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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Han, Sae-Won; Hwang, Pil Gyu; Chung, Doo Hyun; Kim, Dong-Wan; Im, Seock-Ah; Kim, Young Tae; Kim, Tae-You; Heo, Dae Seog; Bang, Yung-Jue; Kim, Noe Kyeong
Issue Date
John Wiley & Sons
Int J Cancer. 2005 Jan 1;113(1):109-15.
AdultAgedAntineoplastic Agents/adverse effects/*therapeutic useCarcinoma, Non-Small-Cell Lung/drug therapy/*metabolismDisease Progression*Drug Resistance, NeoplasmEpidermal Growth Factor/*antagonists & inhibitorsFemaleGene Expression Regulation, NeoplasticHumansImmunohistochemistryLung Neoplasms/drug therapy/*metabolismMaleMiddle AgedPredictive Value of TestsQuinazolines/adverse effects/*therapeutic useReceptor, Epidermal Growth Factor/drug effects/*metabolismSurvival AnalysisTumor Markers, Biological/*metabolism
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.
0020-7136 (Print)
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College of Medicine/School of Medicine (의과대학/대학원)Thoracic Surgery (흉부외과학전공)Journal Papers (저널논문_흉부외과학전공)
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