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Journal of Clinical Oncology, Vol 19, Issue 18 (September), 2001: 3808-3816
© 2001 American Society for Clinical Oncology

RAPID PUBLICATIONS

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

By Matthew J. Ellis, Andrew Coop, Baljit Singh, Louis Mauriac, Antonio Llombert-Cussac, Fritz Jänicke, William R. Miller, Dean B. Evans, Margaret Dugan, Carolyn Brady, Erhard Quebe-Fehling, Mieke Borgs

From the Duke University Comprehensive Cancer Center, Durham, NC; Lombardi Cancer Center, Washington DC; Institut Bergonié, Bordeaux Cedex, France; Instituto Valenciano de Oncologia, Valencia, Spain; Universitaets Frauen-und Poliklinik UKE, Hamburg, Germany; Breast Research Unit, Western General Hospital, Edinburgh, United Kingdom; Novartis Pharma AG, Basel, Switzerland; and Novartis Pharmaceuticals, East Hanover, NJ.

Address reprint requests to Matthew Ellis, MB, PhD, FRCP, Duke University Breast Cancer Program, Box 3446, The Morris Building, Rm 25149F, Duke University Medical Center, Durham, NC 27710; email: ellis053{at}mc.duke.edu

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 ligand-dependent and that the growth-promoting effects of these receptor tyrosine kinases on ER+ breast cancer can be inhibited by potent estrogen deprivation therapy.




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