Newby J C, Johnston S R, Smith I E, Dowsett M
Departments of Academic Biochemistry and Medicine, Royal Marsden Hospital, Fulham Road, London, SW3 6JJ United Kingdom.
Clin Cancer Res. 1997 Sep;3(9):1643-51.
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.
原发性乳腺癌中表皮生长因子受体（EGFR）或c-erbB2的表达已被证明可预测复发/转移性疾病后续接受内分泌治疗时反应不佳的可能性。为了评估这些受体在他莫昔芬耐药发展中的作用，我们采用免疫组织化学方法检测了155例接受他莫昔芬治疗但病情仍进展的乳腺癌患者石蜡包埋切片中这些受体的表达情况。患者被分为初始治疗有反应者（n = 56）、从未有反应者（n = 39）以及辅助治疗期间复发且可能有或没有“反应”者（n = 60）。在61例患者中，还获取了治疗前标本以便与每位患者的耐药标本进行直接比较。对治疗有反应的患者的18份治疗前样本中，无一表达c-erbB2，18份中有1份表达EGFR。在无反应者中，18份治疗前样本中有7份表达EGFR，18份中有4份表达c-erbB2（1例患者两种受体均表达）。结果证实了先前的发现，即单独考虑时，治疗前任一受体的表达往往预示反应不佳的可能性（EGFR，P = 0.046；c-erbB2，P = 0.11）。重要的是，EGFR阳性和/或c-erbB2阳性的患者反应机会比“双阴性”患者差得多（反应率分别为11例中的1例和25例中的17例；P = 0.0039）。与治疗前相比，疾病进展时，无论初始反应如何，两种受体的表达均无显著变化。在他莫昔芬治疗复发时，EGFR与雌激素受体之间的负相关关系依然存在。这些数据有力地反驳了这些受体在治疗期间的获得性表达在人类乳腺癌他莫昔芬耐药发展中起主要作用的观点。
