Expression of epidermal growth factor receptor (EGFR) or of c-erbB2 in primary breast cancer has been shown to predict for a poor chance of subsequent response of recurrent/metastatic disease to endocrine therapy. To assess the role of these receptors in the development of tamoxifen resistance, we examined their expression immunohistochemically on paraffin-embedded sections from breast cancers from 155 patients whose disease was progressing on tamoxifen therapy. Patients were categorized into those who initially responded to therapy (n = 56), those who never responded (n = 39), and those who relapsed while on adjuvant therapy and may or may not have "responded" (n = 60). In 61 cases, pretreatment specimens were also obtained for direct comparison with the resistance specimen for each patient. None of the 18 pretreatment samples from patients who responded to therapy expressed c-erbB2, and 1 of 18 expressed EGFR. Of the nonresponders, 7 of 18 expressed EGFR pretreatment, and 4 of 18 expressed c-erbB2 (1 patient expressed both receptors). Results confirmed previous findings that when considered independently, expression of either receptor pretreatment tended to predict for a poor chance of response (EGFR, P = 0.046; c-erbB2, P = 0.11). Importantly, patients who were either EGFR positive and/or c-erbB2 positive had a much poorer chance of response than "double negatives" (response rates of 1 of 11 and 17 of 25, respectively; P = 0.0039). At the time of disease progression compared to pretreatment, there was no significant change in expression of either receptor, irrespective of initial response. The inverse relationship between EGFR and estrogen receptor was maintained at relapse on tamoxifen. These data argue strongly against the acquired expression of these receptors during treatment playing a major role in the development of tamoxifen resistance in human breast cancer.

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