title: High HER2 expression correlates with response to the combination of lapatinib and trastuzumab.
abstract: OBJECTIVE
  Expression of p95HER2 has been associated with resistance to trastuzumab-based therapy in patients with metastatic breast cancer. Conversely, high levels of HER2 have been linked with increased clinical benefit from anti-HER2 therapy. In this work, we aimed to investigate whether the levels of p95HER2 and HER2 can predict response to anti-HER2 therapy in patients with breast cancer.
  
  
  METHODS
  We measured p95HER2 and HER2 by VeraTag and HERmark, respectively, in primary tumors of patients enrolled in the neoadjuvant phase III study NeoALTTO and correlated these variables with pathologic complete response (pCR) and progression-free survival (PFS) following lapatinib (L), trastuzumab (T), or the combination of both agents (L+T).
  
  
  RESULTS
  A positive correlation between p95HER2 and HER2 levels was found in the 274 cases (60%) in which quantification of both markers was possible. High levels of these markers were predictive for pCR, especially in the hormone receptor (HR)-positive subset of patients. High HER2 expression was associated with increased pCR rate upon L+T irrespective of the HR status. To examine whether the levels of either p95HER2 or HER2 could predict for PFS in patients treated with lapatinib, trastuzumab or L+T, we fit to the PFS data in Cox models containing log2(p95HER2) or log2(HER2). Both variables correlated with longer PFS.
  
  
  CONCLUSIONS
  Increasing HER2 protein expression correlated with increased benefit of adding lapatinib to trastuzumab. HER2 expression is a stronger predictor of pCR and PFS than p95HER2 for response to lapatinib, trastuzumab and, more significantly, L+T.
authors.affiliation: Human Oncology and Pathogenesis Program (HOPP), Memorial Sloan Kettering Cancer Center, New York, New York. scaltrim@mskcc.org.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Scaltriti
authors.affiliation: Molecular Oncology Laboratory, Vall d'Hebron Institute of Oncology, Barcelona, Spain.
authors.forename: Paolo
authors.initials: P
authors.lastname: Nuciforo
authors.affiliation: Frontier Science (Scotland) Ltd., Inverness-shire, Scotland.
authors.forename: Ian
authors.initials: I
authors.lastname: Bradbury
authors.affiliation: Clinical Research, Monogram Biosciences, Inc., South San Francisco, California.
authors.forename: Jeff
authors.initials: J
authors.lastname: Sperinde
authors.affiliation: Frontier Science (Scotland) Ltd., Inverness-shire, Scotland.
authors.forename: Dominique
authors.initials: D
authors.lastname: Agbor-Tarh
authors.affiliation: Frontier Science (Scotland) Ltd., Inverness-shire, Scotland.
authors.forename: Christine
authors.initials: C
authors.lastname: Campbell
authors.affiliation: Clinical Research, Monogram Biosciences, Inc., South San Francisco, California.
authors.forename: Ahmed
authors.initials: A
authors.lastname: Chenna
authors.affiliation: Clinical Research, Monogram Biosciences, Inc., South San Francisco, California.
authors.forename: John
authors.initials: J
authors.lastname: Winslow
authors.affiliation: Experimental Therapeutics Group, Vall d'Hebron Institute of Oncology, Barcelona, Spain.
authors.forename: Violeta
authors.initials: V
authors.lastname: Serra
authors.affiliation: Experimental Therapeutics Group, Vall d'Hebron Institute of Oncology, Barcelona, Spain.
authors.forename: Josep Lluis
authors.initials: JL
authors.lastname: Parra
authors.affiliation: Molecular Oncology Laboratory, Vall d'Hebron Institute of Oncology, Barcelona, Spain.
authors.forename: Ludmila
authors.initials: L
authors.lastname: Prudkin
authors.affiliation: Molecular Oncology Laboratory, Vall d'Hebron Institute of Oncology, Barcelona, Spain.
authors.forename: José
authors.initials: J
authors.lastname: Jimenez
authors.affiliation: Molecular Oncology Laboratory, Vall d'Hebron Institute of Oncology, Barcelona, Spain.
authors.forename: Claudia
authors.initials: C
authors.lastname: Aura
authors.affiliation: Breast Center, Department of Obstetrics and Gynecology, and CCC LMU, University of Munich, Munich, Germany.
authors.forename: Nadia
authors.initials: N
authors.lastname: Harbeck
authors.affiliation: Genetics and Genomics Program, Yale School of Medicine, New Haven, Connecticut.
authors.forename: Lajos
authors.initials: L
authors.lastname: Pusztai
authors.affiliation: Oncology R&D, GlaxoSmithKline, Collegeville, Pennsylvania.
authors.forename: Catherine
authors.initials: C
authors.lastname: Ellis
authors.affiliation: Department of Gynecology and Midwifery, University Hospital Kiel, Kiel, Germany.
authors.forename: Holger
authors.initials: H
authors.lastname: Eidtmann
authors.affiliation: Experimental Therapeutics Group, Vall d'Hebron Institute of Oncology, Barcelona, Spain. Catalan Institution for Research and Advanced Studies (ICREA), Barcelona, Spain.
authors.forename: Joaquin
authors.initials: J
authors.lastname: Arribas
authors.affiliation: Medical Oncology Department, Vall d'Hebron Institute of Oncology, Barcelona, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: Cortes
authors.affiliation: Jules Bordet Institute, Brussels, Belgium.
authors.forename: Evandro
authors.initials: E
authors.lastname: de Azambuja
authors.affiliation: Jules Bordet Institute, Brussels, Belgium.
authors.forename: Martine
authors.initials: M
authors.lastname: Piccart
authors.affiliation: Human Oncology and Pathogenesis Program (HOPP), Memorial Sloan Kettering Cancer Center, New York, New York. Breast Medicine Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: José
authors.initials: J
authors.lastname: Baselga
mesh_terms: D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001706:Biopsy; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D005260:Female; D015870:Gene Expression; D006801:Humans; D000077341:Lapatinib; D020360:Neoadjuvant Therapy; D011799:Quinazolines / Q000008:administration & dosage; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D000068878:Trastuzumab; D016896:Treatment Outcome
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000077341:Lapatinib; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab