dc.contributor.author | Goodall, J | |
dc.contributor.author | Mateo, J | |
dc.contributor.author | Yuan, W | |
dc.contributor.author | Mossop, H | |
dc.contributor.author | Porta, N | |
dc.contributor.author | Miranda, S | |
dc.contributor.author | Perez-Lopez, R | |
dc.contributor.author | Dolling, D | |
dc.contributor.author | Robinson, DR | |
dc.contributor.author | Sandhu, S | |
dc.contributor.author | Fowler, G | |
dc.contributor.author | Ebbs, B | |
dc.contributor.author | Flohr, P | |
dc.contributor.author | Seed, G | |
dc.contributor.author | Rodrigues, DN | |
dc.contributor.author | Boysen, G | |
dc.contributor.author | Bertan, C | |
dc.contributor.author | Atkin, M | |
dc.contributor.author | Clarke, M | |
dc.contributor.author | Crespo, M | |
dc.contributor.author | Figueiredo, I | |
dc.contributor.author | Riisnaes, R | |
dc.contributor.author | Sumanasuriya, S | |
dc.contributor.author | Rescigno, P | |
dc.contributor.author | Zafeiriou, Z | |
dc.contributor.author | Sharp, A | |
dc.contributor.author | Tunariu, N | |
dc.contributor.author | Bianchini, D | |
dc.contributor.author | Gillman, A | |
dc.contributor.author | Lord, CJ | |
dc.contributor.author | Hall, E | |
dc.contributor.author | Chinnaiyan, AM | |
dc.contributor.author | Carreira, S | |
dc.contributor.author | de Bono, JS | |
dc.contributor.author | TOPARP-A investigators, | |
dc.date.accessioned | 2017-04-26T10:02:37Z | |
dc.date.issued | 2017-09-01 | |
dc.identifier.citation | Cancer discovery, 2017, 7 (9), pp. 1006 - 1017 | |
dc.identifier.issn | 2159-8274 | |
dc.identifier.uri | https://repository.icr.ac.uk/handle/internal/622 | |
dc.identifier.eissn | 2159-8290 | |
dc.identifier.doi | 10.1158/2159-8290.cd-17-0261 | |
dc.description.abstract | Biomarkers for more precise patient care are needed in metastatic prostate cancer. We have reported a phase II trial (TOPARP-A) of the PARP inhibitor olaparib in metastatic prostate cancer, demonstrating antitumor activity associating with homologous recombination DNA repair defects. We now report targeted and whole-exome sequencing of serial circulating cell-free DNA (cfDNA) samples collected during this trial. Decreases in cfDNA concentration independently associated with outcome in multivariable analyses (HR for overall survival at week 8: 0.19; 95% CI, 0.06-0.56; P = 0.003). All tumor tissue somatic DNA repair mutations were detectable in cfDNA; allele frequency of somatic mutations decreased selectively in responding patients (χ2P < 0.001). At disease progression, following response to olaparib, multiple subclonal aberrations reverting germline and somatic DNA repair mutations (BRCA2, PALB2) back in frame emerged as mechanisms of resistance. These data support the role of liquid biopsies as a predictive, prognostic, response, and resistance biomarker in metastatic prostate cancer.Significance: We report prospectively planned, serial, cfDNA analyses from patients with metastatic prostate cancer treated on an investigator-initiated phase II trial of olaparib. These analyses provide predictive, prognostic, response, and resistance data with "second hit" mutations first detectable at disease progression, suggesting clonal evolution from treatment-selective pressure and platinum resistance. Cancer Discov; 7(9); 1006-17. ©2017 AACR.See related commentary by Domchek, p. 937See related article by Kondrashova et al., p. 984See related article by Quigley et al., p. 999This article is highlighted in the In This Issue feature, p. 920. | |
dc.format | Print-Electronic | |
dc.format.extent | 1006 - 1017 | |
dc.language | eng | |
dc.language.iso | eng | |
dc.publisher | AMER ASSOC CANCER RESEARCH | |
dc.subject | TOPARP-A investigators | |
dc.subject | Humans | |
dc.subject | Prostatic Neoplasms | |
dc.subject | Piperazines | |
dc.subject | Phthalazines | |
dc.subject | Antineoplastic Agents | |
dc.subject | Prognosis | |
dc.subject | Gene Frequency | |
dc.subject | Mutation | |
dc.subject | Male | |
dc.subject | Poly(ADP-ribose) Polymerase Inhibitors | |
dc.subject | Whole Exome Sequencing | |
dc.subject | Cell-Free Nucleic Acids | |
dc.title | Circulating Cell-Free DNA to Guide Prostate Cancer Treatment with PARP Inhibition. | |
dc.type | Journal Article | |
dcterms.dateAccepted | 2017-04-26 | |
rioxxterms.versionofrecord | 10.1158/2159-8290.cd-17-0261 | |
rioxxterms.licenseref.startdate | 2017-09 | |
rioxxterms.type | Journal Article/Review | |
dc.relation.isPartOf | Cancer discovery | |
pubs.issue | 9 | |
pubs.notes | 6 months | |
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/ICR-CTSU Urology and Head and Neck Trials Team | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Clinical Studies/Prostate Cancer Targeted Therapy Group | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Clinical Studies/Translational Therapeutics | |
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/16/17 Starting Cohort | |
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/ICR-CTSU Urology and Head and Neck Trials Team | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Clinical Studies/Prostate Cancer Targeted Therapy Group | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Clinical Studies/Translational Therapeutics | |
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/16/17 Starting Cohort | |
pubs.organisational-group | /ICR/Students/PhD and MPhil/18/19 Starting Cohort | |
pubs.publication-status | Published | |
pubs.volume | 7 | |
pubs.embargo.terms | 6 months | |
icr.researchteam | Cancer Biomarkers | |
icr.researchteam | Clinical Trials & Statistics Unit | |
icr.researchteam | ICR-CTSU Urology and Head and Neck Trials Team | |
icr.researchteam | Prostate Cancer Targeted Therapy Group | |
icr.researchteam | Translational Therapeutics | |
icr.researchteam | Gene Function | |
dc.contributor.icrauthor | Goodall, Jane | |
dc.contributor.icrauthor | Yuan, Wei | |
dc.contributor.icrauthor | Porta, Nuria | |
dc.contributor.icrauthor | Miranda, Susana | |
dc.contributor.icrauthor | Dolling, David | |
dc.contributor.icrauthor | Flohr, Penelope | |
dc.contributor.icrauthor | Seed, George | |
dc.contributor.icrauthor | Atkin, Mark | |
dc.contributor.icrauthor | Clarke, Matthew | |
dc.contributor.icrauthor | Sumanasuriya, Semini | |
dc.contributor.icrauthor | Rescigno, Pasquale | |
dc.contributor.icrauthor | Sharp, Adam | |
dc.contributor.icrauthor | Gillman, Alexa | |
dc.contributor.icrauthor | Lord, Christopher | |
dc.contributor.icrauthor | Hall, Emma | |
dc.contributor.icrauthor | Carreira, Suzanne | |
dc.contributor.icrauthor | De Bono, Johann | |