title: Identification of a subpopulation of metastatic breast cancer patients with very high HER2 expression levels and possible resistance to trastuzumab.
abstract: BACKGROUND
  Patients with metastatic breast cancer (MBC) overexpressing HER2 (human epidermal growth factor receptor 2) are currently selected for treatment with trastuzumab, but not all patients respond.
  
  
  METHODS
  Using a novel assay, HER2 protein expression (H2T) was measured in formalin-fixed, paraffin-embedded primary breast tumors from 98 women treated with trastuzumab-based therapy for MBC. Using subpopulation treatment effect pattern plots, the population was divided into H2T low (H2T < 13.8), H2T high (H2T ≥ 68.5), and H2T intermediate (13.8 ≤ H2T < 68.5) subgroups. Kaplan-Meier (KM) analyses were carried out comparing the groups for time to progression (TTP) and overall survival (OS). Cox multivariate analyses were carried out to identify correlates of clinical outcome. Bootstrapping analyses were carried out to test the robustness of the results.
  
  
  RESULTS
  TTP improved with increasing H2T until, at the highest levels of H2T, an abrupt decrease in the TTP was observed. KM analyses demonstrated that patients with H2T low tumors [median TTP 4.2 months, hazard ratio (HR) = 3.7, P < 0.0001] or H2T high tumors (median TTP 4.6 months, HR = 2.7, P = 0.008) had significantly shorter TTP than patients whose tumors were H2T intermediate (median TTP 12 months). OS analyses yielded similar results.
  
  
  CONCLUSIONS
  MBC patients with very high levels of H2T may represent a subgroup with de novo resistance to trastuzumab. These results are preliminary and require confirmation in larger controlled clinical cohorts.
authors.affiliation: Division of Clinical Research. Electronic address: mbates@monogrambio.com.
authors.forename: M
authors.initials: M
authors.lastname: Bates
authors.affiliation: Division of Research and Development, Monogram Biosciences, South San Francisco, USA.
authors.forename: J
authors.initials: J
authors.lastname: Sperinde
authors.affiliation: Clinical Division of Oncology, Department of Medicine I, Medical University of Vienna, Vienna, Austria.
authors.forename: W J
authors.initials: WJ
authors.lastname: Köstler
authors.affiliation: Department of Medicine, Lebanon Veterans Affairs Medical Center, Lebanon.
authors.forename: S M
authors.initials: SM
authors.lastname: Ali
authors.affiliation: Department of Medicine, Division of Hematology/Medical Oncology, Penn State Hershey Medical Center, Hershey.
authors.forename: K
authors.initials: K
authors.lastname: Leitzel
authors.affiliation: Clinical Division of Oncology, Department of Medicine I, Medical University of Vienna, Vienna, Austria.
authors.forename: E M
authors.initials: EM
authors.lastname: Fuchs
authors.affiliation: Department of Translational Medicine and Biomarker Development, Division of Biostatics and Bioinformatics, Monogram Biosciences, South San Francisco, USA.
authors.forename: A
authors.initials: A
authors.lastname: Paquet
authors.affiliation: Division of Clinical Research.
authors.forename: Y
authors.initials: Y
authors.lastname: Lie
authors.affiliation: Division of Clinical Research.
authors.forename: T
authors.initials: T
authors.lastname: Sherwood
authors.affiliation: Departments of Clinical Pathology.
authors.forename: R
authors.initials: R
authors.lastname: Horvat
authors.affiliation: Obstetrics and Gynecology, Medical University of Vienna, Vienna, Austria.
authors.forename: C F
authors.initials: CF
authors.lastname: Singer
authors.affiliation: Division of Research and Development, Monogram Biosciences, South San Francisco, USA.
authors.forename: J
authors.initials: J
authors.lastname: Winslow
authors.affiliation: Division of Clinical Research.
authors.forename: J M
authors.initials: JM
authors.lastname: Weidler
authors.affiliation: Division of Clinical Research.
authors.forename: W
authors.initials: W
authors.lastname: Huang
authors.affiliation: Department of Medicine, Division of Hematology/Medical Oncology, Penn State Hershey Medical Center, Hershey.
authors.forename: A
authors.initials: A
authors.lastname: Lipton
mesh_terms: D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology* / Q000235:genetics; D015331:Cohort Studies; D019008:Drug Resistance, Neoplasm; D005260:Female; D005784:Gene Amplification; D018628:Gene Dosage; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D016016:Proportional Hazards Models; D011446:Prospective Studies; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000096:biosynthesis* / Q000235:genetics; D000068878:Trastuzumab; D016896:Treatment Outcome
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; C508053:ERBB2 protein, human