Abstract 4742: Comprehensive analysis of the PI3K-Akt-mTOR pathway in epithelial ovarian carcinoma
Authors: Oishi Tetsuro , Itamochi Hiroaki , Oumi Nao , Kato Misaki , Shoji Tadahiro , Saga Yasushi , Fujiwara Hiroyuki , Shimada Muneaki , Sugiyama Toru , Suzuki Mitsuaki , Kigawa Junzo , Harada Tasuku 
Published: May 2015

[Background] Ovarian clear cell carcinoma (CCC) has shown resistance to standard chemotherapy for epithelial ovarian cancer (EOC). Patients with CCC have a worse prognosis than those with ovarian serous adenocarcinoma (SAC), which is a dominant subtype of EOC. Recently, several reports have focused on mTOR as a therapeutic target for CCC, and the mTOR inhibitor temsirolimus (CCI-779) combined with carboplatin and paclitaxel is in phase II trial for stage III/IV CCC (GOG268 study). However, no molecular biomarker to predict prognosis and/or therapeutic benefit from these agents has been identified. This study evaluated the activation status of all key members of the PI3K-Akt-mTOR pathway in CCC compared with SAC, and to elucidate its clinical relevance as a prognostic biomarker.

[Material& Methods] We studied 70 patients with CCC and 70 with SAC through formalin-fixed, paraffin-embedded tissues and clinical records collected from Tottori University, Iwate Medical University, and Jichi Medical University hospitals. Samples were subjected to immunohistochemistry for expression of PIK3CA, PTEN, p-AKT (Ser473), p-mTOR, p-p70S6K and p-4E-BP1. The expression levels were evaluated by immuno-reactive score (IRS). For statistical analyses, IRS values of 0-3 were scored as poor expression, IRS 4-8 as moderate expression and 9-12 as strong. Additionally, freshly frozen tissues obtained from 31 of 70 patients with CCC and 36 of 70 with SAC were examined for hotspot mutations of the PIK3CA gene by direct sequencing and gene amplification by FISH. The association of these molecular parameters with histologic subtype and clinical outcome were evaluated.

[Results] Strong expression of nuclear p-AKT(Ser473) in CCC was more frequent than in SAC (24.3% vs. 8.6%, p=0.011). Moderate to strong expression of p-4E-BP1 in CCC was less frequent than in SAC (50.0% vs. 68.6%, p=0.038). There were no significant differences between CCC and SAC in expression of other molecules. Expression of these molecules was not associated with tumor stage or patient outcome. Hotspot mutations of PIK3CA were detected in 22.6% of CCC and 13.9% of SAC. Of CCC, the 5-year overall survival rate was significantly lower in PIK3CA mutant cases than in wild type cases (50.0% vs. 78.0%, p= 0.042). On the other hand, there were no differences in survival rate of SAC between mutant and wild types. Amplification of the PIK3CA gene was detected among 33.3% of both CCC and SAC patients, and did not relate to survival rate of each histological subtype.

[Conclusion] These results suggest that the PIK3CA mutation is a promising prognostic biomarker for CCC. Further studies focusing on patients treated with agents targeting PI3K-Akt-mTOR pathway are warranted to develop predictive biomarkers.

Citation Format: Tetsuro Oishi, Hiroaki Itamochi, Nao Oumi, Misaki Kato, Tadahiro Shoji, Yasushi Saga, Hiroyuki Fujiwara, Muneaki Shimada, Toru Sugiyama, Mitsuaki Suzuki, Junzo Kigawa, Tasuku Harada. Comprehensive analysis of the PI3K-Akt-mTOR pathway in epithelial ovarian carcinoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4742. doi:10.1158/1538-7445.AM2014-4742