Molecular correlates associated with a phase II study of temsirolimus (CCI-779) in patients with metastatic or recurrent endometrial cancer—NCIC IND 160

Abstract

3003 Background: PTEN is a tumor suppressor gene and mutations in PTEN causing loss of protein expression/function may play a significant role in the pathogenesis of EC. Loss of PTEN protein expression has been reported in 26–80% of EC and leads to deregulated PI3K/Akt/mTOR signalling which may give neoplastic cells a survival advantage by enhancing angiogenesis, protein translation and cell cycle progression. Inhibition of mTOR, a protein kinase downstream of the PI3K/Akt pathway and target of rapamycins, inhibits proliferation of EC cell lines and formation of EC in PTEN−/+ heterozygous mice. We have evaluated temsirolimus (T) an ester derivative of rapamycin that inhibits mTOR given the frequent loss of PTEN in human EC. Methods: A two stage, phase II study has been conducted to evaluate single agent activity of T in women with recurrent or metastatic EC (chemotherapy naïve, upto 1 prior line of hormonal therapy). Treatment was 25mg i.v. weekly. One cycle is defined as 4 weeks of therapy. Thirty one patients (pts) have been registered; 23 are evaluable for toxicity and 19 for response. Results: Preliminary results have demonstrated encouraging activity and the trial fulfilled predefined criteria for activity. Of 19 pts evaluable for response, 5 have had a confirmed partial response (PR) (26%) and 12 have stable disease (SD) as best response (63%). Two pts had progressive disease (PD) (11%). PTEN, phosphorylated (p) mTOR and p-S6 protein (immunohistochemistry) results are available on 9 pts to date. The preliminary results indicate that responses and stable disease are seen in pts irrespective of PTEN status. Loss of p-mTOR was evident in tumor cells from all pts (range 75–99% loss) and did not correlate with response. Phosphorylated S6 was low in tumor cells in the one pt who had PD (5%), and levels were higher in pts with PR and SD (mean and median 30%). Conclusions: We conclude that Temsirolimus has encouraging single agent activity for in recurrent and metastatic EC, and the findings indicate this is irrespective of PTEN status. We are currently evaluating activity of T in pts previously treated with chemotherapy and molecular correlates in additional specimens. No significant financial relationships to disclose.