Bedeutung der ERBB-Rezeptorfamilie beim Urothelkarzinom der Harnblase: mRNA-Expression und prognostische Relevanz

Zusammenfassung

Hintergrund Es sind widersprüchliche Ergebnisse zur (Über)-Expression der Epidermalen Wachstumsfaktoren (ERBB1 – 4) Rezeptoren beim Urothelkarzinom der Harnblase (UCB) beschrieben. EGFR (ERBB1) und HER2 (ERBB2) stellen interessante und bereits bei anderen Entitäten etablierte therapeutische Zielstrukturen dar. Wir untersuchten die Expression von ERBB 1 – 4 auf mRNA-Ebene.

Material und Methoden 94 Patienten (w = 22; m = 72; medianes Alter: 66,5 (39 – 88) wurden retrospektiv analysiert. In Zystektomiepräparaten wurde die Expression der ERBB-Familie (ERBB1 – 4) auf RNA-Ebene nach Extraktion aus Formalin-fixiertem und Paraffin-eingebettetem Gewebe bestimmt. Die Genexpression wurde mittels Partitionstest, univariable und multivariable Regressionsanalysen in Assoziation mit histopathologischen Parametern, dem rezidivfreien (RFS) und krebsspezifischen Überleben (CSS) untersucht. Das mediane Follow up betrug 28,2 Monate (0,6 – 139).

Ergebnisse Unter Verwendung des für das CSS etablierten Cut off Levels wurde eine Überexpression bei 18 % (ERBB3), 39 % (EGFR), 34 % (HER2, ERBB2), und 30 % (ERBB4) der Patienten beobachtet. In der univariablen Analyse zeigten eine hohe HER2 – (ERBB2-) Expression (p = 0,014), ein höheres pT-Stadium (p = 0,012), ein positiver pN-Status (p = 0,0002) und eine hohe ERBB4-Expression (p = 0,012) eine signifikante Assoziation mit dem RFS. Eine niedrige HER2 – (ERBB2-) Expression (p = 0,042) und ein pN0-Status (p = 0,0003) waren signifikant mit einem längeren CSS assoziiert. Ein positiver pN-Status (p = 0,0011) und eine hohe ERBB4-Expression (p = 0,0073) waren unabhängige Prognosefaktoren für ein reduziertes RFS. Ein positiver pN-Status (p = 0,0016) war ein unabhängiger Prognosefaktor für ein reduziertes CSS. 

Schlussfolgerungen Eine hohe HER2-Expression ist mit einem reduzierten krankheitsspezifischen Überleben bei Patienten mit UCB nach radikaler Zystektomie assoziiert, zeigte jedoch keinen unabhängigen Prognosewert. Weitere Studien müssen klären, welche Patienten von einer zielgerichteten Therapie gegen HER2 (ERBB2) profitieren könnten.

Abstract

Background Altered expression of epidermal growth factor (EGF) family (ErbB) receptors in urothelial carcinoma of the urinary bladder (UCB) has been associated with adverse outcomes. Given the limited treatment options in UCB, EGFR and HER2 (ERBB2) represent established therapeutic targets in other entities. We assessed the expression of ErbB family receptors (ERBB1 – 4) on mRNA levels in correlation with histopathological and clinical parameters in patients treated with radical cystectomy (RC).

Methods 94 patients (female = 22; male = 72; median age: 66.5 years [range 39 – 88]) with UCB (pT1 – 4) treated with RC were included. Median follow-up was 28.2 months (range 0.6 – 139). ErbB mRNA expression levels were determined after extraction from formalin-fixed, paraffin-embedded tissue. Univariate and multivariate Cox proportional hazard models were performed to assess recurrence-free survival (RFS) and cancer-specific survival (CSS).

Results Overexpression was observed in 18 % (ERBB3), 39 % (EGFR), 34 % (HER2, ERBB2) and 30 % (ERBB4) of patients, respectively. Higher pathological stage (p = 0.012), a positive nodal status (p = 0.0002), high ERBB4 (p = 0.012) and high HER2 (ERBB2) levels (p = 0.014) were significantly associated with reduced RFS. A negative lymph node status (p = 0.0003) and low HER2 (ERBB2) (p = 0.042) levels had a favourable prognostic impact on CSS. In multivariate analysis, positive pN stage (p = 0.0011) and high ERBB4 (p = 0.0073) expression were independent predictors of reduced RFS. Higher pN stage (p = 0.0016) was an independent predictor of reduced CSS.

Conclusions Higher HER2 (ERBB2) expression is associated with an unfavourable prognosis in patients with UCB. However, it is not an independent predictor when measured on mRNA levels. Further analyses need to clarify which patients may still benefit from HER2 (ERBB2) targeted drugs.

Schlüsselwörter

Harnblasenkarzinom - Urothelkarzinom - radikale Zystekomie - HER2 - ERBB2 - Prognose

Keywords

bladder cancer - urothelial carcinoma - radical cystectomy - HER2 - ERBB2 - prognostic factors

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