PSMA Heterogeneity and DNA Repair Defects in Prostate Cancer

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•In this retrospective study, expression of membranous prostate-specific membrane antigen (PSMA) was scored via immunohistochemistry and was correlated with sequencing (matching same-patient biopsies) and clinical data. The expression of membranous PSMA was heterogeneous, more common in castration-resistant disease, and associated with a higher Gleason score (P=.04), and worse overall survival (P=.006). In addition, tumors with DNA damage repair had more membranous PSMA expression (P=.016), specifically aberrations in BRCA2 and ATM in the validation cohorts.

•As PSMA theranostics is gaining increasing interest as a valid treatment option for metastatic prostate cancer, this very interesting and provocative study raises important questions regarding the expression of PSMA and genomic markers of response, deserving further investigation.

– Pedro C. Barata, MD

abstract

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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

European Association of Urology

Prostate-Specific Membrane Antigen Heterogeneity and DNA Repair Defects in Prostate Cancer

Eur Urol 2019 Oct 01;76(4)469-478, A Paschalis, B Sheehan, R Riisnaes, DN Rodrigues, B Gurel, C Bertan, A Ferreira, MBK Lambros, G Seed, W Yuan, D Dolling, JC Welti, A Neeb, S Sumanasuriya, P Rescigno, D Bianchini, N Tunariu, S Carreira, A Sharp, W Oyen, JS de Bono

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.