EGFR mutation, immunohistochemistry (IHC) and chromogenic in situ hybridization (CISH) as predictors of sensitivity to erlotinib and gefitinib in patients (pts) with NSCLC.

7031 Background: Erlotinib and gefitinib produce dramatic responses in a subset of pts with NSCLC. Mutations in the EGFR tyrosine kinase (TK), EGFR amplification or polysomy and EGFR overexpression on IHC have all been associated with sensitivity and benefit. This study was undertaken to compare the ability of each of these characteristics to predict clinical benefit.,We studied 44 pts with advanced NSCLC treated with erlotinib (n=24) or gefitinib (n=20) in whom adequate tissue, radiographic and clinical follow-up were available. Sequencing of EGFR exons 19 and 21 was performed as previously described (Pao, et al PNAS, 2004). EGFR copy number was studied by CISH (Zymed). EGFR signals in 30 tumor cells were counted. Detection of ≥6 signals per cell was considered evidence of amplified copy number. EGFR IHC was performed using a DAKO test and scored as 0 vs + (membrane staining in >10% of cells). Fisher's exact test was used to study the association of each feature in pts with partial response (18) or no partial response (26). Analysis of non-responders was performed using time on drug as a surrogate for biologic effect (< vs ≥ 3 months).,Presence of an EGFR mutation in 15/18 tumors that responded was a powerful predictor of response (p <10). EGFR by IHC was scored as + in 10/18 responders and 7/26 non-responders (p=0.07). In 3/3 pts with partial response but no EGFR mutation, IHC was + but CISH was < 6. EGFR amplification by CISH was present in 3/18 responders and 6/26 non-responders (p=0.72). No difference in EGFR expression (p=0.66) was observed between pts without partial response who were on drug for < 3 mos (n=14) and ≥ 3 mos (n=12) while CISH was > 6 in 9/14 (< 3 mos) versus 1/12 (≥3 mos) (p=0.17).,The presence of an EGFR TK mutation is the strongest predictor of sensitivity to gefitinib or erlotinib. EGFR IHC may correlate with radiographic regressions; this observation is consistent with that seen in BR21. Gene amplification was seen in 9/44 (20%) but did not correlate with mutation status or radiographic regression. Further efforts are needed to refine the molecular features of pts without EGFR-TK mutations who benefit from these agents. [Table: see text].