L etrozole I s M ore E ffective N eoadjuvant E ndocrine Therapy T han T amoxifen f or E rbB-1- a nd/or ErbB-2-Positive, E strogen R eceptor-Positiv e P rimary Breast C ancer: E vidence F rom a P hase I II Randomized T rial

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 expression and response to selective aromatase inhibitors is unknown. A neoadjuvant study for primary breast cancer that randomized treatment between letrozole and tamoxifen provided a context within which these issues could be addressed prospectively. Patients and Methods: Postmenopausal patients with estrogen– and/or progesterone receptor–positive (ER and/or PgR) primary breast cancer ineligible for breast-conserving surgery were randomly assigned to 4 months of neoadjuvant letrozole 2.5 mg daily or tamoxifen 20 mg daily in a double-blinded study. Immunohistochemistry (IHC) for ER and PgR was conducted on pretreatment biopsies and assessed by the Allred score. ErbB-1 and ErbB-2 IHC were assessed by intensity and completeness of membranous staining according to published criteria. Results: For study biopsy-confirmed ER and/or PgR cases that received letrozole, 60% responded and 48% underwent successful breast-conserving surgery. The response to tamoxifen was inferior (41%, P .004), and fewer patients underwent breast conservation (36%, P .036). Differences in response rates between letrozole and tamoxifen were most marked for tumors that were positive for ErbB-1 and/or ErbB-2 and ER (88% v 21%, P .0004). Conclusion: ER, ErbB-1, and/or ErbB-2 primary breast cancer responded well to letrozole, but responses to tamoxifen were infrequent. This suggests that ErbB-1 and ErbB-2 signaling through ER is liganddependent and that the growth-promoting effects of these receptor tyrosine kinases on ER breast cancer can be inhibited by potent estrogen deprivation therapy. J Clin Oncol 19:3808-3816. © 2001 by American Society of Clinical Oncology.