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Re: Prediction of Lymph Node Metastasis in Patients

with Bladder Cancer Using Whole Transcriptome Gene

Expression Signatures

Seiler R, Lam LL, Erho N, et al

J Urol 2016;196:1036–41

Expert’s summary:

Seiler and colleagues recently published a 51-gene signature



coding and noncoding transcripts that

allows prediction of lymph node (LN) metastases in patients

with muscle-invasive bladder cancer (MIBC). To generate

their new classifier, they performed whole-transcriptome

analysis on RNA isolated from cystectomy specimens from

a 133-patient discovery cohort and validated their findings

in a validation cohort of 66 patients. Interestingly, none of the

51 genes included in KNN51 overlapped with the 20 genes

from a previously published expression signature (20-gene

lymph node signature [LN20])


. Moreover, KNN51 greatly

outperformed LN20, with an area under the receiver operating

characteristic curve of 0.82 versus 0.46. Every 10% increase in

the KNN51 score was associated with a significant increase in

the presence of LN metastases (odds ratio 2.65,




Thus, KNN51 helps to improve clinical risk stratification for

guiding optimal therapy (eg, neoadjuvant chemotherapy

[NAC]) for patients with MIBC.

Expert’s comments:

Although level 1 evidence demonstrates that NAC improves

survival for patients with MIBC (6% difference in 10-yr overall



, fewer than 20% of eligible patients receive the

recommended care


. The rate of NAC treatment is probably

so low because patients with organ-confined bladder cancer

( pT2), who comprise up to 50% of cases in contemporary

series, have excellent survival following cystectomy alone

(80% cure rate). As a consequence, only 20–25% of unselected

patients benefit fromNAC. This limited survival benefit of NAC

must be weighed against NAC-related toxicity and delay of

cystectomy. Because current staging is inadequate (25% of cN0

patients harbor LN metastases


; up to 50% of patients are

understaged and potentially undertreated


), there is a

clinical need for tools to guide treatment decisions regarding

NAC in patients with MIBC.

In KNN51, Seiler et al present such a tool. It has an

advantage over, for example, LN20 in that both coding and

noncoding transcripts are analyzed. Although the biological

significance of noncoding genes is limited, they are known

to play an important role in gene regulation, which is

undoubtedly essential in cancer formation and metastasis.

Thus, it is not surprising that most genes included in KNN51

are involved in cellular movement, tumor growth, and

metastasis formation.

The big advantage of this study is the cohort of cystectomy

patients used to develop and validate the classifier: all

patients underwent uniform surgery including extended

pelvic lymphadenectomy (ePLND). This stands in contrast to

the practice of other groups that have tried to develop their

own classifier. Because they did not performuniformPLND in

most of their cohorts, the LN counts for these groups have

rangedwidely from2 to


40 LNs. Owing to inadequate PLND,

there is a risk that the LN-negative cohort includes some LN-

positive patients, negating any possible difference in gene

expression between the two cohorts.

Some limitations have to be mentioned. First, the

platform used by Seiler and colleagues was whole-

transcriptome expression analysis. This is a laborious and

costly technique that is not widely available for standard

diagnostic procedures. A more widely used and easily

available technique needs to be validated, such as qualita-

tive real-time polymerase chain reaction. Second, the

samples used originated from radical cystectomy speci-

mens. However, clinical decision-making (eg, NAC or

upfront cystectomy) has to rely on transurethral resection

of bladder (TURB) material. Therefore, KNN51 must first be

validated on TURB samples before it is clinically applicable.

Conflicts of interest:

The author has nothing to disclose.



Smith SC, Baras AS, Dancik G, et al. A 20-gene model for molecular nodal staging of bladder cancer: development and prospective assessment. Lancet Oncol 2011;12:137–43.


Griffiths G, Hall R, Sylvester R, et al. International phase III trial assessing neoadjuvant cisplatin, methotrexate, and vinblastine chemotherapy for muscle-invasive bladder cancer: long-term results of the BA06 30894 trial. J Clin Oncol 2011;29:2171–7.


Booth CM1, Siemens DR, Li G, et al. Perioperative chemotherapy for muscle-invasive bladder cancer: A population-based outcomes study. Cancer 2014;120:1630–8



Roth B, Birkha¨user FD, Zehnder P, Burkhard FC, Thalmann GN, Studer UE. Readaptation of the peritoneum following extended pelvic lymphadenectomy and cystectomy has a significant benefi- cial impact on early postoperative recovery and complications: results of a prospective randomized trial. Eur Urol 2011;59: 204–10.


Culp SH, Dickstein RJ, Grossman HB, et al. Refining patient selection for neoadjuvant chemotherapy before radical cystectomy. J Urol 2014;191:40–7.

Beat Roth


Department of Urology, University of Bern, Bern, Switzerland

*Department of Urology, University Hospital Bern,

CH-3010 Bern, Switzerland.

E-mail address: .


2017 European Association of Urology.

Published by Elsevier B.V. All rights reserved.

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