title: Serum Human Epidermal Growth Factor 2 Extracellular Domain as a Predictive Biomarker for Lapatinib Treatment Efficacy in Patients With Advanced Breast Cancer.
abstract: OBJECTIVE
  We examined the prognostic and predictive value of serum human epidermal growth factor 2 (HER2) extracellular domain (sHER2) in patients with advanced breast cancer treated with lapatinib using data from three randomized trials.
  
  
  METHODS
  We analyzed sHER2 and tissue HER2 (tHER2) data from 1,902 patients (84%) who were randomly assigned to receive lapatinib or control in the trials EGF30001, EGF30008, and EGF100151. Cox regression analyses were performed to correlate both biomarkers with progression-free survival (PFS) and overall survival (OS).
  
  
  RESULTS
  Median sHER2 levels were 25.1 and 10.1 ng/mL in tHER2-amplified (tHER-positive) and nonamplified (tHER-negative) populations, respectively (r = 0.42 for sHER2-tHER2 correlation). Lapatinib had significant PFS benefit over control (hazard ratio [HR], 0.855; P = .004), but not OS (HR, 0.941; P = .33). Lapatinib PFS benefit is independently predicted by higher sHER2 values (HR per 10-ng/mL increase in sHER2: lapatinib-containing therapies, 1.009 v nonlapatinib-containing therapies, 1.044; P(interaction) < .001) and by positive tHER2 (HR [lapatinib v nonlapatinib]: tHER2 positive, 0.638 v tHER2 negative, 0.940; P(interaction) = .001). Within the tHER2-positive subpopulation (n = 515), higher sHER2 values still independently predicted lapatinib PFS benefit (HR per 10-ng/mL increase in sHER2: lapatinib-containing therapies, 1.017 v nonlapatinib-containing therapies, 1.041; P(interaction) = .008). In control arms (n = 936), higher sHER2 was associated with worse prognosis in multivariable analyses (PFS HR per 10 ng/mL: PFS, 1.024; P < .001; and OS, 1.018; P < .001).
  
  
  CONCLUSIONS
  Higher sHER2 predicts greater PFS benefit with lapatinib independent of tHER2 status. High sHER2 is also independently prognostic for worse survival in patients who received nonlapatinib-containing therapies. The predictive role of sHER2 for other anti-HER2 agents requires further research.
authors.affiliation: Chee Khoon Lee, Lucy Davies, Val J. Gebski, Sarah J. Lord, Ian Marschner, and John Simes, University of Sydney; Sarah J. Lord, University of Notre Dame; Ian Marschner, Macquarie University; Paul de Souza, University of Western Sydney, Sydney, New South Wales; Sherene Loi, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia; Angelo Di Leo, Hospital of Prato, Istituto Toscano Tumori, Italy; Stephen Johnston, Royal Marsden Hospital, London; David Cameron, University of Edinburgh, Edinburgh, United Kingdom; Charles Geyer Jr, Virginia Commonwealth University Massey Cancer Center, Richmond, VA; Michael F. Press, University of Southern California, Los Angeles, CA; and Catherine Ellis, GlaxoSmithKline, Collegeville, PA.
authors.forename: Chee Khoon
authors.initials: CK
authors.lastname: Lee
authors.affiliation: Chee Khoon Lee, Lucy Davies, Val J. Gebski, Sarah J. Lord, Ian Marschner, and John Simes, University of Sydney; Sarah J. Lord, University of Notre Dame; Ian Marschner, Macquarie University; Paul de Souza, University of Western Sydney, Sydney, New South Wales; Sherene Loi, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia; Angelo Di Leo, Hospital of Prato, Istituto Toscano Tumori, Italy; Stephen Johnston, Royal Marsden Hospital, London; David Cameron, University of Edinburgh, Edinburgh, United Kingdom; Charles Geyer Jr, Virginia Commonwealth University Massey Cancer Center, Richmond, VA; Michael F. Press, University of Southern California, Los Angeles, CA; and Catherine Ellis, GlaxoSmithKline, Collegeville, PA.
authors.forename: Lucy
authors.initials: L
authors.lastname: Davies
authors.affiliation: Chee Khoon Lee, Lucy Davies, Val J. Gebski, Sarah J. Lord, Ian Marschner, and John Simes, University of Sydney; Sarah J. Lord, University of Notre Dame; Ian Marschner, Macquarie University; Paul de Souza, University of Western Sydney, Sydney, New South Wales; Sherene Loi, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia; Angelo Di Leo, Hospital of Prato, Istituto Toscano Tumori, Italy; Stephen Johnston, Royal Marsden Hospital, London; David Cameron, University of Edinburgh, Edinburgh, United Kingdom; Charles Geyer Jr, Virginia Commonwealth University Massey Cancer Center, Richmond, VA; Michael F. Press, University of Southern California, Los Angeles, CA; and Catherine Ellis, GlaxoSmithKline, Collegeville, PA.
authors.forename: Val J
authors.initials: VJ
authors.lastname: Gebski
authors.affiliation: Chee Khoon Lee, Lucy Davies, Val J. Gebski, Sarah J. Lord, Ian Marschner, and John Simes, University of Sydney; Sarah J. Lord, University of Notre Dame; Ian Marschner, Macquarie University; Paul de Souza, University of Western Sydney, Sydney, New South Wales; Sherene Loi, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia; Angelo Di Leo, Hospital of Prato, Istituto Toscano Tumori, Italy; Stephen Johnston, Royal Marsden Hospital, London; David Cameron, University of Edinburgh, Edinburgh, United Kingdom; Charles Geyer Jr, Virginia Commonwealth University Massey Cancer Center, Richmond, VA; Michael F. Press, University of Southern California, Los Angeles, CA; and Catherine Ellis, GlaxoSmithKline, Collegeville, PA.
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Lord
authors.affiliation: Chee Khoon Lee, Lucy Davies, Val J. Gebski, Sarah J. Lord, Ian Marschner, and John Simes, University of Sydney; Sarah J. Lord, University of Notre Dame; Ian Marschner, Macquarie University; Paul de Souza, University of Western Sydney, Sydney, New South Wales; Sherene Loi, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia; Angelo Di Leo, Hospital of Prato, Istituto Toscano Tumori, Italy; Stephen Johnston, Royal Marsden Hospital, London; David Cameron, University of Edinburgh, Edinburgh, United Kingdom; Charles Geyer Jr, Virginia Commonwealth University Massey Cancer Center, Richmond, VA; Michael F. Press, University of Southern California, Los Angeles, CA; and Catherine Ellis, GlaxoSmithKline, Collegeville, PA.
authors.forename: Angelo
authors.initials: A
authors.lastname: Di Leo
authors.affiliation: Chee Khoon Lee, Lucy Davies, Val J. Gebski, Sarah J. Lord, Ian Marschner, and John Simes, University of Sydney; Sarah J. Lord, University of Notre Dame; Ian Marschner, Macquarie University; Paul de Souza, University of Western Sydney, Sydney, New South Wales; Sherene Loi, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia; Angelo Di Leo, Hospital of Prato, Istituto Toscano Tumori, Italy; Stephen Johnston, Royal Marsden Hospital, London; David Cameron, University of Edinburgh, Edinburgh, United Kingdom; Charles Geyer Jr, Virginia Commonwealth University Massey Cancer Center, Richmond, VA; Michael F. Press, University of Southern California, Los Angeles, CA; and Catherine Ellis, GlaxoSmithKline, Collegeville, PA.
authors.forename: Stephen
authors.initials: S
authors.lastname: Johnston
authors.affiliation: Chee Khoon Lee, Lucy Davies, Val J. Gebski, Sarah J. Lord, Ian Marschner, and John Simes, University of Sydney; Sarah J. Lord, University of Notre Dame; Ian Marschner, Macquarie University; Paul de Souza, University of Western Sydney, Sydney, New South Wales; Sherene Loi, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia; Angelo Di Leo, Hospital of Prato, Istituto Toscano Tumori, Italy; Stephen Johnston, Royal Marsden Hospital, London; David Cameron, University of Edinburgh, Edinburgh, United Kingdom; Charles Geyer Jr, Virginia Commonwealth University Massey Cancer Center, Richmond, VA; Michael F. Press, University of Southern California, Los Angeles, CA; and Catherine Ellis, GlaxoSmithKline, Collegeville, PA.
authors.forename: Charles
authors.initials: C
authors.lastname: Geyer
authors.affiliation: Chee Khoon Lee, Lucy Davies, Val J. Gebski, Sarah J. Lord, Ian Marschner, and John Simes, University of Sydney; Sarah J. Lord, University of Notre Dame; Ian Marschner, Macquarie University; Paul de Souza, University of Western Sydney, Sydney, New South Wales; Sherene Loi, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia; Angelo Di Leo, Hospital of Prato, Istituto Toscano Tumori, Italy; Stephen Johnston, Royal Marsden Hospital, London; David Cameron, University of Edinburgh, Edinburgh, United Kingdom; Charles Geyer Jr, Virginia Commonwealth University Massey Cancer Center, Richmond, VA; Michael F. Press, University of Southern California, Los Angeles, CA; and Catherine Ellis, GlaxoSmithKline, Collegeville, PA.
authors.forename: David
authors.initials: D
authors.lastname: Cameron
authors.affiliation: Chee Khoon Lee, Lucy Davies, Val J. Gebski, Sarah J. Lord, Ian Marschner, and John Simes, University of Sydney; Sarah J. Lord, University of Notre Dame; Ian Marschner, Macquarie University; Paul de Souza, University of Western Sydney, Sydney, New South Wales; Sherene Loi, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia; Angelo Di Leo, Hospital of Prato, Istituto Toscano Tumori, Italy; Stephen Johnston, Royal Marsden Hospital, London; David Cameron, University of Edinburgh, Edinburgh, United Kingdom; Charles Geyer Jr, Virginia Commonwealth University Massey Cancer Center, Richmond, VA; Michael F. Press, University of Southern California, Los Angeles, CA; and Catherine Ellis, GlaxoSmithKline, Collegeville, PA.
authors.forename: Michael F
authors.initials: MF
authors.lastname: Press
authors.affiliation: Chee Khoon Lee, Lucy Davies, Val J. Gebski, Sarah J. Lord, Ian Marschner, and John Simes, University of Sydney; Sarah J. Lord, University of Notre Dame; Ian Marschner, Macquarie University; Paul de Souza, University of Western Sydney, Sydney, New South Wales; Sherene Loi, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia; Angelo Di Leo, Hospital of Prato, Istituto Toscano Tumori, Italy; Stephen Johnston, Royal Marsden Hospital, London; David Cameron, University of Edinburgh, Edinburgh, United Kingdom; Charles Geyer Jr, Virginia Commonwealth University Massey Cancer Center, Richmond, VA; Michael F. Press, University of Southern California, Los Angeles, CA; and Catherine Ellis, GlaxoSmithKline, Collegeville, PA.
authors.forename: Catherine
authors.initials: C
authors.lastname: Ellis
authors.affiliation: Chee Khoon Lee, Lucy Davies, Val J. Gebski, Sarah J. Lord, Ian Marschner, and John Simes, University of Sydney; Sarah J. Lord, University of Notre Dame; Ian Marschner, Macquarie University; Paul de Souza, University of Western Sydney, Sydney, New South Wales; Sherene Loi, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia; Angelo Di Leo, Hospital of Prato, Istituto Toscano Tumori, Italy; Stephen Johnston, Royal Marsden Hospital, London; David Cameron, University of Edinburgh, Edinburgh, United Kingdom; Charles Geyer Jr, Virginia Commonwealth University Massey Cancer Center, Richmond, VA; Michael F. Press, University of Southern California, Los Angeles, CA; and Catherine Ellis, GlaxoSmithKline, Collegeville, PA.
authors.forename: Sherene
authors.initials: S
authors.lastname: Loi
authors.affiliation: Chee Khoon Lee, Lucy Davies, Val J. Gebski, Sarah J. Lord, Ian Marschner, and John Simes, University of Sydney; Sarah J. Lord, University of Notre Dame; Ian Marschner, Macquarie University; Paul de Souza, University of Western Sydney, Sydney, New South Wales; Sherene Loi, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia; Angelo Di Leo, Hospital of Prato, Istituto Toscano Tumori, Italy; Stephen Johnston, Royal Marsden Hospital, London; David Cameron, University of Edinburgh, Edinburgh, United Kingdom; Charles Geyer Jr, Virginia Commonwealth University Massey Cancer Center, Richmond, VA; Michael F. Press, University of Southern California, Los Angeles, CA; and Catherine Ellis, GlaxoSmithKline, Collegeville, PA.
authors.forename: Ian
authors.initials: I
authors.lastname: Marschner
authors.affiliation: Chee Khoon Lee, Lucy Davies, Val J. Gebski, Sarah J. Lord, Ian Marschner, and John Simes, University of Sydney; Sarah J. Lord, University of Notre Dame; Ian Marschner, Macquarie University; Paul de Souza, University of Western Sydney, Sydney, New South Wales; Sherene Loi, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia; Angelo Di Leo, Hospital of Prato, Istituto Toscano Tumori, Italy; Stephen Johnston, Royal Marsden Hospital, London; David Cameron, University of Edinburgh, Edinburgh, United Kingdom; Charles Geyer Jr, Virginia Commonwealth University Massey Cancer Center, Richmond, VA; Michael F. Press, University of Southern California, Los Angeles, CA; and Catherine Ellis, GlaxoSmithKline, Collegeville, PA.
authors.forename: John
authors.initials: J
authors.lastname: Simes
authors.affiliation: Chee Khoon Lee, Lucy Davies, Val J. Gebski, Sarah J. Lord, Ian Marschner, and John Simes, University of Sydney; Sarah J. Lord, University of Notre Dame; Ian Marschner, Macquarie University; Paul de Souza, University of Western Sydney, Sydney, New South Wales; Sherene Loi, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia; Angelo Di Leo, Hospital of Prato, Istituto Toscano Tumori, Italy; Stephen Johnston, Royal Marsden Hospital, London; David Cameron, University of Edinburgh, Edinburgh, United Kingdom; Charles Geyer Jr, Virginia Commonwealth University Massey Cancer Center, Richmond, VA; Michael F. Press, University of Southern California, Los Angeles, CA; and Catherine Ellis, GlaxoSmithKline, Collegeville, PA. p.desouza@uws.edu.au.
authors.forename: Paul
authors.initials: P
authors.lastname: de Souza
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D014408:Biomarkers, Tumor; D001943:Breast Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000201:enzymology* / Q000473:pathology; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D000077341:Lapatinib; D011237:Predictive Value of Tests; D016016:Proportional Hazards Models; D011799:Quinazolines / Q000008:administration & dosage*; D016032:Randomized Controlled Trials as Topic; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000097:blood* / Q000378:metabolism
chemical_list: D014408:Biomarkers, Tumor; D000077341:Lapatinib; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; C508053:ERBB2 protein, human