dc.contributor.author | Carreira, S | |
dc.contributor.author | Porta, N | |
dc.contributor.author | Arce-Gallego, S | |
dc.contributor.author | Seed, G | |
dc.contributor.author | Llop-Guevara, A | |
dc.contributor.author | Bianchini, D | |
dc.contributor.author | Rescigno, P | |
dc.contributor.author | Paschalis, A | |
dc.contributor.author | Bertan, C | |
dc.contributor.author | Baker, C | |
dc.contributor.author | Goodall, J | |
dc.contributor.author | Miranda, S | |
dc.contributor.author | Riisnaes, R | |
dc.contributor.author | Figueiredo, I | |
dc.contributor.author | Ferreira, A | |
dc.contributor.author | Pereira, R | |
dc.contributor.author | Crespo, M | |
dc.contributor.author | Gurel, B | |
dc.contributor.author | Nava Rodrigues, D | |
dc.contributor.author | Pettitt, SJ | |
dc.contributor.author | Yuan, W | |
dc.contributor.author | Serra, V | |
dc.contributor.author | Rekowski, J | |
dc.contributor.author | Lord, CJ | |
dc.contributor.author | Hall, E | |
dc.contributor.author | Mateo, J | |
dc.contributor.author | de Bono, JS | |
dc.date.accessioned | 2021-06-22T10:09:24Z | |
dc.date.available | 2021-06-22T10:09:24Z | |
dc.date.issued | 2021-11-01 | |
dc.identifier.citation | Cancer discovery, 2021 | |
dc.identifier.issn | 2159-8274 | |
dc.identifier.uri | https://repository.icr.ac.uk/handle/internal/4642 | |
dc.identifier.eissn | 2159-8290 | |
dc.identifier.doi | 10.1158/2159-8290.cd-21-0007 | |
dc.description.abstract | 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.This article is highlighted in the In This Issue feature, p. 2659. | |
dc.format | Print-Electronic | |
dc.language | eng | |
dc.language.iso | eng | |
dc.publisher | AMER ASSOC CANCER RESEARCH | |
dc.rights.uri | https://www.rioxx.net/licenses/all-rights-reserved | |
dc.title | Biomarkers Associating with PARP Inhibitor Benefit in Prostate Cancer in the TOPARP-B Trial. | |
dc.type | Journal Article | |
dcterms.dateAccepted | 2021-05-21 | |
rioxxterms.version | AM | |
rioxxterms.versionofrecord | 10.1158/2159-8290.cd-21-0007 | |
rioxxterms.licenseref.uri | https://www.rioxx.net/licenses/all-rights-reserved | |
rioxxterms.licenseref.startdate | 2021-05-27 | |
rioxxterms.type | Journal Article/Review | |
dc.relation.isPartOf | Cancer discovery | |
pubs.notes | No embargo | |
pubs.organisational-group | /ICR | |
pubs.organisational-group | /ICR/Primary Group | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Breast Cancer Research | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Breast Cancer Research/Gene Function | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Therapeutics | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Cancer Biomarkers | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Clinical Studies | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Clinical Studies/Cancer Biomarkers | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Clinical Studies/Clinical Trials & Statistics Unit | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Clinical Studies/Prostate Cancer Targeted Therapy Group | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Molecular Pathology | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Molecular Pathology/Gene Function | |
pubs.organisational-group | /ICR/Students | |
pubs.organisational-group | /ICR/Students/PhD and MPhil | |
pubs.organisational-group | /ICR/Students/PhD and MPhil/18/19 Starting Cohort | |
pubs.organisational-group | /ICR | |
pubs.organisational-group | /ICR/Primary Group | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Breast Cancer Research | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Breast Cancer Research/Gene Function | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Therapeutics | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Cancer Biomarkers | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Clinical Studies | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Clinical Studies/Cancer Biomarkers | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Clinical Studies/Clinical Trials & Statistics Unit | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Clinical Studies/Prostate Cancer Targeted Therapy Group | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Molecular Pathology | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Molecular Pathology/Gene Function | |
pubs.organisational-group | /ICR/Students | |
pubs.organisational-group | /ICR/Students/PhD and MPhil | |
pubs.organisational-group | /ICR/Students/PhD and MPhil/18/19 Starting Cohort | |
pubs.publication-status | Published | |
pubs.embargo.terms | No embargo | |
icr.researchteam | Cancer Biomarkers | |
icr.researchteam | Clinical Trials & Statistics Unit | |
icr.researchteam | Prostate Cancer Targeted Therapy Group | |
icr.researchteam | Gene Function | |
icr.researchteam | Cancer Biomarkers | |
icr.researchteam | Clinical Trials & Statistics Unit | |
icr.researchteam | Prostate Cancer Targeted Therapy Group | |
icr.researchteam | Gene Function | |
dc.contributor.icrauthor | Carreira, Suzanne | |
dc.contributor.icrauthor | Porta, Nuria | |
dc.contributor.icrauthor | Seed, George | |
dc.contributor.icrauthor | Rescigno, Pasquale | |
dc.contributor.icrauthor | Paschalis, Alec | |
dc.contributor.icrauthor | Goodall, Jane | |
dc.contributor.icrauthor | Miranda, Susana | |
dc.contributor.icrauthor | Pereira, Ana Rita | |
dc.contributor.icrauthor | Gurel, Bora | |
dc.contributor.icrauthor | Pettitt, Stephen | |
dc.contributor.icrauthor | Lord, Christopher | |
dc.contributor.icrauthor | Hall, Emma | |
dc.contributor.icrauthor | De Bono, Johann | |