfasserIn]
• Verfasst von: Stenzinger, Albrecht [VerfasserIn]
• Titel: Patients resistant against PSMA-targeting α-radiation therapy often harbor mutations in DNA damage-repair-associated genes
• Verf.angabe: 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
• Jahr: 2020
• Jahr des Originals: 2019
• Umfang: 6 S.
• Fussnoten: Published online Oct. 10, ; Gesehen am 04.06.2020
• Titel Quelle: Enthalten in: Journal of nuclear medicine
• Ort Quelle: New York, NY : Soc., 1964
• Jahr Quelle: 2020
• Band/Heft Quelle: 61(2020), 5, Seite 683-688
• ISSN Quelle: 2159-662X
• ISSN Quelle: 1535-5667
• DOI: doi:10.2967/jnumed.119.234559
• Datenträger: Online-Ressource
• Sprache: eng
• Sach-SW: 225Ac
• Sach-SW: Ac-225
• Sach-SW: next-generation sequencing
• Sach-SW: PSMA-617
• Sach-SW: tumor genome
• K10plus-PPN: 1699772274

Abstract

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.