Breast cancer protein expression as a prognostic marker in sporadic epithelial ovarian cancer (EOC): An NCIC CTG OV.16 correlative study.

Abstract

5018 Background: There are no validated molecular biomarkers in EOC which correlate with prognosis or chemosensitivity. Breast cancer 1 (BRCA1) protein inactivation in sporadic EOC is common and reduced BRCA1 expression has been linked with platinum sensitivity. However, BRCA1 has not been clinically validated as a prognostic or predictive marker in EOC. Methods: The NCIC CTG-led Gynecologic Cancer Intergroup phase III trial, OV.16, compared topotecan/cisplatin followed by carboplatin/paclitaxel to standard carboplatin/paclitaxel in advanced EOC patients. With a median follow-up of 62 months (mo), there was no improvement in progression free survival (PFS) in the topotecan arm (Hoskins P, ASCO 2008). BRCA1 protein expression was determined by immunohistochemistry (IHC) on tissue microarrays of tumour samples from 251 Canadian patients (pts). IHC score was correlated with response rate (RR) and PFS using Cox proportional modeling adjusting for three independent prognostic factors identified in the main study (FIGO stage, residual disease (RD), and ECOG performance status). Preplanned subgroup analysis was performed for pts with minimal RD (microscopic or < 1 cm after debulking). Results: For the whole study group, BRCA1 score analyzed as a continuous variable showed no significant correlation between BRCA1 protein expression and PFS (adjusted HR = 1.15 [0.96, 1.37]; p = 0.12) or RR (HR = 0.89 [0.70, 1.12]; p = 0.32). In 116 pts with minimal RD, higher BRCA1 expression analyzed as a continuous variable was significantly associated with shorter PFS (HR = 1.40 [1.04, 1.89]; p = 0.03), but no significant correlation was found with RR. Exploratory analysis suggested that patients with minimal RD could be divided into low (BRCA1 ≤ 2.5) and high (BRCA1 > 2.5) expression groups. Pts with low BRCA1 expression had a longer PFS compared to those with high expression (median 24.7 and 16.6 mo, respectively; HR = 0.56 [0.35, 0.89]; p = 0.01). Conclusions: This study suggests that BRCA1 protein is a prognostic marker in sporadic EOC patients with minimal RD. Further research is needed to evaluate BRCA1 as a predictive biomarker and to target BRCA1 expression to enhance chemotherapeutic sensitivity. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration GlaxoSmithKline