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Lookup NU author(s): Dr Pasquale RescignoORCiD
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (CC BY-NC-ND).
© 2021 The Authors. PARP inhibitors are approved for treating advanced prostate cancers (APC) 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 IHC and IF 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 BRCA2 deletion. Biallelic, but not monoallelic, PALB2 deleterious alterations were associated with clinical benefit. In the ATM cohort, loss of ATM protein by IHC was associated with a better outcome. RAD51 foci loss identified tumors with biallelic BRCA and PALB2 alterations 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 IHC expression associated with clinical benefit. Significance: Not all APCs with DNA repair defects derive similar benefit from PARP inhibition. Most benefit was seen among patients with BRCA2 homozygous deletions, biallelic loss of PALB2, and loss of ATM protein. Loss of RAD51 foci, evaluating homologous recombination repair function, was found primarily in tumors with biallelic BRCA1/2 and PALB2 alterations.
Author(s): 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, Rodrigues DN, Pettitt SJ, Yuan W, Serra V, Rekowski J, Lord CJ, Hall E, Mateo J, de Bono JS
Publication type: Article
Publication status: Published
Journal: Cancer Discovery
Year: 2021
Volume: 11
Issue: 11
Pages: 2812-2827
Print publication date: 01/11/2021
Online publication date: 01/11/2021
Acceptance date: 21/05/2021
Date deposited: 06/11/2024
ISSN (print): 2159-8274
ISSN (electronic): 2159-8290
Publisher: American Association for Cancer Research Inc.
URL: https://doi.org/10.1158/2159-8290.CD-21-0007
DOI: 10.1158/2159-8290.CD-21-0007
PubMed id: 34045297
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