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7025 Background: Gefitinib (Iressa), a small molecule inhibitor of the epidermal growth factor receptor tyrosine kinase (EGFR-TK), induces objective regressions in 9–18% of NSCLC patients. Bronchioloalveolar histology and smoking history may predict response to gefitinib (Shah, NT, Proc ASCO 2003). Molecular studies to date have not shown any correlation between EGFR status and sensitivity to gefitinib (Bailey LR, Proc AACR 2003). To determine molecular characteristics predictive of sensitivity, we undertook selected analyses in gefitinib-sensitive and –refractory patients. Methods: Unstained slides or pathology blocks were collected on an IRB-approved protocol from 54 of 139 consecutive NSCLC patients treated at MSKCC with single agent gefitinib from 09/98 –11/02. Immunohistochemistry was performed on anonymized samples for total EGFR, the putative target of gefitinib; HER2/NEU, an EGFR family member whose co-expression may predict poorer outcome in NSCLC; phospho-AKT, an activated downstream signaling molecule that may confer resistance to gefitinib; and p53, a tumor suppressor gene frequently altered in NSCLC. Staining was graded by 2 pathologists blinded to clinical variables and outcomes. Results: The status of EGFR, HER2, p-AKT, and p53 are given in the table below. Among 20 patients whose tumors were EGFR(+) and HER2(+), 9 were gefitinib-sensitive; by contrast, only 1 of 8 patients whose tumors were negative for both markers was sensitive (p=0.19). Conclusions: We found no relationship between total EGFR, p-AKT or p53 and sensitivity to gefitinib. HER2 expression (63%) was higher than that usually reported in NSCLC. The high percentage (80%) of HER2-positive tumors among gefitinib-sensitive patients warrants confirmation in a larger series, and strategies to block concurrently both EGFR and HER2 may be clinically useful. Studies on p-EGFR, p-MAPK, and PTEN are in progress. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration AstraZeneca AstraZeneca AstraZeneca Telek AstraZeneca
Pao et al. (Thu,) studied this question.