title: Exploring Morphologic and Molecular Aspects of Endometrial Cancer Under Progesterone Treatment in the Context of Fertility Preservation.
abstract: OBJECTIVE
  The standard treatment of early-stage (FIGO [International Federation of Gynecology and Obstetrics] I) endometrioid endometrial cancer (EEC) is hysterectomy with bilateral salpingo-oophorectomy. An alternative approach for younger women with low-grade EEC who wish to preserve fertility may be hormonal treatment. Previous studies have suggested that progesterone may elicit its antitumor effect in EEC by interacting with the Wingless (Wnt) and/or phosphatidylinositol 3-kinase (PI3K)/Akt pathways. Therefore, we explored whether common activating genetic alterations in Wnt and PI3K/Akt signaling correlated with nonresponsiveness to progesterone therapy for low-grade EEC. In addition, we investigated whether benign morphology under progesterone treatment is accompanied by the absence of genetic changes.
  
  
  METHODS
  We analyzed molecular alterations in the Wnt and PI3K/Akt signaling in 84 serial endometrial samples from 11 premenopausal patients with progesterone receptor-positive low-grade EEC conservatively treated with progesterone and correlated these with histological and clinical follow-up.
  
  
  RESULTS
  There were 6 responders and 5 nonresponders to progesterone treatment. The response rate to progesterone treatment was 55%, and the relapse rate was 83%. All responders had alterations in both the Wnt and PI3K/Akt pathway before treatment. In the nonresponder group, tumors inconsistently showed alterations in none, 1, or both pathways. Normalization of the endometrium morphology under progesterone treatment is accompanied by the absence of the genetic changes found in the specimen before treatment.
  
  
  CONCLUSIONS
  We found that activating molecular alterations in either Wnt or PI3K/Akt signaling pathways did not predict resistance to progesterone treatment. It seems that morphological response goes along with disappearance of the established mutations. This exploratory study suggests that Wnt or PI3K/Akt status is unable to predict response to progesterone treatment in patients with EEC.
authors.affiliation: Departments of *Gynaecology and †Pathology, Leiden University Medical Center, Leiden; and Departments of ‡Gynaecology and §Pathology, Medical Center Haaglanden, The Hague, The Netherlands.
authors.forename: Mignon D J M
authors.initials: MD
authors.lastname: van Gent
authors.forename: Alina R
authors.initials: AR
authors.lastname: Nicolae-Cristea
authors.forename: Cor D
authors.initials: CD
authors.lastname: de Kroon
authors.forename: Elisabeth M
authors.initials: EM
authors.lastname: Osse
authors.forename: Marjolein J
authors.initials: MJ
authors.lastname: Kagie
authors.forename: J Baptist M Z
authors.initials: JB
authors.lastname: Trimbos
authors.forename: Hans Marten
authors.initials: HM
authors.lastname: Hazelbag
authors.forename: Vincent T H B M
authors.initials: VT
authors.lastname: Smit
authors.forename: Tjalling
authors.initials: T
authors.lastname: Bosse
mesh_terms: D000328:Adult; D014408:Biomarkers, Tumor / Q000378:metabolism*; D016889:Endometrial Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*; D005260:Female; D059247:Fertility Preservation; D005500:Follow-Up Studies; D006801:Humans; D007124:Immunoenzyme Techniques; D009367:Neoplasm Staging; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D011374:Progesterone / Q000627:therapeutic use*; D011372:Progestins / Q000627:therapeutic use; D011379:Prognosis; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D012189:Retrospective Studies; D015398:Signal Transduction
chemical_list: D014408:Biomarkers, Tumor; D011372:Progestins; D011374:Progesterone; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt