The search continues: Looking for predictive biomarkers for response to mammalian target of rapamycin inhibition in endometrial cancer

Larissa A. Meyer, Brian M. Slomovitz, Bojana Djordjevic, Shannon N. Westin, David A. Iglesias, Mark F. Munsell, Yunyun Jiang, Rosemarie Schmandt, Russell R. Broaddus, Robert L. Coleman, John M. Galbincea, Karen H. Lu

Research output: Contribution to journalArticle

14 Scopus citations

Abstract

Objective: PI3K/mammalian target of rapamycin (mTOR) pathway aberrations occur in 40% to 80% of endometrial cancer. Prior studies suggest KRAS mutations are associated with resistance to mTOR inhibitors in solid tumors. The objective of this study was to determine if biomarker expression in the PI3K/mTOR pathway or KRAS mutations would predict response to therapy with everolimus, an mTOR inhibitor. Methods: Specimens from a phase II study of everolimus in recurrent endometrioid endometrial cancer were utilized. The primary end point was clinical benefit rate (CBR: objective response and nonprogression at 20 weeks). Correlative studies evaluating PTEN expression and phospho-S6 ribosomal protein (pS6rp) status by immunohistochemistry and KRAS mutational analysis were performed. Results: Six of 28 evaluable patients achieved prolonged stable disease (SD) at 20 weeks (CBR, 21%). Loss of PTEN expression did not predict CBR (P = 0.62) with a positive predictive value (PPV) of 0.13. Five (83%) of 6 patients with SD maintained PTEN expression. Neither pS6rp expression (P = 0.65) nor KRAS mutation (P = 0.99) predicted CBR; the PPV was 0.14 for each. Eighty percent (4/5) of those with SD were KRAS wild type. Combined analysis of pS6rp expression and KRAS mutation provided 100% PPV (95% confidence interval, 39.6%Y100%), suggesting no chance of CBR for these individuals with 100% specificity (95% confidence interval, 46.3%Y100%). Conclusions: S6rp phosphorylation, loss of PTEN expression, and presence of KRAS mutations alone did not correlate with CBR. However, positive pS6rp staining combined with KRAS mutation performed with 100% PPV and specificity to predict nonresponse. Identifying patients who will not benefit from mTOR inhibitors can direct therapy and reduce exposure to agents that add toxicity without clinical benefit.

Original languageEnglish (US)
Pages (from-to)713-717
Number of pages5
JournalInternational Journal of Gynecological Cancer
Volume24
Issue number4
DOIs
StatePublished - May 2014
Externally publishedYes

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Keywords

  • Endometrial cancer
  • MTOR inhibitor
  • Predictive biomarker

ASJC Scopus subject areas

  • Oncology
  • Obstetrics and Gynecology

Cite this

Meyer, L. A., Slomovitz, B. M., Djordjevic, B., Westin, S. N., Iglesias, D. A., Munsell, M. F., Jiang, Y., Schmandt, R., Broaddus, R. R., Coleman, R. L., Galbincea, J. M., & Lu, K. H. (2014). The search continues: Looking for predictive biomarkers for response to mammalian target of rapamycin inhibition in endometrial cancer. International Journal of Gynecological Cancer, 24(4), 713-717. https://doi.org/10.1097/IGC.0000000000000118