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Randomized phase II trial of letrozole plus anti-MUC1 antibody AS1402 in hormone receptor-positive locally advanced or metastatic breast cancer.

AbstractPURPOSE:
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.
EXPERIMENTAL DESIGN:
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.
AuthorsNuhad K Ibrahim, Kemal O Yariz, Ihor Bondarenko, Alexei Manikhas, Vladimir Semiglazov, Anna Alyasova, Volodymyr Komisarenko, Yaroslav Shparyk, James Lee Murray, David Jones, Shai Senderovich, Albert Chau, Fredrik Erlandsson, Gary Acton, Mark Pegram
JournalClinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 17 Issue 21 Pg. 6822-30 (Nov 01 2011) ISSN: 1557-3265 [Electronic] United States
PMID21878535 (Publication Type: Clinical Trial, Phase II, Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Copyright©2011 AACR
Chemical References
  • Antibodies, Monoclonal
  • Antibodies, Monoclonal, Humanized
  • Aromatase Inhibitors
  • FCGR3A protein, human
  • Fc gamma receptor IIA
  • Immunoglobulin Allotypes
  • MUC1 protein, human
  • Mucin-1
  • Nitriles
  • Receptors, Estrogen
  • Receptors, IgG
  • Receptors, Progesterone
  • Triazoles
  • epitumomab
  • Letrozole
Topics
  • Antibodies, Monoclonal (administration & dosage, adverse effects)
  • Antibodies, Monoclonal, Humanized
  • Antineoplastic Combined Chemotherapy Protocols (administration & dosage, adverse effects)
  • Aromatase Inhibitors (administration & dosage, adverse effects)
  • Breast Neoplasms (drug therapy, genetics, metabolism, pathology)
  • Drug Administration Schedule
  • Female
  • Humans
  • Immunoglobulin Allotypes
  • Letrozole
  • Middle Aged
  • Mucin-1 (biosynthesis, genetics, immunology)
  • Neoplasm Metastasis
  • Neoplasm Staging
  • Nitriles (administration & dosage, adverse effects)
  • Receptors, Estrogen (biosynthesis)
  • Receptors, IgG (genetics, immunology)
  • Receptors, Progesterone (biosynthesis)
  • Triazoles (administration & dosage, adverse effects)

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