EURURO Vol. 73 No. 1

130 148

1. Introduction
Prognostic molecular assays are increasingly bring used in
practice to improve risk stratification for men with newly
diagnosed prostate cancer (PCa) to inform treatment
decisions such as whether to recommend immediate
therapy or active surveillance (AS) or whether to administer
adjuvant therapy . National Comprehensive Cancer
Network (NCCN) guidelines state that “men with clinically
localized disease may consider the use of tumor-based
molecular assays” For assays to be accepted for clinical
care, there must be substantial evidence supporting and
validating their ability to predict end points independent of
conventional risk factors NCCN guidelines have noted
the need for such assays to predict clinically relevant end
points including adverse pathology (AP), biochemical
recurrence (BCR), metastases, and disease-specific death
The OncotypeDX Prostate Cancer assay is a biopsy-based
reverse transcription polymerase chain reaction assay that
has been analytically validated tomeasure the expression of
17 genes in RNA extracted from fixed tumor tissue from
prostate needle biopsies . The test provides a Genomic
Prostate Score (GPS) result, scale 0–100, with increasing
scores indicating more biologically aggressive disease. It has
been clinically validated as a strong, independent predictor
of (1) AP (defined as Gleason score [GS] 4 + 3 and/or non–
organ-confined disease) and (2) BCR after radical
prostatectomy (RP) in men with clinically very low –,
low-, and intermediate-risk PCa. In addition, use of GPS has
been associated with increased recommendation and
utilization of AS in men with very low–, low-, and favorable
intermediate–risk patients .
In this study, we assessed the ability of GPS to predict
later, and arguably the most clinically relevant, outcomes—
distant metastases and prostate cancer–specific death
(PCD)—in a large cohort of surgically treated men managed
in a community-based healthcare network with long-term
follow-up.
2. Patients and methods
2.1. Study setting and population
This study was conducted among members of Kaiser Permanente
Northern California (KPNC), an integrated healthcare system with over
4millionmembers in the greater northern California area. KPNCmaintains
a cancer registry for internal and external reporting and quality assurance
requirements that uses strict Surveillance, Epidemiology and End Results
(SEER) protocols . The registry has been found to be essentially 100%
complete in terms of new cancer ascertainment among KPNC members.
In the KPNC database, 6184 men were diagnosed with PCa between
1995 and 2010, and underwent RP within 12 mo of diagnosis. The clinical
follow-up was standard of care, including regular prostate-specific
antigen (PSA) assessments and imaging as clinically determined to assess
recurrence or metastasis. For this study, all eligible men with
adenocarcinoma were included without regard to postsurgical manage-
ment. Clinical exclusion criteria for this study included <6 mo of follow-
up after surgery, receipt of neoadjuvant therapy, and death within 6 mo
of surgery.
2.2. Study design
The study design was collaboratively developed by Genomic Health, Inc.
and KPNC researchers, and finalized prior to the initiation of the study
protocol. Owing to a small number of PCD events as compared with the
overall RP-treated cohort, this study employed a stratified cohort
sampling design within the study eligible cohort, with strata
determined by treatment year, race, and NCCN risk groups. From the full
cohort, all cases with documented PCD and available tissue were
selected, along with non-PCD men sampled at a target ratio of 1:2 to 1:3.
Non-PCD cases with missing tissue were replaced with additional non-
PCD cases with tissue, resulting in a fi nal ratio of 1:2.6. The protocol and
statistical analysis plans were agreed upon by all investigators prior to
study data collection. This study was approved by Kaiser Foundation
Research Institute and Asentral, Inc. (Newburyport, MA, USA) institu-
tional review boards and conformed to Reporting Recommendations for
Tumor Marker Prognostic Studies guidelines Data were locked prior
to analysis.
2.3. Outcome definitions
The investigators had access to all clinical, radiological, and laboratory
data to identify and confirm the study end points. In addition, the KPNC
Cancer Registry was used to ascertain key tumor data elements. PCD was
determined by a review of Cancer Registry and KPNC mortality files with
confirmation of the presence of metastasis or other supporting clinical
evidence. Metastasis was defi ned as clinical evidence of disseminated
PCa, such as a positive bone scan and/or CT scan, positive pathology of a
metastatic site, or a combination of extremely elevated PSA levels and/or
patient-reported symptoms indicative of prostate metastasis. BCR was
defined as either two successive post-RP PSA levels of 0.2 ng/ml, or
initiation of salvage therapy after a rising PSA of 0.1 ng/ml.
2.4. Pathological processing of diagnostic biopsies for
molecular testing
Fixed paraffin-embedded diagnostic biopsy specimens were retrieved
from the KPNC Pathology Specimen Repository and centrally reviewed
by a single urological pathologist (J.S.H.), blinded to clinical outcomes
and historical pathological data, using 2005 International Society of
Urological Pathology consensus guidelines The tissue block with the
Increasingly, doctors are using new molecular tests, such as the17-gene Genomic Prostate
Score (GPS), which can be performed at the time of initial diagnosis to help determine how
aggressive a given patient’s cancer may be. In this study, performed in a large community-
based healthcare network, GPS was shown to be a strong predictor as to whether a man’s
prostate cancer will spread and threaten his life after surgery, providing information that
may help patients and their doctors decide on the best course of management of their
disease.
© 2017 European Association of Urology. Published by Elsevier B.V. All rights reserved.
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