dc.contributor.author | Paschalis, A | |
dc.contributor.author | Sheehan, B | |
dc.contributor.author | Riisnaes, R | |
dc.contributor.author | Rodrigues, DN | |
dc.contributor.author | Gurel, B | |
dc.contributor.author | Bertan, C | |
dc.contributor.author | Ferreira, A | |
dc.contributor.author | Lambros, MBK | |
dc.contributor.author | Seed, G | |
dc.contributor.author | Yuan, W | |
dc.contributor.author | Dolling, D | |
dc.contributor.author | Welti, JC | |
dc.contributor.author | Neeb, A | |
dc.contributor.author | Sumanasuriya, S | |
dc.contributor.author | Rescigno, P | |
dc.contributor.author | Bianchini, D | |
dc.contributor.author | Tunariu, N | |
dc.contributor.author | Carreira, S | |
dc.contributor.author | Sharp, A | |
dc.contributor.author | Oyen, W | |
dc.contributor.author | de Bono, JS | |
dc.date.accessioned | 2020-05-28T12:10:15Z | |
dc.date.issued | 2019-10-01 | |
dc.identifier.citation | European urology, 2019, 76 (4), pp. 469 - 478 | |
dc.identifier.issn | 0302-2838 | |
dc.identifier.uri | https://repository.icr.ac.uk/handle/internal/3659 | |
dc.identifier.eissn | 1873-7560 | |
dc.identifier.doi | 10.1016/j.eururo.2019.06.030 | |
dc.description.abstract | BACKGROUND: Prostate-specific membrane antigen (PSMA; folate hydrolase) prostate cancer (PC) expression has theranostic utility. OBJECTIVE: To elucidate PC PSMA expression and associate this with defective DNA damage repair (DDR). DESIGN, SETTING, AND PARTICIPANTS: Membranous PSMA (mPSMA) expression was scored immunohistochemically from metastatic castration-resistant PC (mCRPC) and matching, same-patient, diagnostic biopsies, and correlated with next-generation sequencing (NGS) and clinical outcome data. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Expression of mPSMA was quantitated by modified H-score. Patient DNA was tested by NGS. Gene expression and activity scores were determined from mCRPC transcriptomes. Statistical correlations utilised Wilcoxon signed rank tests, survival was estimated by Kaplan-Meier test, and sample heterogeneity was quantified by Shannon's diversity index. RESULTS AND LIMITATIONS: Expression of mPSMA at diagnosis was associated with higher Gleason grade (p=0.04) and worse overall survival (p=0.006). Overall, mPSMA expression levels increased at mCRPC (median H-score [interquartile range]: castration-sensitive prostate cancer [CSPC] 17.5 [0.0-60.0] vs mCRPC 55.0 [2.8-117.5]). Surprisingly, 42% (n=16) of CSPC and 27% (n=16) of mCRPC tissues sampled had no detectable mPSMA (H-score <10). Marked intratumour heterogeneity of mPSMA expression, with foci containing no detectable PSMA, was observed in all mPSMA expressing CSPC (100%) and 37 (84%) mCRPC biopsies. Heterogeneous intrapatient mPSMA expression between metastases was also observed, with the lowest expression in liver metastases. Tumours with DDR had higher mPSMA expression (p=0.016; 87.5 [25.0-247.5] vs 20 [0.3-98.8]; difference in medians 60 [5.0-95.0]); validation cohort studies confirmed higher mPSMA expression in patients with deleterious aberrations in BRCA2 (p<0.001; median H-score: 300 [165-300]; difference in medians 195.0 [100.0-270.0]) and ATM (p=0.005; 212.5 [136.3-300]; difference in medians 140.0 [55.0-200]) than in molecularly unselected mCRPC biopsies (55.0 [2.75-117.5]). Validation studies using mCRPC transcriptomes corroborated these findings, also indicating that SOX2 high tumours have low PSMA expression. CONCLUSIONS: Membranous PSMA expression is upregulated in some but not all PCs, with mPSMA expression demonstrating marked inter- and intrapatient heterogeneity. DDR aberrations are associated with higher mPSMA expression and merit further evaluation as predictive biomarkers of response for PSMA-targeted therapies in larger, prospective cohorts. PATIENT SUMMARY: Through analysis of prostate cancer samples, we report that the presence of prostate-specific membrane antigen (PSMA) is extremely variable both within one patient and between different patients. This may limit the usefulness of PSMA scans and PSMA-targeted therapies. We show for the first time that prostate cancers with defective DNA repair produce more PSMA and so may respond better to PSMA-targeting treatments. | |
dc.format | Print-Electronic | |
dc.format.extent | 469 - 478 | |
dc.language | eng | |
dc.language.iso | eng | |
dc.publisher | ELSEVIER | |
dc.rights.uri | https://creativecommons.org/licenses/by/4.0 | |
dc.subject | Humans | |
dc.subject | Glutamate Carboxypeptidase II | |
dc.subject | Antigens, Surface | |
dc.subject | Retrospective Studies | |
dc.subject | DNA Repair | |
dc.subject | Male | |
dc.subject | Prostatic Neoplasms, Castration-Resistant | |
dc.title | Prostate-specific Membrane Antigen Heterogeneity and DNA Repair Defects in Prostate Cancer. | |
dc.type | Journal Article | |
dcterms.dateAccepted | 2019-06-25 | |
rioxxterms.versionofrecord | 10.1016/j.eururo.2019.06.030 | |
rioxxterms.licenseref.uri | https://creativecommons.org/licenses/by-nc-nd/4.0 | |
rioxxterms.licenseref.startdate | 2019-10 | |
rioxxterms.type | Journal Article/Review | |
dc.relation.isPartOf | European urology | |
pubs.issue | 4 | |
pubs.notes | Not known | |
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/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/Prostate Cancer Targeted Therapy Group | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Clinical Studies/Translational Therapeutics | |
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 | 76 | |
pubs.embargo.terms | Not known | |
icr.researchteam | Cancer Biomarkers | |
icr.researchteam | Prostate Cancer Targeted Therapy Group | |
icr.researchteam | Translational Therapeutics | |
dc.contributor.icrauthor | Paschalis, Alec | |
dc.contributor.icrauthor | Sheehan, Beshara | |
dc.contributor.icrauthor | Gurel, Bora | |
dc.contributor.icrauthor | Seed, George | |
dc.contributor.icrauthor | Sumanasuriya, Semini | |
dc.contributor.icrauthor | Rescigno, Pasquale | |
dc.contributor.icrauthor | Carreira, Suzanne | |
dc.contributor.icrauthor | Sharp, Adam | |
dc.contributor.icrauthor | De Bono, Johann | |