title: Regression of Chemotherapy-Resistant Polymerase ε (POLE) Ultra-Mutated and MSH6 Hyper-Mutated Endometrial Tumors with Nivolumab.
abstract: OBJECTIVE
  The management of endometrial carcinoma no longer amenable to treatment with surgery or radiotherapy has not improved significantly with modern chemotherapy. Alternative therapeutic options are desperately needed.
  
  
  METHODS
  We describe 2 heavily pretreated patients with recurrent disease refractory to surgery, radiotherapy, and chemotherapy who were treated with the anti-PD-1 immune checkpoint inhibitor nivolumab.
  
  
  RESULTS
  Patient #1 harbored an ultra-mutated tumor (mutation load/MB = 117.3, total mutations = 4,660) driven by mutation in the exonuclease domain of the DNA polymerase ε gene. Patient #2 harbored a hyper-mutated tumor (mutation load/MB = 33.5, total mutations = 1,037) due to a germinal MSH6 gene mutation. Both patients demonstrated a remarkable clinical response to the anti-PD-1 immune checkpoint inhibitor nivolumab. Patients' clinical responses remain unchanged at the time of the writing of this report, with no grade 3 or higher side effects reported to date.
  
  
  CONCLUSIONS
  Anti-PD-1 inhibitors represent a novel treatment option for recurrent/metastatic, ultra/hyper-mutated human tumors refractory to salvage treatment. Clin Cancer Res; 22(23); 5682-7. ©2016 AACRSee related commentary by Piulats and Matias-Guiu, p. 5623.
authors.affiliation: Department of Obstetrics and Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut. alessandro.santin@yale.edu.
authors.forename: Alessandro D
authors.initials: AD
authors.lastname: Santin
authors.affiliation: Department of Obstetrics and Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut.
authors.forename: Stefania
authors.initials: S
authors.lastname: Bellone
authors.affiliation: Department of Pathology, Yale University School of Medicine, New Haven, Connecticut.
authors.forename: Natalia
authors.initials: N
authors.lastname: Buza
authors.affiliation: Department of Genetics, Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut.
authors.forename: Jungmin
authors.initials: J
authors.lastname: Choi
authors.affiliation: Department of Obstetrics and Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut.
authors.forename: Peter E
authors.initials: PE
authors.lastname: Schwartz
authors.affiliation: Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut.
authors.forename: Joseph
authors.initials: J
authors.lastname: Schlessinger
authors.affiliation: Department of Genetics, Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut.
authors.forename: Richard P
authors.initials: RP
authors.lastname: Lifton
mesh_terms: D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D004257:DNA Polymerase II / Q000235:genetics*; D016889:Endometrial Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism; D005260:Female; D006801:Humans; D008875:Middle Aged; D009154:Mutation / Q000187:drug effects* / Q000235:genetics; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D000077594:Nivolumab; D061026:Programmed Cell Death 1 Receptor / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D061026:Programmed Cell Death 1 Receptor; D000077594:Nivolumab; D004257:DNA Polymerase II