title: Objective, domain-specific HER2 measurement in uterine and ovarian serous carcinomas and its clinical significance.
abstract: HER2 overexpression/amplification is identified in up to 40% of uterine serous carcinomas (USC) and 10% of ovarian serous carcinomas (OSC). However, clinical trials using various HER2-targeted agents failed to show significant responses. FDA-approved HER2 assays target only the protein's intracellular domain (ICD) and not the extracellular domain (ECD). Previous quantitative studies in breast cancer by our group have shown that ICD of HER2 is expressed in some cases that do not express the HER2 ECD. We measured HER2 ICD and ECD in USC and OSC samples, and determined their relationship with clinico-pathologic characteristics and survival.
  
  
  
  We measured HER2 ICD and ECD levels in 2 cohorts of USC and OSC comprising 102 and 175 patients, respectively. HER2 antibodies targeting ICD (CB11) and ECD (SP3) were validated and standardized using the AQUA® method of quantitative immunofluorescence (QIF) and a previously reported HER2 standardization tissue microarray (TMA). Objective, population-based cut-points were used to stratify patients according to HER2 ICD/ECD status.
  
  
  
  In USC, 8% of patients with high HER2 ICD had low ECD levels (6/75 patients). In OSC, 42% of patients with high HER2 ICD had low ECD levels (29/69 patients). HER2 ICD/ECD status in USC and OSC was not significantly associated with major clinico-pathological features or survival.
  
  
  
  Using objective, domain-specific HER2 measurement, 8% of USC and 42% of OSC patients with high HER2 ICD levels do not show uniform overexpression of the ECD. This may be related to the presence of p95 HER2, an oncogenic fragment generated by full protein cleavage or alternative initiation of translation. These observations raise the possibility that USC/OSCs expressing low ECD despite being HER2-positive by ICD measurement, may benefit from therapies directed against the intracellular domain (e.g. lapatinib or afatinib) alone or in combination with extracellular domain-directed drugs (e.g. trastuzumab, pertuzumab, T-DM1).
authors.affiliation: Department of Pathology, Yale School of Medicine, New Haven, CT, USA. Electronic address: daniel.carvajal@yale.edu.
authors.forename: Daniel E
authors.initials: DE
authors.lastname: Carvajal-Hausdorf
authors.affiliation: Department of Pathology, Yale School of Medicine, New Haven, CT, USA; Translational Immuno-oncology Laboratory, Yale Cancer Center, New Haven, CT, USA.
authors.forename: Kurt A
authors.initials: KA
authors.lastname: Schalper
authors.affiliation: Department of Pathology, Yale School of Medicine, New Haven, CT, USA.
authors.forename: Yalai
authors.initials: Y
authors.lastname: Bai
authors.affiliation: Department of Gynecology, Obstetrics and Reproductive Sciences, Yale School of Medicine, New Haven, CT, USA.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Black
authors.affiliation: Department of Gynecology, Obstetrics and Reproductive Sciences, Yale School of Medicine, New Haven, CT, USA.
authors.forename: Alessandro D
authors.initials: AD
authors.lastname: Santin
authors.affiliation: Department of Pathology, Yale School of Medicine, New Haven, CT, USA.
authors.forename: David L
authors.initials: DL
authors.lastname: Rimm
mesh_terms: D000080044:Ado-Trastuzumab Emtansine; D000077716:Afatinib; D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000627:therapeutic use; D015331:Cohort Studies; D005110:Extracellular Space; D005260:Female; D005455:Fluorescent Antibody Technique; D006801:Humans; D042541:Intracellular Space; D000077341:Lapatinib; D008453:Maytansine / Q000031:analogs & derivatives / Q000627:therapeutic use; D008875:Middle Aged; D018297:Neoplasms, Cystic, Mucinous, and Serous / Q000188:drug therapy / Q000378:metabolism*; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D000072417:Protein Domains; D011799:Quinazolines / Q000627:therapeutic use; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D012189:Retrospective Studies; D046888:Tissue Array Analysis; D000068878:Trastuzumab / Q000627:therapeutic use; D014594:Uterine Neoplasms / Q000188:drug therapy / Q000378:metabolism*
chemical_list: D000080044:Ado-Trastuzumab Emtansine; D000077716:Afatinib; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D000077341:Lapatinib; D008453:Maytansine; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; C508053:ERBB2 protein, human; C485206:pertuzumab
keywords: Extracellular domain; HER2; Intracellular domain; Quantitative immunofluorescence; Serous carcinoma; Targeted therapy