Professorial Unit of Surgery, Nottingham City Hospital, Nottingham, United Kingdom.
Tenovus Centre for Cancer Research, Welsh School of Pharmacy, Cardiff University, Cardiff, United Kingdom.
Int J Cancer. 2010 Apr 15;126(8):1806-1816. doi: 10.1002/ijc.24884.
Estrogen receptor (ER)-positive acquired tamoxifen-resistant (TAM-R) MCF-7 breast cancer cell lines exhibit epidermal growth factor receptor (EGFR) expression/signaling and are growth-inhibited by gefitinib (IRESSA). We examined the effect of gefitinib on ER-positive TAM-R and ER-negative hormone-insensitive breast cancer in a Phase II study. Fifty-four patients with breast cancer [ER-positive/acquired TAM-R (n = 28); ER-negative (n = 26)] received oral gefitinib 500 mg/day. Tumor biopsies were taken pre- (n = 28) and 8 weeks post-treatment (n = 14 matched samples). Gefitinib was well tolerated and the clinical benefit rate (objective response or stable disease >24 weeks) was 33.3% overall (n = 18/54), and 53.6 and 11.5% in ER-positive/TAM-R and ER-negative patients, respectively. Pretreatment ER and progesterone receptor-positivity were associated with response (p < 0.001 and 0.016, respectively) and longer progression-free survival (PFS; p= 0.001 and 0.013, respectively). All patients expressed EGFR, but high pretreatment levels predicted poorer outcome (p = 0.005) and shorter PFS (p = 0.012) with gefitinib. In patients with clinical benefit, reduced Ki67 staining during treatment (p = 0.024) was commonly observed, and those with >10% decline in EGFR phosphorylation demonstrated parallel decreases in ERK1/2 MAPK phosphorylation. Acquired tamoxifen resistance appears in part mediated through EGFR signaling and can be blocked with gefitinib.
雌激素受体（ER）阳性获得性他莫昔芬耐药（TAM-R）MCF-7 乳腺癌细胞系表现出表皮生长因子受体（EGFR）表达/信号，并被吉非替尼（IRESSA）抑制生长。我们在一项 II 期研究中检查了吉非替尼对 ER 阳性 TAM-R 和 ER 阴性激素不敏感乳腺癌的影响。54 名乳腺癌患者[ER 阳性/获得性 TAM-R（n = 28）；ER 阴性（n = 26）]接受口服吉非替尼 500mg/天。在治疗前（n = 28）和 8 周后（n = 14 个匹配样本）采集肿瘤活检。吉非替尼耐受性良好，总临床受益率（客观反应或稳定疾病>24 周）为 33.3%（n = 18/54），ER 阳性/TAM-R 和 ER 阴性患者分别为 53.6%和 11.5%。治疗前 ER 和孕激素受体阳性与反应（p < 0.001 和 0.016）和更长的无进展生存期（PFS；p = 0.001 和 0.013）相关。所有患者均表达 EGFR，但高预处理水平预示着更差的结局（p = 0.005）和更短的 PFS（p = 0.012）。在具有临床获益的患者中，治疗期间 Ki67 染色减少（p = 0.024）常见，并且 EGFR 磷酸化下降>10%的患者表现出 ERK1/2 MAPK 磷酸化的平行下降。获得性他莫昔芬耐药似乎部分通过 EGFR 信号介导，并用吉非替尼阻断。
