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.
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.
Authors: Adrienne S McCampbell; Heather A Harris; Judy S Crabtree; Richard C Winneker; Cheryl L Walker; Russell R Broaddus Journal: Cancer Prev Res (Phila) Date: 2010-02-23
Authors: H Sasaki; H Nishii; H Takahashi; A Tada; M Furusato; Y Terashima; G P Siegal; S L Parker; M F Kohler; A Berchuck Journal: Cancer Res Date: 1993-04-15 Impact factor: 12.701
Authors: G L Maxwell; J I Risinger; C Gumbs; H Shaw; R C Bentley; J C Barrett; A Berchuck; P A Futreal Journal: Cancer Res Date: 1998-06-15 Impact factor: 12.701
Authors: Gini F Fleming; Virginia L Brunetto; David Cella; Katherine Y Look; Gary C Reid; Adnan R Munkarah; Richard Kline; Robert A Burger; Annekathryn Goodman; R Tucker Burks Journal: J Clin Oncol Date: 2004-06-01 Impact factor: 44.544
Authors: Carmen J Allegra; J Milburn Jessup; Mark R Somerfield; Stanley R Hamilton; Elizabeth H Hammond; Daniel F Hayes; Pamela K McAllister; Roscoe F Morton; Richard L Schilsky Journal: J Clin Oncol Date: 2009-02-02 Impact factor: 44.544
Authors: A S McCampbell; M L Mittelstadt; R Dere; S Kim; L Zhou; B Djordjevic; P T Soliman; Q Zhang; C Wei; S D Hursting; K H Lu; R R Broaddus; C L Walker Journal: Curr Mol Med Date: 2016 Impact factor: 2.222
Authors: Andrea P Myers; Virginia L Filiaci; Yuping Zhang; Michael Pearl; Kian Behbakht; Vicky Makker; Parviz Hanjani; Susan Zweizig; James J Burke; Gordon Downey; Kimberly K Leslie; Paul Van Hummelen; Michael J Birrer; Gini F Fleming Journal: Gynecol Oncol Date: 2016-04 Impact factor: 5.482
Authors: Andrea P Myers; Panagiotis A Konstantinopoulos; William T Barry; Weixiu Luo; Russell R Broaddus; Vicky Makker; Ronny Drapkin; Joyce Liu; Austin Doyle; Neil S Horowitz; Funda Meric-Bernstam; Michael Birrer; Carol Aghajanian; Robert L Coleman; Gordon B Mills; Lewis C Cantley; Ursula A Matulonis; Shannon N Westin Journal: Int J Cancer Date: 2019-12-13 Impact factor: 7.396
Authors: Shannon N Westin; Michael W Sill; Robert L Coleman; Steven Waggoner; Kathleen N Moore; Cara A Mathews; Lainie P Martin; Susan C Modesitt; Sanghoon Lee; Zhenlin Ju; Gordon B Mills; Russell J Schilder; Paula M Fracasso; Michael J Birrer; Carol Aghajanian Journal: Gynecol Oncol Date: 2019-10-15 Impact factor: 5.482