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Gene Expression Patterns and Profile Changes Pre- and Post-Erlotinib Treatment in Patients with Metastatic Breast Cancer

Authors' Affiliations: ¹ Cancer Therapeutics Branch in Center for Cancer Research and ² Biometrics Research Branch, National Cancer Institute, NIH, Bethesda, Maryland

Requests for reprints: Sherry X. Yang or Sandra M. Swain, Cancer Therapeutics Branch, Center for Cancer Research, National Cancer Institute, Room 5101, Building 8, 8901 Wisconsin Avenue, Bethesda, MD 20889. Phone: 301-451-6882; Fax: 301-496-0047; E-mail: xy32m{at}nih.gov or swains{at}mail.nih.gov.

Purpose: To delineate gene expression patterns and profile changes in metastatic tumor biopsies at baseline and 1 month after treatment with the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor erlotinib in patients with metastatic breast cancer.

Experimental Design: Patients were treated with 150 mg of oral erlotinib daily. Gene expression profiles were measured with Affymetrix U133A GeneChip and immunohistochemistry was used to validate microarray findings.

Results: Estrogen receptor (ER) status by immunohistochemistry is nearly coincided with the two major expression clusters determined by expression of genes using unsupervised hierarchical clustering analysis. One of 10 patients had an EGFR-positive tumor detected by both microarray and immunohistochemistry. In this tumor, tissue inhibitor of metalloproteinases-3 and collagen type 1 2, which are the EGF-down-regulated growth repressors, were significantly increased by erlotinib. Gene changes in EGFR-negative tumors are those of G-protein-linked and cell surface receptor–linked signaling. Gene ontology comparison analysis pretreatment and posttreatment in EGFR-negative tumors revealed biological process categories that have more genes differentially expressed than expected by chance. Among 495 gene ontology categories, the significant differed gene ontology groups include G-protein-coupled receptor protein signaling (34 genes, P = 0.002) and cell surface receptor–linked signal transduction (74 genes, P = 0.007).

Conclusions: ER status reflects the major difference in gene expression pattern in metastatic breast cancer. Erlotinib had effects on genes of EGFR signaling pathway in the EGFR-positive tumor and on gene ontology biological process categories or genes that have function in signal transduction in EGFR-negative tumors.

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