The search continues: Looking for predictive biomarkers for response mTOR inhibition in endometrial cancer.

Abstract

5016 Background: Everolimus is an oral rapamycin analog that selectively inhibits mTOR. PTEN mutations occur in 40-60% of endometrial cancer (EC). Although PTEN loss leads to constitutive activation of AKT and up-regulation of mTOR, it is not clear which EC patients will benefit from this targeted therapy. PS6K is a downstream marker of mTOR activation. Prior studies suggest KRAS mutations are associated with resistance to everolimus. We evaluated primary tumor specimens to determine if expression of biomarkers in the mTOR pathway or KRAS mutations would predict response to therapy. Methods: Correlative studies evaluating PTEN and PS6K expression by immunohistochemistry (IHC) and KRAS mutational analysis were performed from tissue blocks of primary tumor. Response to therapy was estimated with Fisher’s exact test. Positive predictive value (PPV) for each variable was calculated. Tumor from patients enrolled in a single institution, open-labeled, single arm, Phase II study in pretreated patients with recurrent EC of endometrioid histology was utilized. Patients received everolimus (10 mg PO daily/28 day cycles) until progression or toxicity. Results: 6 of 28 (21%) evaluable patients had CBR, with prolonged stable disease at 20 weeks. 24/28 specimens were evaluated for PTEN. Loss of PTEN expression by IHC did not predict response to Everolimus (p=0.62) and had a PPV of 0.13. 5/6 (83%) of patients with SD maintained PTEN expression. 28/28 specimens were evaluable for PS6K expression. PS6K expression by IHC also did not predict response (p=0.65) with a PPV 0.14. 23/28 specimens were evaluable for KRAS mutations. KRAS mutations did not predict response (p=1) with a PPV of 0.14. Interestingly, 80% (4/5) of those with SD were KRAS wildtype. Conclusions: Loss of PTEN expression, PS6K expression and KRAS mutational status did not significantly correlate with response to therapy. However, the trend seen in other studies of KRAS as a marker of resistance to mTOR inhibitors such as everolimus was supported by our findings and deserves further study. In addition, discovery of new predictive biomarkers is needed to identify subsets of patients who will benefit from therapies targeting the mTOR pathway.