Translating a Prognostic DNA Genomic Classifier into the Clinic: Retrospective Validation in 563 Localized Prostate Tumors.
Localized prostate cancer is clinically heterogeneous, despite clinical risk groups that represent relative prostate cancer-specific mortality. We previously developed a 100-locus DNA classifier capable of substratifying patients at risk of biochemical relapse within clinical risk groups.



The 100-locus genomic classifier was refined to 31 functional loci and tested with standard clinical variables for the ability to predict biochemical recurrence (BCR) and metastasis.



Four retrospective cohorts of radical prostatectomy specimens from patients with localized disease were pooled, and an additional 102-patient cohort used to measure the 31-locus genomic classifier with the NanoString platform.



The genomic classifier scores were tested for their ability to predict BCR (n=563) and metastasis (n=154), and compared with clinical risk stratification schemes.



The 31-locus genomic classifier performs similarly to the 100-locus classifier. It identifies patients with elevated BCR rates (hazard ratio=2.73, p<0.001) and patients that eventually develop metastasis (hazard ratio=7.79, p<0.001). Combining the genomic classifier with standard clinical variables outperforms clinical models. Finally, the 31-locus genomic classifier was implemented using a NanoString assay. The study is limited to retrospective cohorts.



The 100-locus and 31-locus genomic classifiers reliably identify a cohort of men with localized disease who have an elevated risk of failure. The NanoString assay will be useful for selecting patients for treatment deescalation or escalation in prospective clinical trials based on clinico-genomic scores from pretreatment biopsies.



It is challenging to determine whether tumors confined to the prostate are aggressive, leading to significant undertreatment and overtreatment. We validated a test based on prostate tumor DNA that improves estimations of relapse risk, and that can help guide treatment planning.
Informatics and Biocomputing Program, Ontario Institute for Cancer Research, Toronto, ON, Canada; Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada.
Emilie
E
Lalonde
Informatics and Biocomputing Program, Ontario Institute for Cancer Research, Toronto, ON, Canada.
Rached
R
Alkallas
Radiation Medicine Program, Princess Margaret Cancer Center, Toronto, ON, Canada.
Melvin Lee Kiang
MLK
Chua
Princess Margaret Cancer Center, University Health Network, Toronto, ON, Canada.
Michael
M
Fraser
Informatics and Biocomputing Program, Ontario Institute for Cancer Research, Toronto, ON, Canada.
Syed
S
Haider
Princess Margaret Cancer Center, University Health Network, Toronto, ON, Canada.
Alice
A
Meng
Princess Margaret Cancer Center, University Health Network, Toronto, ON, Canada.
Junyan
J
Zheng
Informatics and Biocomputing Program, Ontario Institute for Cancer Research, Toronto, ON, Canada.
Cindy Q
CQ
Yao
Centre de recherche du CHU de Québec-Université Laval, Québec City, QC, Canada.
Valerie
V
Picard
Centre de recherche du CHU de Québec-Université Laval, Québec City, QC, Canada.
Michele
M
Orain
Centre de recherche du CHU de Québec-Université Laval, Québec City, QC, Canada.
Helène
H
Hovington
Radiation Medicine Program, Princess Margaret Cancer Center, Toronto, ON, Canada.
Jure
J
Murgic
Radiation Medicine Program, Princess Margaret Cancer Center, Toronto, ON, Canada.
Alejandro
A
Berlin
Centre de recherche du CHU de Québec-Université Laval, Québec City, QC, Canada.
Louis
L
Lacombe
Centre de recherche du CHU de Québec-Université Laval, Québec City, QC, Canada.
Alain
A
Bergeron
Centre de recherche du CHU de Québec-Université Laval, Québec City, QC, Canada.
Yves
Y
Fradet
Centre de recherche du CHU de Québec-Université Laval, Québec City, QC, Canada.
Bernard
B
Têtu
Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden.
Johan
J
Lindberg
Department of Oncology and Pathology, Karolinska Institute, Stockholm, Sweden.
Lars
L
Egevad
Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden.
Henrik
H
Grönberg
Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK.
Helen
H
Ross-Adams
Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK; Department of Urology, Addenbrooke's Hospital, Cambridge, UK; Academic Urology Group, University of Cambridge, Cambridge, UK.
Alastair D
AD
Lamb
Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK.
Silvia
S
Halim
Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK.
Mark J
MJ
Dunning
Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK; Department of Urology, Addenbrooke's Hospital, Cambridge, UK.
David E
DE
Neal
Department of Biostatistics, Princess Margaret Cancer Center, University Health Network, Toronto, ON, Canada.
Melania
M
Pintilie
Department of Pathology and Laboratory Medicine, Toronto General Hospital/University Health Network, Toronto, ON, Canada.
Theodorus
T
van der Kwast
Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada; Radiation Medicine Program, Princess Margaret Cancer Center, Toronto, ON, Canada; Princess Margaret Cancer Center, University Health Network, Toronto, ON, Canada. Electronic address: Rob.Bristow@rmp.uhn.on.ca.
Robert G
RG
Bristow
Informatics and Biocomputing Program, Ontario Institute for Cancer Research, Toronto, ON, Canada; Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada; Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON, Canada. Electronic address: Paul.Boutros@oicr.on.ca.
Paul C
PC
Boutros
D014408:Biomarkers, Tumor / Q000235:genetics*; D000066491:Clinical Decision-Making; D056915:DNA Copy Number Variations; D003661:Decision Support Techniques; D018450:Disease Progression; D018628:Gene Dosage; D020869:Gene Expression Profiling / Q000379:methods*; D006801:Humans; D008297:Male; D060787:Neoplasm Grading; D009362:Neoplasm Metastasis; D009364:Neoplasm Recurrence, Local; D009367:Neoplasm Staging; D011237:Predictive Value of Tests; D011468:Prostatectomy; D011471:Prostatic Neoplasms / Q000145:classification / Q000235:genetics* / Q000473:pathology / Q000601:surgery; D015203:Reproducibility of Results; D012189:Retrospective Studies; D018570:Risk Assessment; D012307:Risk Factors; D013997:Time Factors; D059467:Transcriptome; D016896:Treatment Outcome
D014408:Biomarkers, Tumor
CNA; CNV; Copy number alteration; Genomic classifier; Genomic signature; Localized prostate cancer; Precision medicine; Prognosis