{"paper_id":"3e925a55-2df8-499e-82be-5fd394c158bd","body_text":"We read with great interest the article of Kacan et al. entitled\n“Everolimus as an mTOR Inhibitor Suppresses Endometriotic Im-\nplants: an Experimental Rat Study ” [1] published in your journal.\nThe authors surgically induced endometriosis by the autotrans-\nplantation of uterine tissue in the peritoneal cavity of 24 rats. The\nanimals were randomized in three groups, receiving oral everoli-\nmus, oral anastrozole, or intravenous saline solution for 14 days.\nHistological evaluation was done by the endometriosis score (ac-\ncording to Keenan et al. [2]) and immunohistochemical examina-\ntion was performed by using antibodies against vascular endothe-\nlial growth factor (VEGF), CD117 and BAX. The post-treatment\nanalysis of endometriotic implants revealed that anastrozole and\neverolimus succeeded in significantly decreasing their growth\nand size with no difference in histological and immunohistochem-\nical results between the two drugs. The authors noted at histology\nthat the number of ovarian follicles was not negatively altered by\neverolimus, differently from anastrozole that, as evidenced in lit-\nerature, tends to decrease it [3].\nThe rational of the study is based on the evidence of the pivotal\nrole of mTOR in angiogenesis and growth of endometriotic im-\nplants [4]. The results of the therapy are in line with a previous\nstudy performed on the animal model [5], in which Leconte et al.\nfound that also the administration of temsirolimus (intraperito-\nneal 3 mg/kg), another mTor inhibitor, for 2 weeks led to signifi-\ncant decreases in endometriosis implants growth.\nAlthough the authors should be congratulated for their labora-\ntory findings, we would like to raise some concerns on the admin-\nistration of mTor inhibitors, and in particular everolimus, in the\nclinical treatment of endometriosis. Everolimus is approved by\nFood and Drug Administration (FDA) for the treatment of ad-\nvanced tumors, such as advanced kidney cancer, progressive or\nmetastatic pancreatic or gastrointestinal neuroendocrine tumors,\nand it is currently being also evaluated in gynecological cancers.\nMoreover, its use is indicated for immunosuppression after solid\norgan transplant [6].\nAlthough in oncologic setting it has been reported that pa-\ntients with specific mutations (i.e. PIK3A, PTEN) tend to have high-\ner benefit receiving mTor pathway inhibitors, a first non-negligible\nproblem is that there are no validated predictive biomarkers for\npatientsʼ selection and for monitoring drug efficacy [7]. A second\nconcern is related to the fact that in the experiment endometri-\notic implants were surgically induced only in peritoneum of rats,\nand not in other localizations. Thus, it appears unlikely that drugs\nacting on angiogenesis-related pathways, such as mTor, may treat\nthe symptoms caused by large nodules of deep infiltrating endo-\nmetriosis (DIE), which are mainly composed of fibromuscular tis-\nsue, and may have already been present for some years.\nMore importantly, drugs targeting mTor pathway may cause\nadverse effects [8], including a large variety of metabolic, hema-\ntological, respiratory, renal and dermatological toxicities. These\nsometime serious side effects explain the notable rate of drug dis-\ncontinuation in clinical trials for advanced cancer. Although some\nof them, such as oral stomatitis (30 –60 % of patients) or pneumo-\nnitis, seem to increase with the dosage of the drug, the majority\nare idiosyncratic and unpredictable, and may also occur from days\nto years after the beginning of the therapy. These adverse effects\nmTor Inhibitors for the Treatment of Endometriosis\nmTOR-Inhibitoren zur Behandlung von Endometriose\nAuthors\nFabio Barra 1, 2, Simone Ferrero 1, 2\nAffiliations\n1 Academic Unit of Obstetrics and Gynecology, Ospedale\nPoliclinico San Martino, Genoa, Italy\n2 Department of Neurosciences, Rehabilitation, Ophthal-\nmology, Genetics, Maternal and Child Health (DiNOGMI),\nUniversity of Genoa, Genoa, Italy\nBibliography\nDOI https://doi.org/10.1055/s-0043-124518\nGeburtsh Frauenheilk 2018; 78: 283 –284 © Georg Thieme\nVerlag KG Stuttgart · New York | ISSN 0016 ‑5751\nCorrespondence\nSimone Ferrero, MD, PhD\nAcademic Unit of Obstetrics and Gynecology,\nOspedale Policlinico San Martino\nLargo R. Benzi 10, 16132 Genoa, Italy\nsimone.ferrero@unige.it\nGebFra Science | Letter to the Editor\n283Barra F and Ferrero S. mTor Inhibitors for … Geburtsh Frauenheilk 2018; 78: 283 –284\n\n\nmay be tolerable in oncological therapy, where the primary end-\npoints are disease-free survival and overall survival, but it appears\ndifficult to accept them in young women with endometriosis\nwhere the goal is improving the quality of life. In fact, endome-\ntriosis is a chronic benign disease that requires a long-term ther-\napy combining clinical efficacy (preventing recurrence, control-\nling pain symptoms) with acceptable costs and toxicity. Given this\nbackground, it seems unlikely that everolimus may have a relevant\nrole in the future treatment of women with endometriosis.\nConflict of Interest\nThe authors declare that they have no conflict of interest.\nReferences\n[1] Kacan T, Yildiz C, Baloglu Kacan S et al. Everolimus as an mTOR inhibitor\nsuppresses endometriotic implants: an experimental rat study. Geburtsh\nFrauenheilk 2017; 77: 66 –72\n[2] Keenan JA, Williams-Boyce PK, Massey PJ et al. Regression of endometrial\nexplants in a rat model of endometriosis treated with the immune mod-\nulators loxoribine and levamisole. Fertil Steril 1999; 72: 135 –141\n[3] Oral E, Demir B, Inceboz U. Endometriosis and ovarian reserve. Womens\nHealth (Lond) 2015; 11: 671 –675\n[4] Cinar O, Seval Y, Uz YH et al. Differential regulation of Akt phosphoryl-\nation in endometriosis. Reprod Biomed Online 2009; 19: 864 –871\n[5] Leconte M, Nicco C, Ngo C et al. The mTOR/AKT inhibitor temsirolimus\nprevents deep infiltrating endometriosis in mice. Am J Pathol 2011; 179:\n880–889\n[6] Wesolowski R, Abdel-Rasoul M, Lustberg M et al. Treatment-related mor-\ntality with everolimus in cancer patients. Oncologist 2014; 19: 661 –668\n[7] Gajate P , Alonso-Gordoa T, Martinez-Saez O et al. Prognostic and predic-\ntive role of the PI3K ‑AKT-mTOR pathway in neuroendocrine neoplasms.\nClin Transl Oncol 2017. doi:10.1007/s12094-017-1758-3\n[8] Pallet N, Legendre C. Adverse events associated with mTOR inhibitors.\nExpert Opin Drug Saf 2013; 12: 177 –186\n284 Barra F and Ferrero S. mTor Inhibitors for … Geburtsh Frauenheilk 2018; 78: 283 –284\nGebFra Science | Letter to the Editor","source_license":"CC0","license_restricted":false}