title: HER3, p95HER2, and HER2 protein expression levels define multiple subtypes of HER2-positive metastatic breast cancer.
abstract: Trastuzumab is effective in the treatment of HER2/neu over-expressing breast cancer, but not all patients benefit from it. In vitro data suggest a role for HER3 in the initiation of signaling activity involving the AKT–mTOR pathway leading to trastuzumab insensitivity. We sought to investigate the potential of HER3 alone and in the context of p95HER2 (p95), a trastuzumab resistance marker, as biomarkers of trastuzumab escape. Using the VeraTag® assay platform, we developed a dual antibody proximity-based assay for the precise quantitation of HER3 total protein (H3T) from formalin-fixed paraffin-embedded (FFPE) breast tumors. We then measured H3T in 89 patients with metastatic breast cancer treated with trastuzumab-based therapy, and correlated the results with progression-free survival and overall survival using Kaplan–Meier and decision tree analyses that also included HER2 total (H2T) and p95 expression levels. Within the sub-population of patients that over-expressed HER2, high levels of HER3 and/or p95 protein expression were significantly associated with poor clinical outcomes on trastuzumab-based therapy. Based on quantitative H3T, p95, and H2T measurements, multiple subtypes of HER2-positive breast cancer were identified that differ in their outcome following trastuzumab therapy. These data suggest that HER3 and p95 are informative biomarkers of clinical outcomes on trastuzumab therapy, and that multiple subtypes of HER2-positive breast cancer may be defined by quantitative measurements of H3T, p95, and H2T.
authors: Breast Oncology Research, Division of Hematology/Oncology, Department of Medicine, Penn State Hershey Medical Center, 500 University Drive, Hershey, PA 17033, USA. alipton@hmc.psu.edu
authors: Allan
authors: A
authors: Lipton
authors: Laurie
authors: L
authors: Goodman
authors: Kim
authors: K
authors: Leitzel
authors: Jennifer
authors: J
authors: Cook
authors: Jeff
authors: J
authors: Sperinde
authors: Mojgan
authors: M
authors: Haddad
authors: Wolfgang J
authors: WJ
authors: Köstler
authors: Weidong
authors: W
authors: Huang
authors: Jodi M
authors: JM
authors: Weidler
authors: Suhail
authors: S
authors: Ali
authors: Alicia
authors: A
authors: Newton
authors: Eva-Marie
authors: EM
authors: Fuchs
authors: Agnes
authors: A
authors: Paquet
authors: Christian F
authors: CF
authors: Singer
authors: Reinhard
authors: R
authors: Horvat
authors: Xueguang
authors: X
authors: Jin
authors: Joyee
authors: J
authors: Banerjee
authors: Ali
authors: A
authors: Mukherjee
authors: Yuping
authors: Y
authors: Tan
authors: Yining
authors: Y
authors: Shi
authors: Ahmed
authors: A
authors: Chenna
authors: Jeff
authors: J
authors: Larson
authors: Yolanda
authors: Y
authors: Lie
authors: Thomas
authors: T
authors: Sherwood
authors: Christos J
authors: CJ
authors: Petropoulos
authors: Stephen
authors: S
authors: Williams
authors: John
authors: J
authors: Winslow
authors: Gordon
authors: G
authors: Parry
authors: Michael
authors: M
authors: Bates
mesh_terms: D000911:Antibodies, Monoclonal / Q000276:immunology; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000032:analysis* / Q000235:genetics / Q000276:immunology; D001943:Breast Neoplasms / Q000145:classification / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000401:mortality / Q000556:secondary*; D045744:Cell Line, Tumor; D015331:Cohort Studies; D003663:Decision Trees; D018572:Disease-Free Survival; D019008:Drug Resistance, Neoplasm; D005260:Female; D019084:Fluorescent Antibody Technique, Indirect; D015972:Gene Expression Regulation, Neoplastic; D018734:Genes, erbB-2; D006801:Humans; D053208:Kaplan-Meier Estimate; D009363:Neoplasm Proteins / Q000096:biosynthesis* / Q000235:genetics; D010446:Peptide Fragments / Q000032:analysis / Q000276:immunology; D011379:Prognosis; D017434:Protein Structure, Tertiary; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000032:analysis* / Q000235:genetics / Q000276:immunology; D020893:Receptor, ErbB-3 / Q000032:analysis* / Q000235:genetics / Q000276:immunology; D012189:Retrospective Studies; D016037:Single-Blind Method; D000068878:Trastuzumab; D016896:Treatment Outcome
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D009363:Neoplasm Proteins; D010446:Peptide Fragments; D018719:Erb-b2 Receptor Tyrosine Kinases; D020893:Receptor, ErbB-3; D000068878:Trastuzumab; C508053:ERBB2 protein, human; C581292:ERBB3 protein, human
references: J Clin Oncol. 2006 Jul 1;24(19):3032-8
references: 16809727
references: Patholog Res Int. 2010 Jun 28;2010:814176
references: 21151530
references: PLoS One. 2011 Jan 28;6(1):e16443
references: 21297994
references: Clin Cancer Res. 2005 Sep 15;11(18):6598-607
references: 16166438
references: Diagn Mol Pathol. 2009 Mar;18(1):11-21
references: 19214113
references: Mol Cancer Res. 2009 Sep;7(9):1563-71
references: 19737968
references: Cancer Cell. 2009 May 5;15(5):429-40
references: 19411071
references: Cancer. 2010 Nov 15;116(22):5168-78
references: 20661914
references: Oncogene. 2011 Jun 2;30(22):2547-57
references: 21278786
references: J Clin Oncol. 2002 Feb 1;20(3):719-26
references: 11821453
references: N Engl J Med. 2006 Feb 23;354(8):809-20
references: 16495393
references: Eur J Cancer. 2001 Sep;37 Suppl 4:S3-8
references: 11597398
references: J Clin Oncol. 2002 Jul 15;20(14):3095-105
references: 12118023
references: Arch Pathol Lab Med. 2007;131(1):18-43
references: 19548375
references: Ann Oncol. 2011 Sep;22(9):2014-2020
references: 21289364
references: Cancer Res. 2011 Mar 1;71(5):1871-82
references: 21324925
references: N Engl J Med. 2005 Oct 20;353(16):1673-84
references: 16236738
references: Nat Rev Mol Cell Biol. 2001 Feb;2(2):127-37
references: 11252954
references: Cancer Res. 2008 Jul 15;68(14):5878-87
references: 18632642
references: N Engl J Med. 2012 Jan 12;366(2):109-19
references: 22149875
references: Proc Natl Acad Sci U S A. 2011 Mar 22;108(12):5021-6
references: 21385943
references: Nature. 2007 Jan 25;445(7126):437-41
references: 17206155
references: J Clin Oncol. 2010 Mar 1;28(7):1215-23
references: 19901115
references: Clin Cancer Res. 2010 Aug 15;16(16):4226-35
references: 20664024
references: N Engl J Med. 2005 Oct 20;353(16):1659-72
references: 16236737
references: N Engl J Med. 2001 Mar 15;344(11):783-92
references: 11248153
references: J Clin Oncol. 1999 Sep;17(9):2639-48
references: 10561337
references: Ann Oncol. 2011 Sep;22(9):2007-2013
references: 21285132