Immunohistochemistry to enhance prognostic allocation and guide decision-making of patients with advanced urothelial cancer receiving first-line chemotherapy

Clin Genitourin Cancer. 2015 Apr;13(2):171-7.e1. doi: 10.1016/j.clgc.2014.08.002. Epub 2014 Aug 8.

Abstract

Background: Knowledge of the expression of molecular drivers and potentially druggable targets might enhance prognostic classification of M UC.

Materials and methods: We analyzed archival tissue from patients with UC who underwent first-line chemotherapy for locally advanced (LA) and M disease between the years 2000 and 2013. The following biomarkers were evaluated using IHC: excision repair cross complementation (ERCC) group 1 (ERCC1), epidermal growth factor receptor (EGFR), HER2, VEGFR-3, PDGFRα, p53, and p63. Expression of ERCC1, EGFR, and HER2 was dichotomized as positive (2+, 3+) or negative (≤ 1+). Cox regression models were used to evaluate the association of biomarker expression with progression-free (PFS) and overall survival (OS), after controlling for known prognostic factors.

Results: Since June of 2009, tissues of 88 cases (27 LA, 61 M) were stained. Rates of positive IHC/number evaluable were as follows: ERCC1: 30 of 66 (45%); HER2: 24 of 52 (46%); EGFR: 31 of 54 (57%); VEGFR-3: 50 of 66 (76%); PDGFRα: 10 of 63 (16%); p53: 25 of 56 (45%); and p63: 46 of 53 (87%). In the multivariable model, PDGFRα was significantly prognostic for poorer PFS (hazard ratio [HR], 2.53; 95% confidence interval [CI], 1.01-6.37; P = .047) and trended to significance for poorer OS (HR, 2.66; 95% CI, 0.96-7.42; P = .060) and VEGFR-3 was significantly prognostic for better PFS (HR, 0.33; 95% CI, 0.15-0.74; P = .007) and OS (HR, 0.36; 95% CI, 0.15-0.85; P = .019). The c-index of the model was 0.67 and 0.68 for the 2 end points, respectively.

Conclusion: Tumor VEGFR-3 and PDGFRα expression appeared to confer a divergent prognostic effect. These data underscore the hurdles in defining the role of angiogenesis as a molecular driver and therapeutic target, and the controversial role of IHC to guide therapeutic decision-making.

Keywords: Advanced disease; Chemotherapy; Immunohistochemistry; Transitional cell carcinoma; Urothelial cancer.

MeSH terms

  • Biomarkers, Tumor / metabolism
  • Disease-Free Survival
  • Humans
  • Immunohistochemistry / methods*
  • Neoplasm Metastasis
  • Proportional Hazards Models
  • Receptor, Platelet-Derived Growth Factor alpha / metabolism*
  • Treatment Outcome
  • Urinary Bladder Neoplasms / drug therapy*
  • Urinary Bladder Neoplasms / metabolism
  • Urinary Bladder Neoplasms / pathology
  • Urothelium / drug effects
  • Urothelium / metabolism
  • Urothelium / pathology*
  • Vascular Endothelial Growth Factor Receptor-3 / metabolism*

Substances

  • Biomarkers, Tumor
  • FLT4 protein, human
  • Receptor, Platelet-Derived Growth Factor alpha
  • Vascular Endothelial Growth Factor Receptor-3