title: Phase I study and biomarker analysis of lapatinib and concurrent radiation for locally advanced breast cancer.
abstract: OBJECTIVE
  This phase I study assessed the toxicity and safety of combining daily lapatinib with radiation therapy. Sequential tumor biopsies were obtained to evaluate changes in biomarkers, such as epidermal growth factor receptor (EGFR) and human EGFR-2 (HER2) signaling pathways.
  
  
  METHODS
  Eligibility for this dose-escalation study included unresectable and locally recurrent or chemotherapy-refractory and locally advanced breast cancer, and adequate organ function. Patients underwent three serial biopsies: at baseline, after 1 week of lapatinib alone, and after 1 week of lapatinib and radiation. Endpoints included determination of toxicity, maximum tolerated dose, and analysis of the effect of lapatinib with or without radiation on EGFR and HER2 signaling pathways by immunohistochemistry.
  
  
  RESULTS
  Doses of lapatinib up to 1,500 mg/day were well tolerated. Toxicity of grade 3 or more was limited to radiation dermatitis and pain. Out of 19 patients treated, in field responses per response evaluation criteria in solid tumors criteria were complete in four patients and partial in six patients. Serial biopsies were obtained in 16 patients with no complications. Total Her2 was relatively unchanged while phospho-Her2, phospho-Akt, and phospho-ERK showed variable responses to both lapatinib alone and dual therapy with lapatinib and radiation.
  
  
  CONCLUSIONS
  The combination of lapatinib and radiation was well tolerated in this patient cohort. Overall local response rates were comparable to those reported in other studies in this patient population. Biopsies were safely performed at all time points. Inhibition of HER2 and downstream signaling pathways was identified, although no strong correlation with response was seen.
authors.affiliation: Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, 1111 Highland Ave., Madison 53705, USA. rkimple@humonc.wisc.edu
authors.forename: Randall J
authors.initials: RJ
authors.lastname: Kimple
authors.forename: Janet K
authors.initials: JK
authors.lastname: Horton
authors.forename: Chad A
authors.initials: CA
authors.lastname: Livasy
authors.forename: Janiel M
authors.initials: JM
authors.lastname: Shields
authors.forename: Julia A
authors.initials: JA
authors.lastname: Lawrence
authors.forename: Wingkeung M
authors.initials: WM
authors.lastname: Chiu
authors.forename: Anastasia
authors.initials: A
authors.lastname: Ivanova
authors.forename: David W
authors.initials: DW
authors.lastname: Ollila
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Carey
authors.forename: Jan S
authors.initials: JS
authors.lastname: Halle
authors.forename: Carolyn I
authors.initials: CI
authors.lastname: Sartor
authors.forename: E Claire
authors.initials: EC
authors.lastname: Dees
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000032:analysis; D001706:Biopsy / Q000379:methods; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000532:radiotherapy*; D015331:Cohort Studies; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D000077341:Lapatinib; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D011799:Quinazolines / Q000627:therapeutic use*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D014408:Biomarkers, Tumor; D066246:ErbB Receptors; D000077341:Lapatinib; D051057:Proto-Oncogene Proteins c-akt; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; C508053:ERBB2 protein, human