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, PDGFR alpha, 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%); PDGFR alpha: 10 of 63 (16%); p53: 25 of 56 (45%); and p63: 46 of 53 (87%). In the multivariable model, PDGFR alpha 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 PDGFR alpha 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.

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

Maffezzini, M;
2015

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, PDGFR alpha, 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%); PDGFR alpha: 10 of 63 (16%); p53: 25 of 56 (45%); and p63: 46 of 53 (87%). In the multivariable model, PDGFR alpha 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 PDGFR alpha 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.
File in questo prodotto:
Non ci sono file associati a questo prodotto.

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11567/892752
Citazioni
  • ???jsp.display-item.citation.pmc??? 3
  • Scopus 8
  • ???jsp.display-item.citation.isi??? 10
social impact