title: Randomized phase II trial of letrozole plus anti-MUC1 antibody AS1402 in hormone receptor-positive locally advanced or metastatic breast cancer.
abstract: OBJECTIVE
  AS1402 is a humanized immunoglobulin G1 antibody that targets the aberrantly glycosylated antigen MUC1, which is overexpressed in 90% of breast tumors and contributes to estrogen-mediated growth and survival of breast cancer cells in vitro by modulating estrogen receptor (ER) activity. Aromatase inhibitors have been reported to enhance antibody-dependent cell-mediated cytotoxicity elicited by antibodies in vitro. We compared the outcomes of patients with breast cancer treated with letrozole with or without AS1402.
  
  
  METHODS
  The study population included 110 patients with locally advanced or metastatic hormone receptor-positive breast cancer randomized to receive 2.5 mg letrozole only once daily or with a weekly 9 mg/kg AS1402 infusion. The primary endpoint was overall response rate. Secondary endpoints included progression-free survival, time to progression, and safety. AS1402 exposure and influence of allotypes of FcγRIIIa, FcγRIIa, and MUC1 were evaluated.
  
  
  RESULTS
  The study was stopped early because of a trend toward worse response rates and a higher rate of early disease progression in the AS1402 + letrozole arm. Final analysis revealed no significant difference in efficacy between the study arms. Evaluated gene polymorphisms did not define patient subgroups with improved outcomes. Addition of AS1402 to letrozole was associated with manageable toxicity.
  
  
  CONCLUSIONS
  Because adding AS1402 to letrozole did not improve outcomes compared with letrozole only, blocking ER may be a better strategy for harnessing MUC1 modulation of the ER to a clinical advantage. FcγRIIIa, FcγRIIa, and MUC1 allotype did not predict outcome for patients treated with letrozole with or without AS1402.
authors: Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA. nkibrahim@mdanderson.org
authors: Nuhad K
authors: NK
authors: Ibrahim
authors: Kemal O
authors: KO
authors: Yariz
authors: Ihor
authors: I
authors: Bondarenko
authors: Alexei
authors: A
authors: Manikhas
authors: Vladimir
authors: V
authors: Semiglazov
authors: Anna
authors: A
authors: Alyasova
authors: Volodymyr
authors: V
authors: Komisarenko
authors: Yaroslav
authors: Y
authors: Shparyk
authors: James Lee
authors: JL
authors: Murray
authors: David
authors: D
authors: Jones
authors: Shai
authors: S
authors: Senderovich
authors: Albert
authors: A
authors: Chau
authors: Fredrik
authors: F
authors: Erlandsson
authors: Gary
authors: G
authors: Acton
authors: Mark
authors: M
authors: Pegram
mesh_terms: D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000009:adverse effects; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects; D047072:Aromatase Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007126:Immunoglobulin Allotypes; D000077289:Letrozole; D008875:Middle Aged; D018396:Mucin-1 / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D009570:Nitriles / Q000008:administration & dosage* / Q000009:adverse effects; D011960:Receptors, Estrogen / Q000096:biosynthesis; D017452:Receptors, IgG / Q000235:genetics / Q000276:immunology; D011980:Receptors, Progesterone / Q000096:biosynthesis; D014230:Triazoles / Q000008:administration & dosage* / Q000009:adverse effects
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D047072:Aromatase Inhibitors; C496124:FCGR3A protein, human; C080568:Fc gamma receptor IIA; D007126:Immunoglobulin Allotypes; C060192:MUC1 protein, human; D018396:Mucin-1; D009570:Nitriles; D011960:Receptors, Estrogen; D017452:Receptors, IgG; D011980:Receptors, Progesterone; D014230:Triazoles; C547393:epitumomab; D000077289:Letrozole