title: Phase II study of predictive biomarker profiles for response targeting human epidermal growth factor receptor 2 (HER-2) in advanced inflammatory breast cancer with lapatinib monotherapy.
abstract: OBJECTIVE
  Inflammatory breast cancer (IBC) is one of the most aggressive forms of breast cancer. Lapatinib, an oral reversible inhibitor of epidermal growth factor receptor (EGFR) and human EGFR 2 (HER-2), demonstrated clinical activity in four of five IBC patients in phase I trials. We conducted a phase II trial to confirm the sensitivity of IBC to lapatinib, to determine whether response is HER-2 or EGFR dependent, and to elucidate a molecular signature predictive of lapatinib sensitivity.
  
  
  METHODS
  Our open-label multicenter phase II trial (EGF103009) assessed clinical activity and safety of lapatinib monotherapy in patients with recurrent or anthracycline-refractory IBC. Patients were assigned to cohorts A (HER-2-overexpressing [HER-2+]) or B(HER-2-/EGFR+) and fresh pretreatment tumor biopsies were collected.
  
  
  RESULTS
  Forty-five patients (30 in cohort A; 15 in cohort B) received lapatinib 1,500 mg once daily continuously. Clinical presentation and biomarker analyses demonstrated a tumor molecular signature consistent with IBC. Lapatinib was generally well tolerated, with primarily grade 1/2 skin and GI toxicities. Fifteen patients (50%) in cohort A had clinical responses to lapatinib in skin and/or measurable disease (according to Response Evaluation Criteria in Solid Tumors) compared with one patient in cohort B. Within cohort A, phosphorylated (p) HER-3 and lack of p53 expression predicted for response to lapatinib (P < .05). Tumors coexpressing pHER-2 and pHER-3 were more likely to respond to lapatinib (nine of 10 v four of 14; P = .0045). Prior trastuzumab therapy and loss of phosphate and tensin homolog 10 (PTEN) did not preclude response to lapatinib.
  
  
  CONCLUSIONS
  Lapatinib is well tolerated with clinical activity in heavily pretreated HER-2+, but not EGFR+/HER-2-, IBC. In this study, coexpression of pHER-2 and pHER-3 in tumors seems to predict for a favorable response to lapatinib. These findings warrant further investigation of lapatinib monotherapy or combination therapy in HER-2+ IBC.
authors.affiliation: Department of Medicine-Breast Unit, Royal Marsden Hospital, London, United Kingdom.
authors.forename: Stephen
authors.initials: S
authors.lastname: Johnston
authors.forename: Maureen
authors.initials: M
authors.lastname: Trudeau
authors.forename: Bella
authors.initials: B
authors.lastname: Kaufman
authors.forename: Hamouda
authors.initials: H
authors.lastname: Boussen
authors.forename: Kimberley
authors.initials: K
authors.lastname: Blackwell
authors.forename: Patricia
authors.initials: P
authors.lastname: LoRusso
authors.forename: Donald P
authors.initials: DP
authors.lastname: Lombardi
authors.forename: Slim
authors.initials: S
authors.lastname: Ben Ahmed
authors.forename: Dennis L
authors.initials: DL
authors.lastname: Citrin
authors.forename: Michelle L
authors.initials: ML
authors.lastname: DeSilvio
authors.forename: Jennifer
authors.initials: J
authors.lastname: Harris
authors.forename: Ron E
authors.initials: RE
authors.lastname: Westlund
authors.forename: Vanessa
authors.initials: V
authors.lastname: Salazar
authors.forename: Tal Z
authors.initials: TZ
authors.lastname: Zaks
authors.forename: Neil L
authors.initials: NL
authors.lastname: Spector
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000378:metabolism*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D015331:Cohort Studies; D005260:Female; D006801:Humans; D007124:Immunoenzyme Techniques; D007249:Inflammation; D000077341:Lapatinib; D008207:Lymphatic Metastasis / Q000175:diagnosis; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy / Q000378:metabolism; D011799:Quinazolines / Q000627:therapeutic use*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D020893:Receptor, ErbB-3 / Q000378:metabolism; D012680:Sensitivity and Specificity; D012878:Skin Neoplasms / Q000175:diagnosis
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D000077341:Lapatinib; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; D020893:Receptor, ErbB-3