PSMA Heterogeneity and DNA Repair Defects in Prostate Cancer

[Balsam01]

TAKE-HOME MESSAGE

•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

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.

[Patrick-Turner]

So therefore, from what the researcher docs are saying here, Lu177 works better for Pca which has defective repair mechanism in their Pca cells. So what makes the repair mechanism defective? The above suggests it just a random thing, and varies between men, so that Pca cells with good ability to repair is due to plain old luck of the draw when we start life with whatever DNA we get when conceived.

BUT, maybe we work to make the DRM, ( defective repair mechanism ) worse by maybe using chemo, Xtandi, Zytiga, before using nuclides Lu177 Ac 225 etc, and get increased PsMa avidity, and thus better reduction of the Pca.

It seems we already know low PsMa avidity found in PsMa Ga68 scans will mean Lu177 just won't work well because not much Lu177 gathers at tumour sites.

So the higher the PsMa avidity the better.

Then there is the relationship between Psa and PsMa and maybe best results with Lu177 will be where PsMa is high regardless of Psa, and probably best where Psa is low, PsMa is high, so that lots of Lu177 gathers at the smaller tumours which make a smaller Psa.

In other words, army of Lu177 molecules more easily smashes the small Pca mets that would smash large mets.

A research doc here, Dr Louise Emmett strongly suggested to me that because I had chemo before Lu177, then Zytiga or Xtandi will work again when they had failed before I had chemo. She said either of these agents increase PsMa "expression", ie, makes more Lu177 gather at tumour sites, and Lu177 would work better than without the Zyt or Xtan.

So this research doc contacted my onco and discussed it with him and he put me onto Xtandi after No 3 Lu177. Now my Psa and PsMa avidity was already going down due to the 3 doses of Lu177 I had. But the No 4 Lu177 led to much bigger reduction of Psa. I still had some PsMa avidity shown in the PsMa scan after the end of 4 treatment cycles, but this lower level plus lower Psa level showed I had a good response to Lu177. Psa is now 0.4, down from 25.0 before I began Lu177.

The very smart doc managing my Lu177 therapy said I had a good response to Lu177, and that now we must just wait and see what happens, because giving more Lu177 is like sending another army in to defeat an already broken enemy, and just how this enemy re-groups is unknown. So it appears my doctors are implementing the findings of the research doc report you gave us to read because the research doc here already must know about it.

Anyway, researcher Dr Louise Emmett got a government grant to conduct a trial to give Lu177 combined with Xtandi and it is now underway at St Vincents Hospital in Sydney. She may find that patients who have had chemo before Lu177 might do better because of the damage that does to cancer DNA. Of course is sobering to know chemo has an effect on all our DNA. Chemo is a vile nasty primitive poison which has so far been impossible to make it only go to cancer cells.

If only we could target chemo to only attack cancer cells, then it would be hugely more effective, with far fewer side effects which limit how much chemo can be used.

BTW, if Lu177 was not targeted to Pca cells using PsMa ligand chemical, then Lu177 would not work. If the Lu177 levels needed at tumours was the same for all parts of the body it would kill a man fast because of radiation overdose, like being near a nuclear explosion.

We can only hope that researchers find out more and more and that treatments include the application of the findings so we get a better end result, ie, more Pca cells are killed. I hope that when my Pca does grow back up again, docs will have the ammo to deal with it.

Patrick Turner.