A reported 20-gene expression signature to predict lymph node-positive disease at radical cystectomy for muscle-invasive bladder cancer is clinically not applicable.
BACKGROUND
Neoadjuvant chemotherapy (NAC) for muscle-invasive bladder cancer (MIBC) provides a small but significant survival benefit. Nevertheless, controversies on applying NAC remain because the limited benefit must be weight against chemotherapy-related toxicity and the delay of definitive local treatment. Therefore, there is a clear clinical need for tools to guide treatment decisions on NAC in MIBC. Here, we aimed to validate a previously reported 20-gene expression signature that predicted lymph node-positive disease at radical cystectomy in clinically node-negative MIBC patients, which would be a justification for upfront chemotherapy.


METHODS
We studied diagnostic transurethral resection of bladder tumors (dTURBT) of 150 MIBC patients (urothelial carcinoma) who were subsequently treated by radical cystectomy and pelvic lymph node dissection. RNA was isolated and the expression level of the 20 genes was determined on a qRT-PCR platform. Normalized Ct values were used to calculate a risk score to predict the presence of node-positive disease. The Cancer Genome Atlas (TCGA) RNA expression data was analyzed to subsequently validate the results.


RESULTS
In a univariate regression analysis, none of the 20 genes significantly correlated with node-positive disease. The area under the curve of the risk score calculated by the 20-gene expression signature was 0.54 (95% Confidence Interval: 0.44-0.65) versus 0.67 for the model published by Smith et al. Node-negative patients had a significantly lower tumor grade at TURBT (p = 0.03), a lower pT stage (p<0.01) and less frequent lymphovascular invasion (13% versus 38%, p<0.01) at radical cystectomy than node-positive patients. In addition, in the TCGA data, none of the 20 genes was differentially expressed in node-negative versus node-positive patients.


CONCLUSIONS
We conclude that a 20-gene expression signature developed for nodal staging of MIBC at radical cystectomy could not be validated on a qRT-PCR platform in a large cohort of dTURBT specimens.
Department of Pathology, Erasmus MC Cancer Institute, Erasmus Medical Center, Rotterdam, The Netherlands.
Kim E M
KE
van Kessel
Department of Urology, Cancer Computational Biology Center, Erasmus MC Cancer Institute, Erasmus Medical Center, Rotterdam, The Netherlands.|Department of Urology, Erasmus MC Cancer Institute, Erasmus Medical Center, Rotterdam, The Netherlands.
Harmen J G
HJ
van de Werken
Department of Pathology, Erasmus MC Cancer Institute, Erasmus Medical Center, Rotterdam, The Netherlands.
Irene
I
Lurkin
Department of Pathology, Erasmus MC Cancer Institute, Erasmus Medical Center, Rotterdam, The Netherlands.
Angelique C J
AC
Ziel-van der Made
Department of Pathology, Erasmus MC Cancer Institute, Erasmus Medical Center, Rotterdam, The Netherlands.
Ellen C
EC
Zwarthoff
Department of Urology, Erasmus MC Cancer Institute, Erasmus Medical Center, Rotterdam, The Netherlands.
Joost L
JL
Boormans
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000378:metabolism; D002277:Carcinoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology* / Q000601:surgery; D015653:Cystectomy; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008197:Lymph Node Excision; D008207:Lymphatic Metastasis / Q000175:diagnosis*; D008297:Male; D008875:Middle Aged; D019042:Muscle Neoplasms / Q000378:metabolism / Q000473:pathology; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D012189:Retrospective Studies; D059467:Transcriptome; D001749:Urinary Bladder Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology* / Q000601:surgery
D014408:Biomarkers, Tumor