Whole blood GRHL2 expression as a prognostic biomarker in metastatic hormone-sensitive and castration-resistant prostate cancer.

Background: As potent systemic therapies transition earlier in the prostate cancer disease course, molecular biomarkers are needed to guide optimal treatment selection for metastatic hormone-sensitive prostate cancer (mHSPC). The value of whole blood RNA to detect candidate biomarkers in mHSPC remains largely undefined.
Methods: In this cohort study, we used a previously optimised whole blood reverse transcription polymerase chain reaction assay to assess the prognostic utility [measured by seven-month undetectable prostate-specific antigen (PSA) and time to castration-resistance (TTCR)] of eight prostate cancer-associated gene transcripts in 43 mHSPC patients. Transcripts with statistically significant associations (P<0.05) were further investigated in a metastatic castration-resistant prostate cancer (mCRPC) cohort (n=119) receiving contemporary systemic therapy, exploring associations with PSA >50% response (PSA ₅₀ ), progression-free survival (PFS) and overall survival (OS). Clinical outcomes were prospectively collected in a protected digital database. Kaplan-Meier estimates and multivariable Cox proportional-hazards models assessed associations between gene transcripts and clinical outcomes (mHSPC covariates: disease volume, docetaxel use and haemoglobin level; mCRPC covariates: prior exposure to chemotherapy or ARPIs, haemoglobin, performance status and presence of visceral disease). Follow-up was performed monthly during ARPI treatment, three-weekly during taxane chemotherapy, and three-monthly during androgen deprivation therapy (ADT) monotherapy. Serial PSA measurements were performed before each follow-up visit and repeat imaging was at the discretion of the investigator.
Results: Detection of circulating Grainyhead-like 2 ( GRHL2 ) transcript was associated with poor outcomes in mHSPC and mCRPC patients. Detectable GRHL2 expression in mHSPC was associated with a lower rate of seven-month undetectable PSA levels (25% vs. 65%, P=0.059), and independently associated with shorter TTCR (HR 7.3, 95% CI: 1.5-36, P=0.01). In the mCRPC cohort, GRHL2 expression predicted significantly lower PSA ₅₀ response rates (46% vs. 69%, P=0.01), and was independently associated with shorter PFS (HR 3.1, 95% CI: 1.8-5.2, P<0.001) and OS (HR 2.9, 95% CI: 1.6-5.1, P<0.001). Associations were most apparent in patients receiving ARPIs.
Conclusions: Detectable circulating GRHL2 was a negative prognostic biomarker in our mHSPC and mCRPC cohorts. These data support further investigation of GRHL2 as a candidate prognostic biomarker in metastatic prostate cancer, in addition to expanding efforts to better understand a putative role in therapeutic resistance to AR targeted therapies.
Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/tau-20-1444). TT serves as an unpaid editorial board member of Translational Andrology and Urology from Aug 2019 to Jul 2021. EMK reports receiving honoraria from Janssen and Ipsen; travel & accommodation from Astellas Pharma, Pfizer and Ipsen; and institutional research funding from Astellas Pharma, AstraZeneca, Bristol Myers Squibb, Pfizer, and Merck Serono. AAA reports receiving compensation as a Consultant from Astellas Pharma, Janssen, and Novartis; speakers bureau for Astellas, Janssen, Novartis, Amgen, Ipsen, Bristol Myers Squibb, Merck Serono and Bayer; honoraria from Astellas, Novartis, Sanofi, AstraZeneca, Tolmar, Telix; Merck Serono; Janssen, Bristol Myers Squibb, Ipsen, Bayer, Pfizer, Amgen, Noxopharm, and Merck Sharpe Dome; research funding from Astellas (investigator), Merck Serono (investigator), Astra Zeneca (investigator), Bristol Myers Squibb (institutional), Astra Zeneca (institutional), Aptevo Therapeutics (institutional), Glaxo Smith Kline (institutional), Pfizer (institutional), MedImmune (institutional), Astellas (institutional), SYNthorx (institutional), Bionomics (institutional), Sanofi Aventis (institutional), Novartis (institutional), and Ipsen (institutional); travel and accommodation from Astellas, Merck Serono, Amgen, Novartis, Janssen, Tolmar, Pfizer;and is on the Scientific Advisory Board for Astellas, Novartis, Sanofi, AstraZeneca, Tolmar, Pfizer, Telix; Merck Serono; Janssen, Bristol Myers Squibb, Ipsen, Bayer, Merck Sharpe Dome, Amgen and Noxopharm. The other authors have no conflicts of interest to declare.
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