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: | , , , , , , , , , , , , , , |
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| Format: | Article (Journal) |
| Language: | English |
| Published: |
2020
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| 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 |
MARC
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| 245 | 1 | 0 | |a Patients resistant against PSMA-targeting α-radiation therapy often harbor mutations in DNA damage-repair-associated genes |c 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 |
| 246 | 3 | 3 | |a Patients resistant against PSMA-targeting α[alpha]-radiation therapy often harbor mutations in DNA damage-repair-associated genes |
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| 520 | |a 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. | ||
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