Biological markers of cisplatin resistance in advanced testicular germ cell tumors (GCT)

Abstract

16063 Background: GCT of the testis show exquisite sensitivity to treatment with cisplatin. Despite the high cure rates provided by platinum-based chemotherapy, 10–20% of patients (pts) die from progressive disease. Although various cellular pathways may influence cisplatin efficacy, their actual impact has not been comprehensively investigated in tumor samples from advanced subgroups of testicular GCT. In order to define a novel molecular profile of treatment response and cisplatin resistance in GCT, we here immunohistochemically assessed the expression status of proteins in the Rb and p53 tumor suppressor pathways including p53, MDM2, and G1-phase Cyclins D1 and D2 (CD1 and CD2) in advanced testicular cancer and correlated the results with the clinical course. Methods: Paraffin-embedded tumor tissues from 84 pts with advanced GCT treated with cisplatin-based chemotherapy from 1980 to 2003 were analyzed. The immunoreactivity of p53, MDM2, CD1 and CD2 was scored according to the percentage of stained nuclei per total number of nuclei in the sample preparation. The cut-off values for tumor cell staining were defined as follows: p53 nuclear overexpression if ≥ 10% tumor nuclei stained; MDM2 overexpression if > 40% tumor nuclei stained; any trace of staining was scored as positive for CD1 expression and CD2 overexpression was considered if ≥ 5% tumor nuclei stained. Statistical analyses were performed to evaluate both the predictive and the prognostic impact of each molecular marker. Results: The percentages of positive expression of p53, MDM2, CD1 and CD2 were 56, 57, 37.5 and 55%, respectively. From univariate analysis, positive CD2 expression was found to be marginally associated with shorter median duration of progression-free survival (p = 0.06). In multivariate analysis, CD2 overexpression no longer retained statistical significance with treatment response nor survival. Conclusions: Aberrant CD2 expression, a previously described early-event in germ cell tumorigenesis, appears to further determine a shorter progression-free survival in patients with advanced GCT. Further larger studies are required to validate the selective usage of the D-Type Cyclin CD2 during acquisition of cisplatin resistance by GCT. No significant financial relationships to disclose.