Letrozole is more effective neoadjuvant endocrine therapy than tamoxifen for ErbB-1- and/or ErbB-2-positive, estrogen receptor-positive primary breast cancer: Evidence from a phase III randomized trial

Purpose: Expression of ErbB-1 and ErbB-2 (epidermal growth factor receptor and HER2/neu) in breast cancer may cause tamoxifen resistance, but not all studies concur. Additionally, the relationship between ErbB-1 and ErbB-2 ex pression and response to selective aromatase inhibitors is unknown. A neoad juvant study for primary breast cancer that randomized treatment between le trozole and tamoxifen provided a context within which these issues could be addressed prospectively. Patients and Methods: Postmenopausal patients with estrogen- and/or progest erone receptor-positive (ER+ and/or PgR+) primary breast cancer ineligible for breast-conserving surgery were randomly assigned to 4 months of neoadju vant letrozole 2.5 mg daily or tamoxifen 20 mg daily in a double-blinded st udy. Immunohistochemistry (IHC) for ER and PgR was conducted on pretreatmen t biopsies and assessed by the Allred score. ErbB-1 and ErbB-2 IHC were ass essed by intensity and completeness of membranous staining according to pub lished criteria. cases that received letrozole, 60% responded and 48% under went successful breast-conserving surgery. The response to tamoxifen was in ferior (41%, P = .004), and fewer patients underwent breast conservation (3 6%, P = .036). Differences in response rates between letrozole and tamoxife n were most marked for tumors that were positive for ErbB-1 and/or ErbB-2 a nd ER (88% v 21%, P = .0004). Conclusion: ER+, ErbB-1+, and/or ErbB-2+ primary breast cancer responded we ll to letrozole, but responses to tamoxifen were infrequent. This suggests that ErbB-1 and ErbB-2 signaling through ER is ligand-dependent and that th e growth-promoting effects of these receptor tyrosine kinases on ER+ breast cancer can be inhibited by potent estrogen deprivation Clin Oncol 19:3808- 3816. (C) 2001 by American Society of Clinical Oncology.