A 17-gene assay to predict prostate cancer aggressiveness in the context of Gleason grade heterogeneity, tumor multifocality, and biopsy undersampling.
BACKGROUND
Prostate tumor heterogeneity and biopsy undersampling pose challenges to accurate, individualized risk assessment for men with localized disease.


OBJECTIVE
To identify and validate a biopsy-based gene expression signature that predicts clinical recurrence, prostate cancer (PCa) death, and adverse pathology.


METHODS
Gene expression was quantified by reverse transcription-polymerase chain reaction for three studies-a discovery prostatectomy study (n=441), a biopsy study (n=167), and a prospectively designed, independent clinical validation study (n=395)-testing retrospectively collected needle biopsies from contemporary (1997-2011) patients with low to intermediate clinical risk who were candidates for active surveillance (AS).


METHODS
The main outcome measures defining aggressive PCa were clinical recurrence, PCa death, and adverse pathology at prostatectomy. Cox proportional hazards regression models were used to evaluate the association between gene expression and time to event end points. Results from the prostatectomy and biopsy studies were used to develop and lock a multigene-expression-based signature, called the Genomic Prostate Score (GPS); in the validation study, logistic regression was used to test the association between the GPS and pathologic stage and grade at prostatectomy. Decision-curve analysis and risk profiles were used together with clinical and pathologic characteristics to evaluate clinical utility.


CONCLUSIONS
Of the 732 candidate genes analyzed, 288 (39%) were found to predict clinical recurrence despite heterogeneity and multifocality, and 198 (27%) were predictive of aggressive disease after adjustment for prostate-specific antigen, Gleason score, and clinical stage. Further analysis identified 17 genes representing multiple biological pathways that were combined into the GPS algorithm. In the validation study, GPS predicted high-grade (odds ratio [OR] per 20 GPS units: 2.3; 95% confidence interval [CI], 1.5-3.7; p<0.001) and high-stage (OR per 20 GPS units: 1.9; 95% CI, 1.3-3.0; p=0.003) at surgical pathology. GPS predicted high-grade and/or high-stage disease after controlling for established clinical factors (p<0.005) such as an OR of 2.1 (95% CI, 1.4-3.2) when adjusting for Cancer of the Prostate Risk Assessment score. A limitation of the validation study was the inclusion of men with low-volume intermediate-risk PCa (Gleason score 3+4), for whom some providers would not consider AS.


CONCLUSIONS
Genes representing multiple biological pathways discriminate PCa aggressiveness in biopsy tissue despite tumor heterogeneity, multifocality, and limited sampling at time of biopsy. The biopsy-based 17-gene GPS improves prediction of the presence or absence of adverse pathology and may help men with PCa make more informed decisions between AS and immediate treatment.


RESULTS
Prostate cancer (PCa) is often present in multiple locations within the prostate and has variable characteristics. We identified genes with expression associated with aggressive PCa to develop a biopsy-based, multigene signature, the Genomic Prostate Score (GPS). GPS was validated for its ability to predict men who have high-grade or high-stage PCa at diagnosis and may help men diagnosed with PCa decide between active surveillance and immediate definitive treatment.
Glickman Urological and Kidney Institute, Cleveland Clinic, Cleveland, OH, USA. Electronic address: kleine@ccf.org.
Eric A
EA
Klein
Department of Urology, University of California, San Francisco and UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, CA, USA; Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA, USA.
Matthew R
MR
Cooperberg
Robert J. Tomsich Pathology and Laboratory Medicine Institute, Cleveland Clinic, Cleveland, OH, USA.
Cristina
C
Magi-Galluzzi
Department of Urology, University of California, San Francisco and UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, CA, USA; Department of Pathology, University of California, San Francisco, San Francisco, CA, USA.
Jeffry P
JP
Simko
Robert J. Tomsich Pathology and Laboratory Medicine Institute, Cleveland Clinic, Cleveland, OH, USA.
Sara M
SM
Falzarano
Genomic Health, Inc., Redwood City, CA, USA.
Tara
T
Maddala
Department of Urology, University of California, San Francisco and UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, CA, USA; Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA, USA.
June M
JM
Chan
Genomic Health, Inc., Redwood City, CA, USA.
Jianbo
J
Li
Department of Urology, University of California, San Francisco and UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, CA, USA.
Janet E
JE
Cowan
Genomic Health, Inc., Redwood City, CA, USA.
Athanasios C
AC
Tsiatis
Genomic Health, Inc., Redwood City, CA, USA.
Diana B
DB
Cherbavaz
Genomic Health, Inc., Redwood City, CA, USA.
Robert J
RJ
Pelham
Department of Urology, University of California, San Francisco and UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, CA, USA.
Imelda
I
Tenggara-Hunter
Department of Pathology, University of California, San Francisco, San Francisco, CA, USA; Genomic Health, Inc., Redwood City, CA, USA.
Frederick L
FL
Baehner
Genomic Health, Inc., Redwood City, CA, USA.
Dejan
D
Knezevic
Genomic Health, Inc., Redwood City, CA, USA.
Phillip G
PG
Febbo
Genomic Health, Inc., Redwood City, CA, USA.
Steven
S
Shak
Department of Quantitative Health Sciences, Cleveland Clinic, Cleveland, OH, USA.
Michael W
MW
Kattan
Genomic Health, Inc., Redwood City, CA, USA.
Mark
M
Lee
Department of Urology, University of California, San Francisco and UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, CA, USA. Electronic address: pcarroll@urology.ucsf.edu.
Peter R
PR
Carroll
D000368:Aged; D000465:Algorithms; D061765:Endoscopic Ultrasound-Guided Fine Needle Aspiration; D015870:Gene Expression; D006801:Humans; D008297:Male; D008875:Middle Aged; D060787:Neoplasm Grading; D009364:Neoplasm Recurrence, Local / Q000235:genetics*; D009367:Neoplasm Staging; D011468:Prostatectomy; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology*; D018570:Risk Assessment / Q000379:methods; D059467:Transcriptome
Clinical utility; Clinical validation; Gene expression; Genomic Prostate Score; Heterogeneity; Prostate neoplasms; Surgical pathology