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
ABSTRACT
OBJECTIVE: To evaluate the presence of allelic loss in 16q22.1, including the locus of E-cadherin, in pleural effusions in breast cancer patients. STUDY DESIGN: Molecular analysis of DNA was performed using a DNA extraction kit (NucleoSpin, Macherey-Nagel, Germany). Loss of heterozygosity (LOH) in primary tumors and pleural effusions was analyzed using a microsatellite marker of the CDH1 gene, D16S265, described in previous studies. LOH was evaluated by radioactive polymerase chain reaction assay in 17 samples of pleural effusions and breast tissues (primary tumors and nonneoplastic adjacent tissue) from breast cancer patients: 7 positive for neoplastic cells, 6 suspected and 4 cases without evidence of neoplastic cells in the effusions. RESULTS: Thirteen cases (76%) were informative. LOH was detected in 5 cases (38.5%). In 3 of them LOH was detected only in the cytologic sample, and in 2 of them LOH was detected in the primary tumor and cytologic sample. CONCLUSION: Results show that LOH in the CDH1 gene can identify tumor cells in pleural effusions when morphologic analysis is difficult.
