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

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Date
2021-05-27
ICR Author
Miranda, Susana
Carreira, Suzanne
Hall, Emma
Lord, Christopher
De Bono, Johann
Pettitt, Stephen
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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
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Type
Journal Article
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Abstract
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.
URI
https://repository.icr.ac.uk/handle/internal/4642
DOI
https://doi.org/10.1158/2159-8290.cd-21-0007
https://doi.org/10.1158/2159-8290.cd-21-0007
https://doi.org/10.1158/2159-8290.cd-21-0007
 
Collections
  • Breast Cancer Research
  • Cancer Therapeutics
  • Clinical Studies
  • Molecular Pathology
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

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