Evaluation of nuclear NF-κB, transglutaminase2, and ERCC1 as predictors of platinum resistance in testicular tumors

Abstract

Purpose: Testicular germ cells tumor (TGCT) are associated with a high cure rate and are treated with platinum-based chemotherapy. However, a group of testicular cancer patients may have a very unfavorable evolution and insensitivity to the main therapeutic agent chemotherapy (CT) cisplatin. The aim of this study was to evaluate the risk of recurrence and overall survival related to the expression of nuclear factor kappa-B (NF-κB), transglutaminase 2 (TG2) and excision repair cross-complementation group 1 (ERCC1) in patients with TGCT treated with platinum combinations.

Patients and methods: A retrospective study was performed with TGCT patients treated with platinum-based chemotherapy. Immunohistochemical analysis was performed and the expression was correlated with clinical and laboratory data.

Results: Fifty patients were included, the mean age was 28.4 years (18 to 45), and 76% were non-seminoma. All patients were treated with standard cisplatin, etoposide and bleomycin or cisplatin, and etoposide. Patient's analyzed immunodetection for NF-κB, TG2, and ERCC1 were positive in 76%, 54% and 42%, respectively. Multivariate analysis identified that positive expressions to ERCC1 and NF-κB are independent risk factors for higher recurrence TGCT after chemotherapy (RR 2.96 and 3.16, respectively). Patients with positive expression of ERCC1 presented a poor overall survival rate for 10-year follow (p=0.001).

Conclusions: The expression of ERCC1 and NF-κB give a worse prognosis for relapse, and only ERCC1 had an influence on the overall survival of TGCT patients treated with platinum-based chemotherapy. These may represent markers that predict poor clinical outcome and response to cisplatin.

Keywords: Cisplatin; Testicular Neoplasms; transglutaminase 2 [Supplementary Concept].

Figure 1. Representative images of H&E and immunostaining for the tumor markers (x400): A) H&E of non-seminoma testicular Tumor. Arrows indicate immunopositivity for: B) ERCC1; C) NF-κB; D) TG2.

Figure 2. A) Relative risk for relapse to ERCC1 positive cases; stratified mode adjustments for factors such as age, clinical stage (CS), alpha-fetoprotein (AFP), beta-hCG, lactate dehydrogenase (LDH) and histology non-seminoma. B) The relative risk for relapse to NF-KB positive cases; stratified mode adjustments for factors such as age, clinical stage (CS), alphafetoprotein (AFP), beta-hCG, lactate dehydrogenase (LDH) and histology non-seminoma. C) The relative risk for relapse to TG2 positive cases; stratified mode adjustments for factors such as age, clinical stage (CS), alpha-fetoprotein (AFP), beta-hCG, lactate dehydrogenase (LDH) and histology non-seminoma. Amounts right corresponds to p and ranges (n=50).

Figure 3. Kaplan-Meier estimate of overall survival probability according to ERCC1, p <0.001. A) NF-κB, p=0.084; B) and TG2, p=0.066; C). The differences in OS between categories of interest were analyzed using the log-rank test, and the significance level was set at α=0.05.