title: Predicting everolimus treatment efficacy in patients with advanced endometrial carcinoma: a GINECO group study.
abstract: This study aimed to determine whether the expression of various tumor biomarkers of the mTOR pathway predicts tumor response to everolimus in metastatic recurrent endometrial cancer. Tumor blocks from 44 patients of a phase II clinical trial receiving everolimus until progression or toxicity were collected and evaluated at 3 and 6 months for response. Thirty-six blocks were available for analysis of ER, PR, HER2, LKB1, PI3K, PTEN, pAKT, 4E-BP1, p4E-BP1, and S6RP expression by immunohistochemistry, PTEN deletion by FISH, and mutational status of K-RAS, PIK3CA, PTEN, and AKT1 genes. Twelve of 34 evaluable patients had partial response or stable disease (PR, SD) and 22 had progressive disease (PD). Immunohistochemistry showed that no protein expression could predict response to everolimus. Neither could loss of PTEN expression or PTEN deletion or PTEN mutation predict patient outcome. Thirty-one samples were assessable for K-RAS mutations (ten for PR+SD and 21 for PD). There are only four patients with K-RAS mutations and none of them responded to treatment. Median progression-free survival (PFS) and overall survival (OS) were longer in patients without K-RAS mutations (PFS 3.12 ± 1.7 months versus 1.05 ± 0.4 months, p < 0.001; OS 9.28 ± 2.0 months versus 2.30 ± 1.4 months, p = 0.034). In conclusion, the level of expression of proteins of the PI3K/mTOR pathway tested in this study cannot predict response to everolimus. However, endometrial cancer patients with K-RAS mutations do not seem to derive benefit from everolimus treatment.
authors.affiliation: Department of Medical Oncology, Léon Bérard Cancer Center, 28 rue Laennec, Lyon, 69008, France, olivier.tredan@lyon.unicancer.fr.
authors.forename: Olivier
authors.initials: O
authors.lastname: Trédan
authors.forename: Isabelle
authors.initials: I
authors.lastname: Treilleux
authors.forename: Qing
authors.initials: Q
authors.lastname: Wang
authors.forename: Nicolas
authors.initials: N
authors.lastname: Gane
authors.forename: Daniel
authors.initials: D
authors.lastname: Pissaloux
authors.forename: Nathalie
authors.initials: N
authors.lastname: Bonnin
authors.forename: Thierry
authors.initials: T
authors.lastname: Petit
authors.forename: Jacques
authors.initials: J
authors.lastname: Cretin
authors.forename: Nathalie
authors.initials: N
authors.lastname: Bonichon-Lamichhane
authors.forename: Frank
authors.initials: F
authors.lastname: Priou
authors.forename: Sandrine
authors.initials: S
authors.lastname: Lavau-Denes
authors.forename: Véronique
authors.initials: V
authors.lastname: Mari
authors.forename: Gilles
authors.initials: G
authors.lastname: Freyer
authors.forename: Daniela
authors.initials: D
authors.lastname: Lebrun
authors.forename: Jérôme
authors.initials: J
authors.lastname: Alexandre
authors.forename: Isabelle
authors.initials: I
authors.lastname: Ray-Coquard
mesh_terms: D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use; D016889:Endometrial Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D000068338:Everolimus; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D051059:PTEN Phosphohydrolase / Q000096:biosynthesis / Q000235:genetics; D019869:Phosphatidylinositol 3-Kinases / Q000096:biosynthesis; D011237:Predictive Value of Tests; D051057:Proto-Oncogene Proteins c-akt / Q000096:biosynthesis / Q000235:genetics; D020123:Sirolimus / Q000031:analogs & derivatives* / Q000627:therapeutic use; D058570:TOR Serine-Threonine Kinases / Q000096:biosynthesis; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D000068338:Everolimus; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D020123:Sirolimus; D058570:TOR Serine-Threonine Kinases; C546842:MTOR protein, human; C494918:AKT1 protein, human; C494929:PTEN protein, human