Nuklearmedizin 2019; 58(02): 145-146
DOI: 10.1055/s-0039-1683592
Vorträge
Dosimetrie und Strahlenbiologie
Georg Thieme Verlag KG Stuttgart · New York

Resistance against PSMA-targeting alpha-radiation therapy coincides with mutations in DNA-repair associated genes

C Kratochwil
1   Uniklinik Heidelberg, Nuklearmedizin, Heidelberg
,
CP Heussel
2   Thoraxklinik, Radiologie, Heidelberg
,
F Bruchertseifer
3   European Commission – Joint Research Centre, Directorate for Nuclear Safety and Security, Karlsruhe
,
U Haberkorn
1   Uniklinik Heidelberg, Nuklearmedizin, Heidelberg
,
A Morgenstern
3   European Commission – Joint Research Centre, Directorate for Nuclear Safety and Security, Karlsruhe
,
A Stenzinger
4   Uniklinik Heidelberg, Pathologie, Heidelberg
,
S Duensing
5   Uniklinik Heidelberg, Molekulare Uroonkologie, Heidelberg
,
FL Giesel
1   Uniklinik Heidelberg, Nuklearmedizin, Heidelberg
› Author Affiliations
Further Information

Publication History

Publication Date:
27 March 2019 (online)

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Ziel/Aim:

PSMA-targeting alpha-radiation therapy (PSMA-TαT) is currently one of the most promising developments in the field of metastatic castration-resistant prostate cancer. However, there is a subgroup of patients with poor response, despite high expression of PSMA in their tumors. Aim of this work was to characterize a selection of highly radiation-resistant lesions, non-responding to PSMA-TαT by targeted next-generation sequencing (tNGS).

Methodik/Methods:

Out of 60 patients treated with Actinium-225 labeled PSMA-617 we identified 10 patients that presented with poor response despite high tumor-uptake in PSMA-PET/CT and were able to perform CT-guided biopsies with histologic validation of the non-responding lesions in 6 of them. The relevant index lesions were analyzed by focused next-generation-sequencing interrogating 37 core DNA damage-repair genes.

Ergebnisse/Results:

Tissue of 6 high quality index lesions fulfilling the stringent inclusion criteria were derived from the 6 patients and successfully analyzed by the tNGS panel. In these 6 index-lesions, we found a total of 14 whole-gene deletions, deleterious or presumably deleterious mutations affecting TP53 (n = 3); CHEK2 (n = 2), ATM (n = 2); BRCA1, PALB2, MSH2, MSH6, NBN, FANCB and PMS1 (n = 1 each). The average number of deleterious or presumably deleterious mutations was 2.3 (range, 0 – 6) per patient. In addition, a number of mutations or variants of unknown significance in ATM, BRCA1, MSH2, SLX4, ERCCx and various Fanconi-genes were detected.

Schlussfolgerungen/Conclusions:

Conclusions: Index lesions of tumors with inherent resistant against PSMA-targeting alpha-therapy are often harboring mutated DNA damage-repair genes. Combination of PSMA-RLT with PARP-inhibitors, which are also known to have therapeutic activity in prostate cancer, might be a promising objective to achieve over-additive anti-tumor effects.