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Quantitative Measurement of Epidermal Growth Factor Receptor Is a Negative Predictive Factor for Tamoxifen Response in Hormone Receptor–Positive Premenopausal Breast Cancer

Jennifer M. Giltnane, Lisa Rydén, Melissa Cregger, Pär-Ola Bendahl, Karin Jirström, David L. Rimm

From the Department of Pathology, Yale University School of Medicine, New Haven, CT; Division of Pathology, Departments of Laboratory Medicine and Oncology, Lund University, Lund; and the Institution of Clinical Sciences, Malmo University Hospital, Malmo, Sweden

Address reprint requests to David L. Rimm, MD, PhD, Department of Pathology, Yale University School of Medicine, 310 Cedar St, PO Box 208023, New Haven, CT 06520-8023; e-mail: david.rimm{at}yale.edu

Purpose Although there is evidence for interaction between epidermal growth factor receptor (EGFR) and estrogen receptor (ER), it is still not clear how this affects response to endocrine therapies like tamoxifen. Here we assess the relationship between EGFR expression and tamoxifen response, with a new quantitative technology.

Patients and Methods A tissue microarray was constructed from breast cancer from a cohort of 564 patients enrolled in a randomized clinical trial for adjuvant tamoxifen treatment in early breast cancer, with a median follow-up of 14 years. EGFR expression was measured using automated quantitative analysis, a fluorescence-based method for quantitative analysis of in situ protein expression.

Results In ER-positive patients, tamoxifen-treated patients with low EGFR expression (n = 113) showed a significant effect by 2 years of adjuvant tamoxifen (P = .01), in contrast to no treatment effect in the EGFR-high group (n = 73, P = .69). The untreated group showed 49% v 57% 10-year recurrence-free survival for EGFR low versus high (P = .466) in the corresponding group of ER-positive patients. A significant beneficial effect of tamoxifen treatment was seen in the EGFR-low group (hazard ratio [HR] = 0.43 (95% CI, 0.22 to 0.84; P = .013) in contrast to no effect in the EGFR-high group (HR = 1.14; 95% CI, 0.59 to 2.22; P = .7) by using a Cox model.

Conclusion This study provides clinical evidence that confirms the basic work that has shown high EGFR can indicate resistance to tamoxifen. It suggests that careful measurement of EGFR protein expression might define a subset of low-stage patients that could benefit from an alternative therapy.

Supported by grants from the National Institutes of Health including the Avon–National Cancer Institute Progress for Patients Grant and R33 CA 106709 (D.L.R.), and grants from Gunnar Nilsson Cancer Foundation and Fru Berta Kamprad's Foundation (L.R.), and South Swedish Breast Cancer Group and South-East Swedish Breast Cancer Group.

J.G. and L.R. contributed equally to this work.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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