title: Biomarker analyses in CLEOPATRA: a phase III, placebo-controlled study of pertuzumab in human epidermal growth factor receptor 2-positive, first-line metastatic breast cancer.
abstract: OBJECTIVE
  To explore the prognostic and/or predictive value of human epidermal growth factor receptor 2 (HER2) pathway-related biomarkers in the phase III CLEOPATRA study of pertuzumab plus trastuzumab plus docetaxel versus placebo plus trastuzumab plus docetaxel as first-line treatment for patients with HER2-positive metastatic breast cancer.
  
  
  METHODS
  Mandatory tumor and serum samples were collected (N = 808; 58% to 99.8% were assessable), and amphiregulin, betacellulin, epidermal growth factor (EGF), transforming growth factor alpha, EGF receptor, HER2, HER3, insulin-like growth factor 1 receptor, PTEN, phosphorylated AKT, PIK3CA, CMYC, serum HER2 extracellular domain (sHER2), and FCγR were assessed using appropriate assays. Two types of correlations were investigated using univariable Cox regression: predictive effects (qualitative association of biomarkers with pertuzumab progression-free survival [PFS] benefit) and prognostic effects independent of treatment arm (relationship of each biomarker to clinical outcome in both arms pooled).
  
  
  RESULTS
  Pertuzumab consistently showed a PFS benefit, independent of biomarker subgroups (hazard ratio < 1.0), including estrogen receptor-negative and -positive subgroups. High HER2 protein, high HER2 and HER3 mRNA levels, wild-type PIK3CA, and low sHER2 showed a significantly better prognosis (P < .05). PIK3CA showed the greatest prognostic effect, with longer median PFS for patients whose tumors expressed wild-type versus mutated PIK3CA in both the control (13.8 v 8.6 months) and pertuzumab groups (21.8 v 12.5 months).
  
  
  CONCLUSIONS
  Through comprehensive prospective analyses, CLEOPATRA biomarker data demonstrate that HER2 is the only marker suited for patient selection for the trastuzumab plus pertuzumab-based regimen in HER2-positive metastatic breast cancer. HER2, HER3, and PIK3CA were relevant prognostic factors.
authors.affiliation: José Baselga, Memorial Sloan Kettering Cancer Center, New York, NY; Javier Cortés, Vall d'Hebron University Hospital, Barcelona, Spain; Seock-Ah Im, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea; Emma Clark and Graham Ross, Roche Products, Welwyn Garden City, United Kingdom; Astrid Kiermaier, F. Hoffmann-La Roche, Basel, Switzerland; and Sandra M. Swain, Washington Cancer Institute, MedStar Washington Hospital Center, Washington, DC. baselgaj@mskcc.org.
authors.forename: José
authors.initials: J
authors.lastname: Baselga
authors.affiliation: José Baselga, Memorial Sloan Kettering Cancer Center, New York, NY; Javier Cortés, Vall d'Hebron University Hospital, Barcelona, Spain; Seock-Ah Im, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea; Emma Clark and Graham Ross, Roche Products, Welwyn Garden City, United Kingdom; Astrid Kiermaier, F. Hoffmann-La Roche, Basel, Switzerland; and Sandra M. Swain, Washington Cancer Institute, MedStar Washington Hospital Center, Washington, DC.
authors.forename: Javier
authors.initials: J
authors.lastname: Cortés
authors.affiliation: José Baselga, Memorial Sloan Kettering Cancer Center, New York, NY; Javier Cortés, Vall d'Hebron University Hospital, Barcelona, Spain; Seock-Ah Im, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea; Emma Clark and Graham Ross, Roche Products, Welwyn Garden City, United Kingdom; Astrid Kiermaier, F. Hoffmann-La Roche, Basel, Switzerland; and Sandra M. Swain, Washington Cancer Institute, MedStar Washington Hospital Center, Washington, DC.
authors.forename: Seock-Ah
authors.initials: SA
authors.lastname: Im
authors.affiliation: José Baselga, Memorial Sloan Kettering Cancer Center, New York, NY; Javier Cortés, Vall d'Hebron University Hospital, Barcelona, Spain; Seock-Ah Im, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea; Emma Clark and Graham Ross, Roche Products, Welwyn Garden City, United Kingdom; Astrid Kiermaier, F. Hoffmann-La Roche, Basel, Switzerland; and Sandra M. Swain, Washington Cancer Institute, MedStar Washington Hospital Center, Washington, DC.
authors.forename: Emma
authors.initials: E
authors.lastname: Clark
authors.affiliation: José Baselga, Memorial Sloan Kettering Cancer Center, New York, NY; Javier Cortés, Vall d'Hebron University Hospital, Barcelona, Spain; Seock-Ah Im, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea; Emma Clark and Graham Ross, Roche Products, Welwyn Garden City, United Kingdom; Astrid Kiermaier, F. Hoffmann-La Roche, Basel, Switzerland; and Sandra M. Swain, Washington Cancer Institute, MedStar Washington Hospital Center, Washington, DC.
authors.forename: Graham
authors.initials: G
authors.lastname: Ross
authors.affiliation: José Baselga, Memorial Sloan Kettering Cancer Center, New York, NY; Javier Cortés, Vall d'Hebron University Hospital, Barcelona, Spain; Seock-Ah Im, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea; Emma Clark and Graham Ross, Roche Products, Welwyn Garden City, United Kingdom; Astrid Kiermaier, F. Hoffmann-La Roche, Basel, Switzerland; and Sandra M. Swain, Washington Cancer Institute, MedStar Washington Hospital Center, Washington, DC.
authors.forename: Astrid
authors.initials: A
authors.lastname: Kiermaier
authors.affiliation: José Baselga, Memorial Sloan Kettering Cancer Center, New York, NY; Javier Cortés, Vall d'Hebron University Hospital, Barcelona, Spain; Seock-Ah Im, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea; Emma Clark and Graham Ross, Roche Products, Welwyn Garden City, United Kingdom; Astrid Kiermaier, F. Hoffmann-La Roche, Basel, Switzerland; and Sandra M. Swain, Washington Cancer Institute, MedStar Washington Hospital Center, Washington, DC.
authors.forename: Sandra M
authors.initials: SM
authors.lastname: Swain
mesh_terms: D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000032:analysis*; D001943:Breast Neoplasms / Q000097:blood / Q000737:chemistry / Q000188:drug therapy* / Q000401:mortality; D058534:Class I Phosphatidylinositol 3-Kinases; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D009154:Mutation; D009362:Neoplasm Metastasis; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D011379:Prognosis; D011446:Prospective Studies; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000032:analysis*; D011960:Receptors, Estrogen / Q000032:analysis
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D058534:Class I Phosphatidylinositol 3-Kinases; D019869:Phosphatidylinositol 3-Kinases; D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; C484760:PIK3CA protein, human; C508053:ERBB2 protein, human; C485206:pertuzumab