ABSTRACT
PURPOSE: To administer the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor erlotinib to patients with operable untreated breast cancer during the immediate preoperative period and to measure an antiproliferative and/or a proapoptotic effect in the post-therapy specimen and determine a biomarker profile associated with evidence of erlotinib-mediated cellular activity. PATIENTS AND METHODS: Newly diagnosed patients with stages I to IIIA invasive breast cancer were treated with erlotinib 150 mg/d orally for 6 to 14 days until the day before surgery. Erlotinib plasma levels were measured by tandem mass spectrometry the day of surgery. Drug-induced changes in tumor cell proliferation and apoptosis were assessed by Ki67 immunohistochemistry and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-biotin nick-end labeling analysis, respectively, in biopsies from the pretherapy and surgical specimens. Biopsies were also evaluated for P-EGFR, P-HER-2, P-MAPK, P-Akt, P-S6, and S118 P-ER alpha. RESULTS: In drug-sensitive PC9 xenografts, 5 days of treatment with erlotinib were enough to induce a maximal inhibition of cell proliferation and induction of apoptosis. Forty-one patients completed preoperative treatment with erlotinib. Grade Subject(s)
Antineoplastic Agents/therapeutic use
, Biomarkers, Tumor/metabolism
, Breast Neoplasms/drug therapy
, Breast Neoplasms/surgery
, Neoadjuvant Therapy/methods
, Neoplasms, Hormone-Dependent/drug therapy
, Neoplasms, Hormone-Dependent/surgery
, Protein Kinase Inhibitors/therapeutic use
, Protein-Tyrosine Kinases/antagonists & inhibitors
, Quinazolines/therapeutic use
, Adult
, Aged
, Animals
, Antineoplastic Agents/blood
, Antineoplastic Agents/pharmacology
, Breast Neoplasms/metabolism
, Breast Neoplasms/pathology
, Cell Proliferation/drug effects
, Chemotherapy, Adjuvant
, ErbB Receptors/metabolism
, Erlotinib Hydrochloride
, Female
, Humans
, Immunohistochemistry
, In Situ Nick-End Labeling
, Ki-67 Antigen/metabolism
, Mice
, Mice, Nude
, Middle Aged
, Neoplasm Staging
, Neoplasms, Hormone-Dependent/metabolism
, Neoplasms, Hormone-Dependent/pathology
, Protein Kinase Inhibitors/blood
, Protein Kinase Inhibitors/pharmacology
, Quinazolines/blood
, Quinazolines/pharmacology
, Receptor, ErbB-2/metabolism
, Receptors, Estrogen/metabolism
, Receptors, Progesterone/metabolism
, Signal Transduction/drug effects
, Tandem Mass Spectrometry
, Treatment Outcome
, Xenograft Model Antitumor Assays