Epidermal growth factor receptor (EGFR) downstream molecules as response predictive markers for gefitinib (Iressa®, ZD1839) in chemotherapy-resistant non-small cell lung cancer
Epidermal growth factor receptor (EGFR) downstream molecules as response predictive markers for gefitinib (Iressa®, ZD1839) in chemotherapy-resistant non-small cell lung cancer
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DOI：
10.1002/ijc.20550
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发表时间：
2005-01-01
影响因子：
6.4
通讯作者：
Kim, NK
中科院分区：
文献类型：
--
作者：
Han, SW;Hwang, PG;Kim, NK
在既往研究中，吉非替尼在化疗难治性NSCLC中显示出有意义的抗肿瘤活性和可耐受的毒性。此外，EGFR表达未能显示与反应的相关性。为了确定反应的预测标志物，我们通过免疫组织化学研究了EGFR的关键信号分子（EGFR、p-EGFR、p-Akt、p-Erk、p-STAT 3）的肿瘤表达，并分析了它们与反应的相关性。在65例接受吉非替尼（250 mg/d）治疗化疗难治性NSCLC的患者中，有14例（21.5%）部分缓解，21例（32.3%）疾病稳定，21例（32.3%）疾病进展。总生存期和进展时间的中位持续时间分别为6.7个月和2.8个月。对34例具有可评价组织标本的患者进行免疫组化。EGFR过表达（2+或3+）占32.4%，p-EGFR阳性占26.5%。p-Akt、p-Erk和p-STAT 3的阳性表达率分别为50%、38.2%和79.4%。EGFR表达与p-EGFR及其下游分子无关。EGFR或p-EGFR状态与缓解无关。p-Erk阳性表达与不良反应显著相关（-组38.1%，1+组14.3%，2+组0%; p = 0.046）。此外，具有阳性p-Akt和阴性p-Erk核表达的肿瘤表现出最佳反应（60%），而在相反的情况下[p-Akt（-），p-Erk（+）]没有反应。p-Akt（2+）的强核染色与TTP延长（HR 0.25，95%CI 0.08- 0.79，p = 0.018）和OS延长（HR 0.16，95%CI 0.04-0.62，p = 0.008）相关。这些结果支持了这样的假设，即吉非替尼的反应性可能是由活化的EGFR下游分子如p-Akt和p-Erk预测的。(C)2004 Wiley-Liss，Inc.
Gefitinib has shown meaningful antitumor activity with tolerable toxicity in chemotherapy-refractory NSCLC in previous studies. Moreover, EGFR expression failed to show a correlation with response. In an attempt to identify predictive markers of response, we have investigated the tumoral expression of key signaling molecules of EGFR (EGFR, p-EGFR, p-Akt, p-Erk, p-STAT3) by immunohistochemistry and analyzed their correlations with response. Of 65 patients who received gefitinib (250 mg/day) for chemotherapy-refractory NSCLC, there were 14 partial responses (21.5%), 21 stable diseases (32.3%) and 21 progressive diseases (32.3%). Median durations of overall survival and time to progression were 6.7 months and 2.8 months, respectively. Immunohistochemistry was performed in 34 patients with evaluable tissue specimens. EGFR was overexpressed (2+ or 3+) in 32.4% and p-EGFR was positive in 26.5%. The expressions of p-Akt, p-Erk and p-STAT3 were positive(1+ or 2+) in 50%, 38.2% and 79.4%, respectively. The EGFR expression was not correlated with p-EGFR or the downstream molecules. EGFR or p-EGFR status did not correlate with response. Positive expression of p-Erk was significantly associated with poor response (38.1% in -, 14.3% in 1+, 0% in 2+; p = 0.046). Furthermore, tumors with positive p-Akt and negative p-Erk nuclear expression exhibited the best response (60%), whereas there was no response in the opposite [p-Akt (-), p-Erk (+)] cases. Intense nuclear staining of p-Akt (2+) was associated with prolonged TTP (HR 0.25, 95% confidence interval [CI] 0.08-0.79,p = 0.018) and OS (HR 0.16, 95% CI 0.04-0.62, p = 0.008). These results support the assumption that gefitinib responsiveness might be predicted by activated EGFR downstream molecules such as p-Akt and p-Erk. (C) 2004 Wiley-Liss, Inc.