Predictive value of molecular subtyping in NMIBC by RT-qPCR of ERBB2, ESR1, PGR and MKI67 from formalin fixed TUR biopsies
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Johannes Breyer1,*, Ralph Markus Wirtz2,3,*, Wolfgang Otto1,*, Mark Laible4, Kornelia Schlombs4, Philipp Erben5,*, Maximilian Christian Kriegmair5,*, Robert Stoehr6,*, Sebastian Eidt3,*, Stefan Denzinger1, Maximilian Burger1,* and Arndt Hartmann6,*
1Department of Urology, University of Regensburg, Regensburg, Germany
2STRATIFYER Molecular Pathology GmbH, Cologne, Germany
3Institute of Pathology at The St Elisabeth Hospital Köln-Hohenlind, Cologne, Germany
4BioNTech Diagnostics GmbH, Mainz, Germany
5Department of Urology, University Medical Centre Mannheim, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany
6Institute of Pathology, University of Erlangen-Nuremberg, Erlangen, Germany
*On behalf of the BRIDGE Consortium
Johannes Breyer, email: [email protected]
Keywords: molecular subtypes, non-muscle-invasive bladder cancer, prognosis, RT-qPCR, mRNA
Received: November 15, 2016 Accepted: June 02, 2017 Published: June 28, 2017
Expression of ESR1, PGR, HER2 and Ki67 is important for risk stratification and therapy in breast cancer. Hormone receptor expression can also be found in MIBC, reflecting luminal and basal subtypes of breast cancer. Thus the purpose was to investigate on the mRNA expression of the aforementioned markers and their prognostic value in pT1 bladder cancer.
Retrospective analysis of clinical data and Formalin-Fixed Paraffin-Embedded tissues (FFPE) of patients with stage pT1 NMIBC who underwent transurethral resection of the bladder was performed. mRNA expression was measured by single step RT-qPCR. Relative gene expression was determined by normalization to two housekeeping genes (CALM2, B2M) using the 40-ΔΔCT method. Correlation of mRNA expression with outcome was assessed using Kaplan-Meier analysis and multivariate Cox regression analysis.
From overall 302 patients, 255 samples could be analyzed with valid measurements. Subtype distribution was Luminal-A in 11.4%, Luminal-B in 38.8%, triple negative in 36.9% and ERBB2 in 12.9%, respectively. Kaplan-Meier analysis revealed molecular subtyping being statistical significant for RFS (p=0.0408) and PFS (p=0.0039). Luminal-A patients did have the best RFS and PFS. Multivariate analysis revealed molecular subtyping to be significant for PFS (L-R Chi2 of 11.89, p=0.0078). Elevated expression of HER2 was statistically significant for PFS (p=0.0025) and discriminated among G3 tumors a high risk group (60% PFS) from a low risk risk group (90% PFS) after 5 year follow-up (p<0.001).
Expression of ESR1, PGR and HER2 has predictive value in stage pT1 NMIBC and reveals potential therapeutic targets.
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