Epidermal growth factor receptor (EGFR) downstream molecules as response predictive markers for gefitinib (Iressa®, ZD1839) in chemotherapy‐resistant non‐small cell lung cancer

Abstract

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.