Exploratory analysis of nibrin in advanced ovarian cancer (AOC) patients treated in the phase III OVA-301 trial.

Abstract

5566 Background: Nibrin (p95/NBS1) is a protein with an essential function in DNA double-strand break repair by homologous recombination. Therefore, we have investigated its value as a possible biomarker in patients with AOC by immunohistochemistry (IHC). Methods: IHC staining was performed in 138 samples from a subset of patients that have participated in the phase III OVA-301 trial, in which the combination of trabectedin plus pegylated liposomal doxorubicin (PLD) or PLD alone were randomly administered for advanced disease after failure of platinum-based chemotherapy (Monk 2010; Monk 2012). A computerized image analysis system was used to calculate the total percentage of nibrin-positive cells. Nibrin expression was considered as a continuous variable. The analysis of overall response rate (ORR) and progression-free survival (PFS) was based on independent oncologist assessment. Overall survival (OS) was defined from randomization to death/last contact. All the comparisons had an exploratory nature; an alpha cut-off value of 0.05 (two-sided) was established as statistically significant. Results: For PFS, there was a statistically significant correlation between high levels of nibrin and short PFS (HR = 1.014, 95% CI: 1.004-1.024, p=0.0047). Similarly, for OS, there was a statistically significant correlation between high levels of nibrin and worse OS (HR = 1.009, 95% CI: 1.001-1.017, p = 0.0295). A multivariate analysis showed that high levels of nibrin were independently correlated to a worse PFS (HR = 1.012, 95% CI: 1.002-1.022, p = 0.0147) and to a worse OS (HR = 1.010, 95% CI: 1.002-1.018, p=0.0192). After stratification according to platinum-sensitivity, high nibrin showed a significant correlation with lower ORR (ORR = 1.02, 95% CI: 1.01-1.03, p=0.0009), short PFS and OS values only in the platinum-sensitive patients. Conclusions: The results point out the potential importance of nibrin expression in the clinical outcome of patients with AOC. In particular, high protein expression of nibrin seems to be associated with a worse clinical outcome. Prospective clinical trials evaluating the clinical usefulness of this marker with other standard of care treatments are warranted. Clinical trial information: NCT00113607.