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reported slightly higher progression rates , but patients
were recruited during the 1980s, when treatment and
follow-up differed from current practice. Another limitation
was that only 61% of patients enrolled in the study fulfilled
all the testing criteria. Small tumour biopsies resulting in
insufficient RNA amounts were the main problem. This may
be compensated for in future studies using PCR protocols
with less template requirements and with the use of FFPE
specimens, for which more tumour material is usually
available for testing. A final limitation was the use of FF
biopsies, which is not standard practice in the clinical
setting and is more labour-intensive. However, our
comparative analyses of 52 FF and FFPE paired tumour
samples showed high correlation between the test results.
As different parts of the same tumours were compared,
some of the variation observed may be caused by true
biological differences and tumour heterogeneity.
We propose that the progression score may be applied to
improve clinical decision-making and for counselling of
patients with NMIBC. Cystectomy may be beneficial for
clinically high-risk patients with a high progression score,
while continued surveillance and BCG instillations may be
beneficial for clinically high-risk patients with a low
progression score. Patients with low clinical risk but high
progression scores may be monitored as clinically high-risk
patients. The 12-gene progression score in combination
with the EORTC risk score is very promising and should be
incorporated in future clinical studies of treatment and
follow-up procedures to allow a precision medicine
approach to bladder cancer.
5. Conclusions
This large-scale, prospective validation study provides
evidence of the independent prognostic value of a 12-gene
progression score for risk assessment in NMIBC. Future use
of the progression score in clinical trials may help in
stratifying patients to optimise treatment and follow-up.
Author contributions: Lars Dyrskjøt had full access to all the data in the
study and takes responsibility for the integrity of the data and the
accuracy of the data analysis.
Study concept and design: Dyrskjøt, Steyerberg, Zwarthoff, Real, Malats,
Malmstro¨m, Ørntoft.
Acquisition of data: Dyrskjøt, Reinert, Algaba, Hermann, Mogensen,
Beukers, Marquez, Segersten, Høyer, Ulhøi, Hartmann, Sto¨hr, Wach,
Nawroth, Schwamborn, Tulic, Simic, Junker, Harving, Petersen, Jensen,
Keck, Grimm, Horstmann, Maurer.
Analysis and interpretation of data: Dyrskjøt, Reinert, Christensen,
Steyerberg, Nieboer, Ørntoft.
Drafting of the manuscript: Dyrskjøt.
Critical revision of the manuscript for important intellectual content:
Ørntoft.
Statistical analysis: Dyrskjøt, Nieboer, Steyerberg.
Obtaining funding: Dyrskjøt, Ørntoft.
Administrative, technical, or material support: Algaba, Hermann, Mogensen,
Høyer, Ulhøi, Hartmann, Sto¨hr, Schwamborn, Tulic, Simic, Junker,
Harving, Petersen, Jensen, Keck, Grimm, Horstmann, Maurer, Malmstro¨m.
Supervision: Dyrskjøt, Ørntoft.
Other: None.
Financial disclosures: Lars Dyrskjøt certifies that all conflicts of interest,
including specific financial interests and relationships and affiliations
relevant to the subject matter or materials discussed in the manuscript
(eg, employment/affiliation, grants or funding, consultancies, honoraria,
stock ownership or options, expert testimony, royalties, or patents filed,
received, or pending), are the following: None.
Funding/Support and role of the sponsor: This work was supported by
grants from the John and Birthe Meyer Foundation, The Lundbeck
Foundation, The Danish Cancer Biobank, and The European Community’s
Seventh Framework Programme FP7 (#201663). Supported, in part, by
RTICC from Instituto de Salud Carlos III (RD12/0036/0034, RD12/0036/
0050), cofunded by FEDER funds, and Asociacio´ n Espan˜ola Contra el
Ca´ncer. The sponsors had no role in the study.
Appendix A. Supplementary data
Supplementary data associated with this article can be
found, in the online version, at
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