Journal of Clinical Oncology, 2007 ASCO Annual Meeting Proceedings (Post-Meeting Edition).
Vol 25, No 18S (June 20 Supplement), 2007: 14112
© 2007 American Society of Clinical Oncology

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Abstract

Predicting and monitoring tumor response to epidermal growth factor receptor inhibitor gefitinib in patients with locally advanced esophageal adenocarcinoma

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD; The Johns Hopkins University, Baltimore, MD

14112

Background: This study aimed to validate an ex vivo chemosensitivity assay to measure the pharmacodynamic effect of gefitinib on esophageal adenocarcinoma (EAC) prior to treatment with pre-operative concomitant chemoradiotherapy (CRT). Methods: A 14 day run-in period with 250 mg/day of gefitinib preceded CRT. Endoscopic biopsies (D 0 and 14) in 4 patients with T_2–3N_0/1M_0/1a EAC were analyzed by ex vivo chemosensitivity assay. Day 0 tissue was exposed to gefitinib ex vivo, then tumor was exposed to gefitinib for 14 days in vivo (ie in the patient). Phosphorylation of the EGFR, raf/MEK/ERK and PI3/AKT pathways was measured by Western blot. Profiles were compared for correlation between ex vivo and in vivo exposure, and patterns were correlated with response to CRT. The effects were also characterized by immunohistochemistry (IHC). EGFR, K-Ras, and PI3K mutations, serum concentrations of gefitinib and PTEN status were measured as potential confounders. Results: One patient with stage T3N1 died of unexplained hemorrhage during surgery. Three had clinical and path stages of: T3N1/T0N0, T3N0/T3N0, T3N1/T2N1. Gefitinib levels were constant, confirming exposure of target tissue to the drug. Ex vivo exposure yielded four distinct pathway patterns. The exact same patterns were seen after in vivo exposure. No mutations were identified in exons 18–21 of the EGFR, exons 2/3 of K-ras or exons 9/22 of PI3K. PTEN levels were similar in all tumors. PCNA expression correlated with raf/MEK/ERK pathway inhibition, but not with inhibition of EGFR activity. IHC correlated with Western blot for expression of EGFR, and phospho- and total ERK levels. No correlation was observed between gefitinib effect and pathologic response to CRT. Conclusions: This study used a novel ex vivo chemosensitivity assay to demonstrate the activity of gefitinib to inhibit target in tumor tissue obtained from patients with EAC. The exact correlation of pre- and post-treatment profiles suggests potential use in the pre-treatment setting to predict in vivo effects of targeted therapies. This approach may facilitate the further refinement of patient selection to maximize potential benefit while sparing patients unlikely to respond to a given agent.

No significant financial relationships to disclose.