Edmond M Kwan1, Heidi Fettke2, Maria M Docanto2, Sarah Q To2, Patricia Bukczynska2, Andrew Mant3, David Pook1, Nicole Ng4, Lisa-Jane K Graham5, Stefano Mangiola6, Eva Segelov1, Kate Mahon7, Ian D Davis3, Phillip Parente3, Carmel Pezaro3, Tilman Todenhöfer8, Lisa G Horvath9, Arun A Azad10. 1. Department of Medicine, School of Clinical Sciences, Monash University, Melbourne, VIC, Australia; Department of Medical Oncology, Monash Health, Melbourne, VIC, Australia. 2. Department of Medicine, School of Clinical Sciences, Monash University, Melbourne, VIC, Australia. 3. Medical Oncology Unit, Eastern Health, Melbourne, VIC, Australia; Eastern Health Clinical School, Monash University, Melbourne, VIC, Australia. 4. Department of Medical Oncology, Monash Health, Melbourne, VIC, Australia. 5. Medical Oncology, Chris O'Brien Lifehouse, Camperdown, NSW, Australia. 6. The Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia; Department of Medical Biology, University of Melbourne, Melbourne, VIC, Australia. 7. Medical Oncology, Chris O'Brien Lifehouse, Camperdown, NSW, Australia; University of Sydney, Sydney, NSW, Australia; Garvan Institute of Medical Research, Sydney, NSW, Australia. 8. Department of Urology, Eberhard-Karls-University, Tübingen, Germany. 9. Medical Oncology, Chris O'Brien Lifehouse, Camperdown, NSW, Australia; Royal Prince Alfred Hospital, Camperdown, Sydney, NSW, Australia; University of Sydney, Sydney, NSW, Australia; Garvan Institute of Medical Research, Sydney, NSW, Australia. 10. Department of Medicine, School of Clinical Sciences, Monash University, Melbourne, VIC, Australia; Department of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia; Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, VIC, Australia. Electronic address: Arun.Azad@monash.edu.
Abstract
BACKGROUND: The treatment paradigm for metastatic castration-resistant prostate cancer (mCRPC) has evolved significantly in recent years. Identifying predictive and/or prognostic biomarkers in the context of this rapidly expanding therapeutic armamentarium remains a pressing and unmet clinical need. OBJECTIVE: To develop a prognostic whole-blood gene signature for mCRPC patients. DESIGN, SETTING, AND PARTICIPANTS: As part of an ongoing prospective, multicentre biomarker research study (Australian Prostate Biomarker Alliance), we enrolled 115 mCRPC patients commencing chemotherapy (n = 34) or androgen receptor (AR) pathway inhibitors therapy (n = 81) and obtained pretreatment whole-blood samples in PAXgene RNA tubes. Gene expression was assessed using reverse transcription-polymerase chain reaction. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Gene transcripts correlating with overall survival (OS) at p < 0.10 in univariate Cox regression models were incorporated into a multigene signature. Kaplan-Meier survival estimates and multivariate analyses were used to assess association with clinical outcomes. Prognostic strength of the signature was estimated using a concordance probability estimate (CPE). RESULTS AND LIMITATIONS: Based on univariate analysis for OS, the following genes were incorporated into a multigene signature: AR splice variant 7 (AR-V7), and three androgen-regulated genes: GRHL2, HOXB13, and FOXA1. The number of positive transcripts clearly stratified survival outcomes (median OS: not reached vs 24.8 mo vs 16.2 mo for 0, 1, and ≥2 transcripts, respectively; p = 0.0052). Notably, this multigene signature retained prognostic significance on multivariable analysis (hazard ratio, 2.1; 95% confidence interval, 1.1-4.0; p = 0.019). Moreover, CPE for this model was 0.78, indicating strong discriminative capacity. Limitations include short follow-up time. CONCLUSIONS: Our data demonstrate the prognostic utility of a novel whole-blood AR-based signature in mCRPC patients commencing contemporary systemic therapies. Our pragmatic assay requires minimal processing, can be performed in most hospital laboratories, and could represent a key prognostic tool for risk stratification in mCRPC. PATIENT SUMMARY: We found that expression of certain genes associated with the androgen receptor could help determine how long men with advanced prostate cancer survive after starting modern drug therapies.
BACKGROUND: The treatment paradigm for metastatic castration-resistant prostate cancer (mCRPC) has evolved significantly in recent years. Identifying predictive and/or prognostic biomarkers in the context of this rapidly expanding therapeutic armamentarium remains a pressing and unmet clinical need. OBJECTIVE: To develop a prognostic whole-blood gene signature for mCRPC patients. DESIGN, SETTING, AND PARTICIPANTS: As part of an ongoing prospective, multicentre biomarker research study (Australian Prostate Biomarker Alliance), we enrolled 115 mCRPC patients commencing chemotherapy (n = 34) or androgen receptor (AR) pathway inhibitors therapy (n = 81) and obtained pretreatment whole-blood samples in PAXgene RNA tubes. Gene expression was assessed using reverse transcription-polymerase chain reaction. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Gene transcripts correlating with overall survival (OS) at p < 0.10 in univariate Cox regression models were incorporated into a multigene signature. Kaplan-Meier survival estimates and multivariate analyses were used to assess association with clinical outcomes. Prognostic strength of the signature was estimated using a concordance probability estimate (CPE). RESULTS AND LIMITATIONS: Based on univariate analysis for OS, the following genes were incorporated into a multigene signature: AR splice variant 7 (AR-V7), and three androgen-regulated genes: GRHL2, HOXB13, and FOXA1. The number of positive transcripts clearly stratified survival outcomes (median OS: not reached vs 24.8 mo vs 16.2 mo for 0, 1, and ≥2 transcripts, respectively; p = 0.0052). Notably, this multigene signature retained prognostic significance on multivariable analysis (hazard ratio, 2.1; 95% confidence interval, 1.1-4.0; p = 0.019). Moreover, CPE for this model was 0.78, indicating strong discriminative capacity. Limitations include short follow-up time. CONCLUSIONS: Our data demonstrate the prognostic utility of a novel whole-blood AR-based signature in mCRPC patients commencing contemporary systemic therapies. Our pragmatic assay requires minimal processing, can be performed in most hospital laboratories, and could represent a key prognostic tool for risk stratification in mCRPC. PATIENT SUMMARY: We found that expression of certain genes associated with the androgen receptor could help determine how long men with advanced prostate cancer survive after starting modern drug therapies.
Authors: Edmond M Kwan; Heidi Fettke; Megan Crumbaker; Maria M Docanto; Sarah Q To; Patricia Bukczynska; Andrew Mant; Nicole Ng; Siavash Foroughi; Lisa-Jane K Graham; Anne-Maree Haynes; Sarah Azer; Lisi Elizabeth Lim; Eva Segelov; Kate Mahon; Ian D Davis; Phillip Parente; Carmel Pezaro; Tilman Todenhöfer; Niranjan Sathianathen; Christine Hauser; Lisa G Horvath; Anthony M Joshua; Arun A Azad Journal: Transl Androl Urol Date: 2021-04
Authors: Tanzila Khan; Therese M Becker; Kieran F Scott; Joseph Descallar; Paul de Souza; Wei Chua; Yafeng Ma Journal: Front Oncol Date: 2022-03-18 Impact factor: 6.244
Authors: Sarennya Pathmanandavel; Megan Crumbaker; Andrew O Yam; Andrew Nguyen; Christopher Rofe; Elizabeth Hovey; Craig Gedye; Edmond M Kwan; Christine Hauser; Arun A Azad; Peter Eu; Andrew J Martin; Anthony M Joshua; Louise Emmett Journal: J Nucl Med Date: 2021-07-29 Impact factor: 10.057