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

Kwan, EM; Fettke, H; Crumbaker, M; Docanto, MM; To, SQ; Bukczynska, P; Mant, A; Ng, N; Foroughi, S; Graham, LK; Haynes, AM; Azer, S; Lim, LE; Segelov, E; Mahon, K; Davis, ID; Parente, P; Pezaro, C; Todenh&#246;fer, T; Sathianathen, N; Hauser, C; Horvath, LG; Joshua, AM; Azad, AA

Author(s): Kwan, EM; Fettke, H; Crumbaker, M; Docanto, MM; To, SQ; Bukczynska, P; Mant, A; Ng, N; Foroughi, S; Graham, LK; Haynes, AM; Azer, S; Lim, LE; Segelov, E; Mahon, K; Davis, ID; Parente, P; Pezaro, C; Todenhöfer, T; Sathianathen, N; Hauser, C; Horvath, LG; Joshua, AM; Azad, AA;
Details: Publication Year 2021-04,Volume 10,Issue #4,Page 1688-1699
Journal Title: Translational Andrology and Urology
Abstract: 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.
Publisher: AME Publishing Company
Keywords: Grainyhead-like 2 (GRHL2); biomarker; castration-resistant; hormone-sensitive; prostate cancer
Research Division(s): Personalised Oncology
PubMed ID: 33968657
Publisher's Version: https://doi.org/10.21037/tau-20-1444
Open Access at Publisher's Site: https://doi.org/10.21037/tau-20-1444
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2021-05-17 11:04:11

Last Modified: 2021-05-17 11:47:20