Development and clinical validation of an in situ biopsy-based multimarker assay for risk stratification in prostate cancer.
OBJECTIVE
Prostate cancer aggressiveness and appropriate therapy are routinely determined following biopsy sampling. Current clinical and pathologic parameters are insufficient for accurate risk prediction leading primarily to overtreatment and also missed opportunities for curative therapy.


METHODS
An 8-biomarker proteomic assay for intact tissue biopsies predictive of prostate pathology was defined in a study of 381 patient biopsies with matched prostatectomy specimens. A second blinded study of 276 cases validated this assay's ability to distinguish "favorable" versus "nonfavorable" pathology independently and relative to current risk classification systems National Comprehensive Cancer Network (NCCN and D'Amico).


RESULTS
A favorable biomarker risk score of ≤0.33, and a nonfavorable risk score of >0.80 (possible range between 0 and 1) were defined on "false-negative" and "false-positive" rates of 10% and 5%, respectively. At a risk score ≤0.33, predictive values for favorable pathology in very low-risk and low-risk NCCN and low-risk D'Amico groups were 95%, 81.5%, and 87.2%, respectively, higher than for these current risk classification groups themselves (80.3%, 63.8%, and 70.6%, respectively). The predictive value for nonfavorable pathology was 76.9% at biomarker risk scores >0.8 across all risk groups. Increased biomarker risk scores correlated with decreased frequency of favorable cases across all risk groups. The validation study met its two coprimary endpoints, separating favorable from nonfavorable pathology (AUC, 0.68; P < 0.0001; OR, 20.9) and GS-6 versus non-GS-6 pathology (AUC, 0.65; P < 0.0001; OR, 12.95).


CONCLUSIONS
The 8-biomarker assay provided individualized, independent prognostic information relative to current risk stratification systems, and may improve the precision of clinical decision making following prostate biopsy.
Metamark Genetics Inc., Cambridge, Massachusetts.
Peter
P
Blume-Jensen
Department of Pathology and Molecular Medicine, Queen's University, Kingston, Ontario, Canada.
David M
DM
Berman
Department of Pathology, Yale University Medical School, New Haven, Connecticut.
David L
DL
Rimm
Metamark Genetics Inc., Cambridge, Massachusetts.
Michail
M
Shipitsin
Urology Austin, Austin, Texas.
Mathew
M
Putzi
Metamark Genetics Inc., Cambridge, Massachusetts.
Thomas P
TP
Nifong
Metamark Genetics Inc., Cambridge, Massachusetts.
Clayton
C
Small
Metamark Genetics Inc., Cambridge, Massachusetts.
Sibgat
S
Choudhury
Metamark Genetics Inc., Cambridge, Massachusetts.
Teresa
T
Capela
Impacts Inc., Montreal, Quebec, Canada.
Louis
L
Coupal
Metamark Genetics Inc., Cambridge, Massachusetts.
Christina
C
Ernst
Metamark Genetics Inc., Cambridge, Massachusetts.
Aeron
A
Hurley
Metamark Genetics Inc., Cambridge, Massachusetts.
Alex
A
Kaprelyants
Metamark Genetics Inc., Cambridge, Massachusetts.
Hua
H
Chang
Metamark Genetics Inc., Cambridge, Massachusetts.
Eldar
E
Giladi
Metamark Genetics Inc., Cambridge, Massachusetts.
Julie
J
Nardone
Metamark Genetics Inc., Cambridge, Massachusetts.
James
J
Dunyak
Dana-Farber Cancer Institute, Boston, Massachusetts.
Massimo
M
Loda
Glickman Urological and Kidney Institute, Cleveland Clinic, Cleveland, Ohio.
Eric A
EA
Klein
Department of Anatomic Pathology, Cleveland Clinic, Cleveland, Ohio.
Cristina
C
Magi-Galluzzi
Centre Hospitalier de l'Université de Montréal, Montreal, Quebec, Canada.
Mathieu
M
Latour
Department of Pathology, Urology and Oncology, Johns Hopkins Hospital, Baltimore, Maryland.
Jonathan I
JI
Epstein
Dana-Farber Cancer Institute, Boston, Massachusetts.
Philip
P
Kantoff
Centre Hospitalier de l'Université de Montréal, Montreal, Quebec, Canada. fred.saad@umontreal.ca.
Fred
F
Saad
D000368:Aged; D014408:Biomarkers, Tumor / Q000096:biosynthesis* / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000235:genetics* / Q000473:pathology; D011379:Prognosis; D017430:Prostate-Specific Antigen / Q000097:blood; D011468:Prostatectomy; D011471:Prostatic Neoplasms / Q000097:blood / Q000235:genetics* / Q000473:pathology / Q000601:surgery; D040901:Proteomics; D018570:Risk Assessment
D014408:Biomarkers, Tumor; D017430:Prostate-Specific Antigen