Biomarkers Associating with PARP Inhibitor Benefit in Prostate Cancer in the TOPARP-B Trial.

View/ Open
Date
2021-05-27ICR Author
Author
Carreira, S
Porta, N
Arce-Gallego, S
Seed, G
Llop-Guevara, A
Bianchini, D
Rescigno, P
Paschalis, A
Bertan, C
Baker, C
Goodall, J
Miranda, S
Riisnaes, R
Figueiredo, I
Ferreira, A
Pereira, R
Crespo, M
Gurel, B
Nava Rodrigues, D
Pettitt, SJ
Yuan, W
Serra, V
Rekowski, J
Lord, CJ
Hall, E
Mateo, J
de Bono, JS
Type
Journal Article
Metadata
Show full item recordAbstract
PARP inhibitors are approved for treating advanced prostate cancers (APCs) with various defective DNA repair genes; however, further studies to clinically qualify predictive biomarkers are warranted. Herein we analyzed TOPARP-B Phase II clinical trial samples, evaluating whole exome and low-pass whole genome sequencing and immunohistochemical assays evaluating ATM and RAD51 foci (testing homologous recombination repair function). BRCA1/2 germline and somatic pathogenic mutations associated with similar benefit from olaparib; greater benefit was observed with homozygous BRCA deletion. Biallelic, but not mono-allelic, PALB2 deleterious alterations were associated with clinical benefit. In the ATM cohort, loss of ATM protein by immunohistochemistry associated with better outcome. RAD51 foci loss identified tumors with biallelic BRCA and PALB2 alteration while most ATM- and CDK12-altered APCs had higher RAD51 foci levels. Overall, APCs with homozygous BRCA2 deletion are exceptional responders; PALB2 biallelic loss and loss of ATM immunohistochemical expression associated with clinical benefit.
DOI
Research team
Cancer Biomarkers
Clinical Trials & Statistics Unit
Prostate Cancer Targeted Therapy Group
Gene Function
Cancer Biomarkers
Clinical Trials & Statistics Unit
Prostate Cancer Targeted Therapy Group
Gene Function
Language
eng
Date accepted
2021-05-21
License start date
2021-05-27
Citation
Cancer discovery, 2021