Biomarkers Associating with PARP Inhibitor Benefit in Prostate Cancer in the TOPARP-B Trial
| العنوان: | Biomarkers Associating with PARP Inhibitor Benefit in Prostate Cancer in the TOPARP-B Trial |
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| المؤلفون: | Chloe Baker, Emma Hall, Daniel Nava Rodrigues, Claudia Bertan, Susana Miranda, Nuria Porta, Ruth Riisnaes, Mateus Crespo, Alec Paschalis, Wei Yuan, Joaquin Mateo, Johann S. de Bono, Sara Arce-Gallego, Stephen J. Pettitt, Violeta Serra, Bora Gurel, Suzanne Carreira, Diletta Bianchini, Jane Goodall, Pasquale Rescigno, Christopher J. Lord, Alba Llop-Guevara, Ana Ferreira, Rita Pereira, Jan Rekowski, George Seed, Ines Figueiredo |
| المساهمون: | Institut Català de la Salut, [Carreira S, Porta N, Seed G] The Institute of Cancer Research, London, UK. [Arce-Gallego S, Llop-Guevara A, Serra V] Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. Vall d’Hebron Hospital Universitari, Barcelona, Spain. [Mateo J] The Institute of Cancer Research, London, UK. The Royal Marsden NHS Foundation Trust, London, UK. Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. Vall d’Hebron Hospital Universitari, Barcelona, Spain, Vall d'Hebron Barcelona Hospital Campus |
| المصدر: | Cancer Discovery Scientia |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | 0301 basic medicine, Male, ADN - Reparació, Neoplasms::Neoplasms by Site::Urogenital Neoplasms::Genital Neoplasms, Male::Prostatic Neoplasms [DISEASES], Genetic Phenomena::DNA Repair [PHENOMENA AND PROCESSES], DNA Repair, DNA repair, PALB2, RAD51, Otros calificadores::Otros calificadores::/farmacoterapia [Otros calificadores], Antineoplastic Agents, Poly(ADP-ribose) Polymerase Inhibitors, Other subheadings::Other subheadings::/drug therapy [Other subheadings], fenómenos genéticos::reparación del ADN [FENÓMENOS Y PROCESOS], Germline, Medicaments antineoplàstics, Olaparib, 03 medical and health sciences, Prostate cancer, chemistry.chemical_compound, 0302 clinical medicine, Medicine, Humans, business.industry, Prostatic Neoplasms, Pròstata - Càncer - Tractament, medicine.disease, 3. Good health, neoplasias::neoplasias por localización::neoplasias urogenitales::neoplasias de los genitales masculinos::neoplasias de la próstata [ENFERMEDADES], 030104 developmental biology, Oncology, chemistry, 030220 oncology & carcinogenesis, PARP inhibitor, Cancer research, Homologous recombination, business, Biomarkers |
| الوصف: | Pròstata; PARP; Biomarcadors Próstata; PARP; Biomarcadores Prostate; PARP; biomarkers 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. TOPARP is an investigator-initiated trial; we are grateful for the support and funding from AstraZeneca, and for the study grants from Cancer Research UK (CRUK/11/029; C12540/A12829; C12540/A13230; C12540/A20447). ICR-CTSU also receives program grant funding from Cancer Research UK (Grant number: C1491/A15955, C1491/A25351). We acknowledge research funding for this work from Cancer Research UK, Prostate Cancer UK, the Movember Foundation through the London Movember Centre of Excellence (CEO13_2-002), the Prostate Cancer Foundation, and the UK Department of Health through an Experimental Cancer Medicine Centre (ECMC) grant. Professor Johann de Bono is a National Institute for Health Research (NIHR) Senior Investigator. The views expressed in this article are those of the author(s) and not necessarily those of the NHS, the NIHR, or the Department of Health; research at the Royal Marsden Hospital is supported by a Biomedical Research Centre grant. Pasquale Rescigno was supported by a PCF Young Investigator Award 19YOUN19. The authors affiliated to VHIO acknowledge funding from “La Caixa” Foundation and European Institute of Innovation and Technology/Horizon 2020 (LCF/TR/CC19/52470003), Fundacion FERO and Fundacion Cellex. J. Mateo, A. Llop-Guevara and V. Serra received grants from Fundacion Cientifica AECC (LABAE16020PORTT) and an ERAPERMED2019-215. J. Mateo gratefully acknowledges funding from the European Union’s Horizon 2020 research and innovation program (Marie Skłodowska-Curie grant 837900), Instituto de Salud Carlos III (Grant PI18/01384), Fundación AECC, CRIS Cancer Foundation and the US Department of Defense CDMRP (Impact Award PC170510P1). S. Arce-Gallego Research. Downloaded from cancerdiscovery.aacrjournals.org on July 1, 2021. © 2021 American Association for Cancer Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on May 27, 2021; DOI: 10.1158/2159-8290.CD-21-0007 3 and V. Serra were supported by Instituto de Salud Carlos III (FI19/00280, CPII19/00033). |
| وصف الملف: | application/pdf |
| تدمد: | 2159-8290 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::6b5d78c938c629cb6907d0513760b356Test https://pubmed.ncbi.nlm.nih.gov/34045297Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....6b5d78c938c629cb6907d0513760b356 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 21598290 |
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