S100A9 and EGFR gene signatures predict disease progression in muscle invasive bladder cancer patients after chemotherapy

• Published in: Annals of oncology Vol. 25; no. 5; pp. 974 - 979
• Main Authors: Kim, W.T., Kim, J., Yan, C., Jeong, P., Choi, S.Y., Lee, O.J., Chae, Y.B., Yun, S.J., Lee, S.C., Kim, W.J.
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 01-05-2014; Oxford University Press
• Subjects: Aged; Antineoplastic agents; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Apoptosis; Biological and medical sciences; Biomarkers, Tumor - genetics; Biomarkers, Tumor - metabolism; Calgranulin B - genetics; Calgranulin B - metabolism; Cell Line, Tumor; Cisplatin - pharmacology; Cisplatin - therapeutic use; Combined Modality Therapy; Disease Progression; drug resistance; Drug Resistance, Neoplasm; epidermal growth factor; ErbB Receptors - genetics; ErbB Receptors - metabolism; Female; Gene Expression; Humans; Male; Medical sciences; Middle Aged; Multiple tumors. Solid tumors. Tumors in childhood (general aspects); Neoplasm Invasiveness; Neoplasm Recurrence, Local - genetics; Neoplasm Recurrence, Local - prevention & control; Nephrology. Urinary tract diseases; Pharmacology. Drug treatments; Prognosis; Proportional Hazards Models; receptor; Treatment Failure; Tumors; Tumors of the urinary system; urinary bladder; urinary bladder neoplasms; Urinary Bladder Neoplasms - drug therapy; Urinary Bladder Neoplasms - genetics; Urinary Bladder Neoplasms - pathology; Urinary system involvement in other diseases. Miscellaneous; Urinary tract. Prostate gland; urinary bladder neoplasms; receptor; drug resistance; epidermal growth factor; urinary bladder; Human; Calgranulin B; Treatment resistance; Urinary system disease; Urinary tract disease; Malignant tumor; Muscle invasive bladder cancer; Bladder tumor; Epidermal growth factor receptor; Gene expression profile; Chemotherapy; Treatment; Epidermal growth factor; Urinary system; Urinary bladder; Bladder disease; Predictive factor; Cancer; Biological receptor
• ISSN: 0923-7534; 1569-8041
• DOI: 10.1093/annonc/mdu037

In our previous gene expression profile analysis, IL1B, S100A8, S100A9, and EGFR were shown to be important mediators of muscle invasive bladder cancer (MIBC) progression. The aim of the present study was to investigate the ability of these gene signatures to predict disease progression after chemotherapy in patients with locally recurrent or metastatic MIBC.
Patients with locally advanced MIBC who received chemotherapy were enrolled. The expression signatures of four genes were measured and carried out further functional analysis to confirm our findings.
Two of the four genes, S100A9 and EGFR, were determined to significantly influence disease progression (P = 0.023, 0.045, respectively). Based on a receiver operating characteristic curve, a cut-off value for disease progression was determined. Patients with the good-prognostic signature group had a significantly longer time to progression and cancer-specific survival time than those with the poor-prognostic signature group (P < 0.001, 0.042, respectively). In the multivariate Cox regression analysis, gene signature was the only factor that significantly influenced disease progression [hazard ratio: 4.726, confidence interval: 1.623–13.763, P = 0.004]. In immunohistochemical analysis, S100A9 and EGFR positivity were associated with disease progression after chemotherapy. Protein expression of S100A9/EGFR showed modest correlation with gene expression of S100A9/EGFR (r = 0.395, P = 0.014 and r = 0.453, P = 0.004). Our functional analysis provided the evidence demonstrating that expression of S100A9 and EGFR closely associated chemoresistance, and that inhibition of S100A9 and EGFR may sensitize bladder tumor cells to the cisplatin-based chemotherapy.
The S100A9/EGFR level is a novel prognostic marker to predict the chemoresponsiveness of patients with locally recurrent or metastatic MIBC.