TY - JOUR
T1 - Randomized phase II trial of letrozole plus Anti-MUC1 antibody AS1402 in hormone receptor-positive locally advanced or metastatic breast cancer
AU - Ibrahim, Nuhad K.
AU - Yariz, Kemal O.
AU - Bondarenko, Ihor
AU - Manikhas, Alexei
AU - Semiglazov, Vladimir
AU - Alyasova, Anna
AU - Komisarenko, Volodymyr
AU - Shparyk, Yaroslav
AU - Murray, James Lee
AU - Jones, David
AU - Senderovich, Shai
AU - Chau, Albert
AU - Erlandsson, Fredrik
AU - Acton, Gary
AU - Pegram, Mark
PY - 2011/11/1
Y1 - 2011/11/1
N2 - Purpose: 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 FcgRIIIa, FcgRIIa, 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 maybe a better strategy for harnessingMUC1modulation of the ER to a clinical advantage. FcgRIIIa, FcgRIIa, and MUC1 allotype did not predict outcome for patients treated with letrozole with or without AS1402.
AB - Purpose: 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 FcgRIIIa, FcgRIIa, 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 maybe a better strategy for harnessingMUC1modulation of the ER to a clinical advantage. FcgRIIIa, FcgRIIa, and MUC1 allotype did not predict outcome for patients treated with letrozole with or without AS1402.
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U2 - 10.1158/1078-0432.CCR-11-1151
DO - 10.1158/1078-0432.CCR-11-1151
M3 - Article
C2 - 21878535
AN - SCOPUS:80455144484
SN - 1078-0432
VL - 17
SP - 6822
EP - 6830
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 21
ER -