Response to primary chemotherapy (CHT) in advanced epithelial ovarian cancer (EOC) patients (pts) and molecular characterization of CHT-resistant tumor cell populations: Findings from the Arianna 02 Project

16059 Background: Despite a high response rate to CHT the prognosis of pts with advanced EOC remains poor. The molecular analysis of pre- and post-CHT tumor specimen may enable the identification of CHT resistant tumor cell populations and thereby lead to adapted treatment options. Methods: Stage III-IV EOC pts diagnosed by laparoscopy and biopsy and not suitable for optimal debulking surgery were eligible. Gene-expression profiles generated from total RNA using the Affymetrix U133A oligonucleotide microarray containing over 22,000 probe sets were obtained at diagnosis and on surgical specimens after 6 courses of primary carboplatin/paclitaxel CHT. Initial comparative analysis focused on proliferative and invasive tumor activity, and on growth factor- and hormone receptors expression. Results: 30 pts were enrolled and data were analyzed according to response to CHT and to time to relapse after surgery. Initial expression analysis results reveal that the quantitative determination of growth factor- and hormone receptors in pre- and post-treatment samples can be used to discriminate responders from non-responders and relates to clinical outcome. Moreover, multiple CHT-resistant tumor cell populations displayed pronounced estrogen receptor expression suggesting a role of hormone receptors in the development of CHT resistance. Conclusions: While hormonal therapies are used in the treatment of other endocrine related tumors, they are not approved for the treatment of EOC. Treatment of EOC cell lines with estrogens down-regulates GnRH activity and promotes cell growth, while tamoxifen has an opposite effect. However, further biological data are lacking in this setting and only few clinical trials have addressed this possibility so far. We have found that the expression of hormone receptors in vivo persists in CHT-resistant tumor cell populations after CHT for EOC. We suggest that hormone receptor activity contributes to the initial development of CHT resistance; hence endocrine therapies particularly in an early setting may be advantageous to a subset of pts and are worth studying. No significant financial relationships to disclose.