Response to supraphysiological testosterone is predicted by a distinct androgen receptor cistrome.

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Can we test for this?

The androgen receptor (AR) is a master transcription factor that regulates prostate cancer (PC) development and progression. Inhibition of AR signaling by androgen deprivation is the first-line therapy with initial efficacy for advanced and recurrent PC. Paradoxically, supraphysiological levels of testosterone (SPT) also inhibit PC progression. However, as with any therapy, not all patients show a therapeutic benefit, and responses differ widely in magnitude and duration. In this study, we evaluated whether differences in the AR cistrome before treatment can distinguish between SPT-responding (R) and -nonresponding (NR) tumors. We provide the first preclinical evidence to our knowledge that SPT-R tumors exhibit a distinct AR cistrome when compared with SPT-NR tumors, indicating a differential biological role of the AR. We applied an integrated analysis of ChIP-Seq and RNA-Seq to the pretreatment tumors and identified an SPT-R signature that distinguishes R and NR tumors. Because transcriptomes of SPT-treated clinical specimens are not available, we interrogated available castration-resistant PC (CRPC) transcriptomes and showed that the SPT-R signature is associated with improved survival and has the potential to identify patients who would respond to SPT. These findings provide an opportunity to identify the subset of patients with CRPC who would benefit from SPT therapy.

JCI insight. 2022 May 23*** epublish ***

Xintao Qiu, Lisha G Brown, Jennifer L Conner, Holly M Nguyen, Nadia Boufaied, Sarah Abou Alaiwi, Ji-Heui Seo, Talal El Zarif, Connor Bell, Edward O'Connor, Brian Hanratty, Mark Pomerantz, Matthew L Freedman, Myles Brown, Michael C Haffner, Peter S Nelson, Felix Y Feng, David P Labbé, Henry W Long, Eva Corey

urotoday.com/recent-abstrac...

[Hidden]

We can test for some of the genetic defects that might predict response. I have had 2 germline tests (one was free - hence the redundancy) and one somatic test (MO wants me to have them once a quarter) and no mutations.

19. Genetic mutations

a. TP53 and/or HRD Gene mutations in BAT hyper-responders: Molecular and clinical characterization of metastatic castration-resistant prostate cancer (mCRPC) patients achieving deep PSA responses to bipolar androgen therapy (BAT). | Journal of Clinical Oncology

ascopubs.org/doi/abs/10.120...

b. BRCA2 and ATM mutations are hyper-responder case study: Extreme Response to High-dose Testosterone in BRCA2- and ATM-mutated Prostate Cancer - PMC

ncbi.nlm.nih.gov/labs/pmc/a...

c. JCI Insight - Response to supraphysiological testosterone is predicted by a distinct androgen receptor cistrome

insight.jci.org/articles/vi...

d. Supraphysiologic Testosterone Therapy in the Treatment of Prostate Cancer: Models, Mechanisms and Questions - PMC

ncbi.nlm.nih.gov/pmc/articl...

[KocoPr in reply to Hidden]

Thanks Russ, in reading the BRCA/ATM mutations the one patient who had complete PFS had both somatic and germline BRCA and ATM mutations. I know your having great success on BAT. I noticed on your BIO I didn’t see any genetic testing.Im curious on your DNA damage repair mutations. Did you ever get that done?

[Hidden in reply to KocoPr]

I've had germline and somatic NGS testing. No mutations found. ATM, BRCA1, and BRCA2 were checked.

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Thanks for the replies. As soon as I can clear my desk a little I will try to find out more.