Urologic Oncology 5 (2000) 183–184
1078-1439/00/$ – see front matter © 2000 Elsevier Science Inc. All rights reserved.
Introduction to the special issue
The First and Second International Workshops on Diagnostic and
Prognostic Markers in Bladder Cancer
The development of biomarkers for bladder cancer has
reached the point where clinical application is now a reality.
The Bladder Cancer Marker Network of the National Can-
cer Institute has been developing and assessing biomarkers
for diagnostic and prognostic use for over a decade. In the
last several years, it has become obvious that both increased
interest and activity in this area on a global scale warranted
a meeting dedicated to this topic. As a result of the efforts of
numerous investigators in this field, the First International
Workshop on Diagnostic and Prognostic Markers in Blad-
der Cancer was held in Barcelona, Spain, in May 1997, and
the Second International Workshop was held at the same
venue in October 1998. These meetings were conducted in
workshop format to maximize interaction among the partic-
ipants with the goal of providing a framework for increas-
ingly productive activity in the area of bladder cancer mark-
ers. Five manuscripts from these workshops are included in
this issue of
Urologic Oncology.
The First Workshop began with a review of the then cur-
rent state of the art. This was followed by in-depth discus-
sions of the laboratory and clinical problems in marker de-
velopment and implementation, the currently available and
evaluable markers, the mechanisms to identify new mark-
ers, the evaluation of markers in clinical trials, and the role
of collaborative efforts in bringing new markers to clinical
use. Fundamental to the goal of bringing useful markers to
the clinic was the characterization of the various phases of
marker development. The Bladder Cancer Marker Network
has defined four phases through which markers are devel-
oped. These are as follows:
• Phase 1: Assay development and prevalence in clinical
material
• Phase 2: Initial evaluation of clinical utility
• Phase 3: Confirmation of clinical utility
• Phase 4: Validation and technology transfer.
Phase 1 includes development of a reproducible assay and
prevalence studies of the marker in human material. In this
phase of assay development, the use of well characterized
cell lines and clinical samples should result in a reliable and
reproducible assay that can be applied to clinical specimens.
Prevalence studies of the analyte in a small number of spec-
imens are performed once a reliable assay is developed. A
marker with a very low prevalence is unlikely to be clini-
cally useful. A marker that is present in almost all cancer
specimens is likely to be important for diagnosis but not
useful for defining tumor subtypes with differing biologic
activity. When clinical correlation or other biologic infor-
mation suggests that the marker may be relevant in a spe-
cific subset of cancers, the marker should be tested in that
subset.
Phase 2 development is the initial evaluation of the
biomarker assay for a defined clinical question. Clinical or
pathologic endpoints are correlated with assay results to
generate hypotheses concerning clinical utility. These stud-
ies most commonly use stage, grade, and clinical outcome
as endpoints. Statistical considerations include power (espe-
cially when multiple markers are being assessed), sensitiv-
ity, and specificity.
Phase 3 development tests the clinical utility of a marker in
a defined clinical setting using methodology, cut-off, and sample
size based on phase 2 studies. Studies should be designed with
sufficient power to test the clinical utility of the assay.
Phase 4 development validates the conclusions reached
in phase 3 and transfers the assay to other laboratories. The
assay and cutoff used here should be the same as in phase 3.
The goal of this phase is to develop a working assay through
the assessment of inter-institutional and inter-laboratory
variability, quality control, etc.
While others have given different names and numbers to
the above phases of development, the concepts involved are
similar and are essential for the development of biomarkers
and the assessment of their suitability for clinical use.
The First Workshop engendered considerable debate often
resulting in heated discussions. The participants composed a
group with a highly diverse background sharing a common in-
terest in improving the care of patients with bladder cancer
through the use of biomarkers. Concern was expressed regard-
ing long development times, the inconsistent characterization
of markers, and the need for increased collaboration between
laboratory and clinical investigators in this field. These nega-
tive concerns were countered by discussion of the progress be-
ing made in this area, the development of powerful new mo-
lecular tools to develop new biomarkers, and the ongoing
collaborations that have made this progress possible. The
members discussed ways of optimizing specimen collection,