title: HER2/CEP17 Ratios and Clinical Outcome in HER2-Positive Early Breast Cancer Undergoing Trastuzumab-Containing Therapy.
abstract: BACKGROUND
  Adjuvant therapy comprising the HER2 receptor antagonist trastuzumab is associated with a significant improvement in disease-free and overall survival as compared to chemotherapy alone in localized HER2-positive breast cancer (BC). However, a subset of HER2-positive tumors seems to respond less favorably to trastuzumab. Various mechanisms have been proposed for trastuzumab resistance, such as high HER2 to Chromosome 17 FISH (HER2/CEP17) ratios and the possibility that single agent trastuzumab may not suffice to efficiently block HER2 downstream signaling thresholds. In a retrospective analysis we evaluated whether HER2/CEP17 ratios might have an impact on disease-free survival (DFS).
  
  
  METHODS
  Clinical records of Stage I-III BC patients with HER2-positive tumors were reviewed at our institution from 2007-2013. We analyzed demographics, tumor characteristics including tumor size and grade, lymph node involvement and estrogen receptor expression as well as treatment with respect to chemotherapeutic regimens from the clinical charts. HER2/CEP17 ratios were determined by routine pathology analysis using in situ fluorescent hybridization (FISH). Upon statistical preview we defined three groups of HER2 amplification based on FISH ratio (2.2 to 4, >4 to 8, >8), in order to evaluate an association between HER2 gene amplification and DFS with trastuzumab containing therapies. DFS was analyzed using Cox-regression.
  
  
  RESULTS
  A total of 332 patients with HER2-positive BC were reviewed. Median age was 54 (range 23-89) years. The majority of tumors were classified T1 (50%) or T2 (39%), node negative (52%) and of high grade G3 histology (70%). We identified 312 (94%) tumors as immunohistochemistry (IHC) score 3+ and HER2/CEP17 ratios were available from 278 patients (84%). 30% (N = 84) had tumors with high HER2/CEP17 ratios (>8). Univariate analysis found no correlation between outcome, age, histological grade, sequence as well as anthracycline content of chemotherapy. However, a prognostic impact was detected for tumor size (p = 0.02), nodal status (p<0.01), proliferation index (p<0.01), level (≥20%) of estrogen receptor expression (p = 0.03) and neoadjuvant therapeutic setting (p = 0.03), respectively. Importantly, univariate and multivariable analysis revealed that standard trastuzumab containing chemotherapy resulted in impaired disease free survival among tumors with FISH ratio >8 (p<0.01). Although less pronounced, a similar association was found also with respect to high HER2 gene copy numbers (>12) and DFS (p = 0.01).
  
  
  CONCLUSIONS
  In early BC patients, tumors with high HER2 amplification ratios (>8), may less likely respond to standard trastuzumab-containing therapies. Although, we obtained a similar effect for high HER2 gene copy numbers, this provides only an indirect speculation and not a proof that high HER2/CEP17 ratios may induce HER2 resistance.
authors.affiliation: Breast-Center Zürich, Zürich, Switzerland.|Department of Clinical Pharmacology and Toxicology, University Hospital Zurich, Zürich, Switzerland.
authors.forename: Albina
authors.initials: A
authors.lastname: Stocker
authors.affiliation: Breast-Center Zürich, Zürich, Switzerland.
authors.forename: Marie-Luise
authors.initials: ML
authors.lastname: Hilbers
authors.affiliation: Breast-Center Zürich, Zürich, Switzerland.
authors.forename: Claire
authors.initials: C
authors.lastname: Gauthier
authors.affiliation: Breast-Center Zürich, Zürich, Switzerland.
authors.forename: Josias
authors.initials: J
authors.lastname: Grogg
authors.affiliation: Department of Clinical Pharmacology and Toxicology, University Hospital Zurich, Zürich, Switzerland.
authors.forename: Gerd A
authors.initials: GA
authors.lastname: Kullak-Ublick
authors.affiliation: Department of Epidemiology, Biostatistics and Prevention Institute, University of Zurich, Zürich, Switzerland.
authors.forename: Burkhardt
authors.initials: B
authors.lastname: Seifert
authors.affiliation: Institute of Surgical Pathology, University Hospital Zurich, Zürich, Switzerland.
authors.forename: Zsuzsanna
authors.initials: Z
authors.lastname: Varga
authors.affiliation: Breast-Center Zürich, Zürich, Switzerland.|Department of Clinical Pharmacology and Toxicology, University Hospital Zurich, Zürich, Switzerland.
authors.forename: Andreas
authors.identifier: http://orcid.org/0000-0001-7257-9312
authors.initials: A
authors.lastname: Trojan
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D002886:Chromosomes, Human, Pair 17; D005260:Female; D018734:Genes, erbB-2; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008875:Middle Aged; D012189:Retrospective Studies; D000068878:Trastuzumab / Q000627:therapeutic use*; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D000068878:Trastuzumab