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Eur Urol. 2019 Oct;76(4):469-478. doi: 10.1016/j.eururo.2019.06.030. Epub 2019 Jul 22.

Prostate-specific Membrane Antigen Heterogeneity and DNA Repair Defects in Prostate Cancer.

Author information

1
The Institute of Cancer Research, Sutton, UK; The Royal Marsden NHS Foundation Trust, Sutton, UK.
2
The Institute of Cancer Research, Sutton, UK.
3
The Institute of Cancer Research, Sutton, UK; The Royal Marsden NHS Foundation Trust, Sutton, UK; Department of Clinical Medicine and Surgery, AOU Federico II, Naples, Italy; Department of Translational Medical Sciences, AOU Federico II, Naples, Italy.
4
The Institute of Cancer Research, Sutton, UK; The Royal Marsden NHS Foundation Trust, Sutton, UK. Electronic address: johann.de-Bono@icr.ac.uk.

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.

KEYWORDS:

BRCA2; Castration-resistant prostate cancer; Defective DNA repair; Prostate cancer; Prostate-specific membrane antigen; Theranostics; Treatment resistance; Tumour heterogeneity

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