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.
Cancer discovery. 2021 May 27 [Epub ahead of print]
Suzanne Carreira, Nuria Porta, Sara Arce-Gallego, George Seed, Alba Llop-Guevara, Diletta Bianchini, Pasquale Rescigno, Alec Paschalis, Claudia Bertan, Chloe Baker, Jane Goodall, Susana Miranda, Ruth Riisnaes, Ines Figueiredo, Ana Ferreira, Rita Pereira, Mateus Crespo, Bora Gurel, Daniel Nava Rodrigues, Stephen J Pettitt, Wei Yuan, Violeta Serra, Jan Rekowski, Christopher J Lord, Emma Hall, Joaquin Mateo, Johann S de Bono
Division of Clinical Studies, Institute of Cancer Research., Vall d'Hebron Institute of Oncology (VHIO)., Cancer Biomarkers Team, Institute of Cancer Research., Experimental Therapeutics Group, Vall d'Hebron Institute of Oncology (VHIO)., Uro-oncology, Kent Oncology Center, Maidstone., Cancer Research UK Cancer Therapeutics Unit, Institute of Cancer Research., Clinical Studies, The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust., Institute of Cancer Research., Section of Medicine, Institute of Cancer Research., Clinical Studies, Institute of Cancer Reseach., CRUK Gene Function Laboratory, Institute of Cancer Research., Cancer Biomarkers, Institute of Cancer Research., Clinical Trials & Statistics Unit, Institute of Cancer Research., Clinical Trials and Statistics Unit, Institute of Cancer Research., Prostate Cancer Translational Research, Vall d'Hebron Institute of Oncology (VHIO)., Clinical Studies, Institute of Cancer Research .