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The Search Continues: Looking for Predictive Biomarkers for Response to Mammalian Target of Rapamycin Inhibition in Endometrial Cancer

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

International Journal of Gynecological Cancer: May 2014 - Volume 24 - Issue 4 - p 713–717
doi: 10.1097/IGC.0000000000000118
Uterine Cancer

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%–100%), suggesting no chance of CBR for these individuals with 100% specificity (95% confidence interval, 46.3%–100%).

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.

Departments of *Gynecologic Oncology & Reproductive Medicine, †Pathology/Laboratory Medicine, ‡Biostatistics, and §Hematopathology, The University of Texas M. D. Anderson Cancer Center, Houston, TX.

B.M.S. is now with the Morristown Medical Center, Women’s Cancer Center, Morristown, NJ; and B.D. is now with the University of Ottawa, The Ottawa Hospital, Ottawa, Ontario, Canada.

Address correspondence and reprint requests to Larissa A. Meyer, MD, MPH, Department of Gynecologic Oncology and Reproductive Medicine, University of Texas, MD Anderson Cancer Center, 1155 Pressler St, Unit 1362, Houston, TX 77030. E-mail: lmeyer@mdanderson.org.

Funding was provided by NIH 2P50 CA098258-06 SPORE in Uterine Cancer; NIH Training of Academic Gynecologic Oncologists Grant T32-CA101642.

The authors declare no conflicts of interest.

Received October 3, 2013

Accepted January 30, 2014

© 2014 by the International Gynecologic Cancer Society and the European Society of Gynaecological Oncology.