title: HER2 protein and gene variation between primary and metastatic breast cancer: significance and impact on patient care.
abstract: OBJECTIVE
  To analyze HER2 status in primary breast cancer (PBC) compared with correspondent metachronous metastases and to investigate whether BC phenotype may be predictive of change in HER2 expression.
  
  
  METHODS
  HER2 was investigated by immunohistochemistry, silver in situ hybridization (SISH), and FISH, in a series of 137 tumors, building up a tissue microarray to concurrently analyze each single PBC and metastatic (MBC) on the same slide.
  
  
  RESULTS
  HER2 status was discordant in 14 cases (10%): 12 negative in PBC and positive in metastases and two positive in PBC and negative in metastases (P = 0.04). These findings were confirmed by a PCR based test termed Multiplex Ligation-dependent Probe Amplification (MLPA). HER2 status changed in hormone receptor-positive BC more frequently than in negative ones (P = 0.002). In addition, we evaluated HER2 gene and chromosome 17 copy number by SISH in the 123 cases with unchanged HER2 status during progression. We found consistent HER2 gene copy number stability in the 100 nonamplified cases. Conversely, of the 23 amplified PBC, 13 (57%) demonstrated a significant increase in the HER2 gene and chromosome 17 copy number in their paired metastases (P = 0.01), as defined by SISH (k = 0.54, P < 0.0001) and MLPA. Patients who changed HER2 status from negative to positive, presented significant longer time to progression when treated with trastuzumab compared to those who were untreated (P = 0.04).
  
  
  CONCLUSIONS
  When feasible, HER2 reassessment in metastatic lesions should be carefully taken into account, especially for metastases coming from primary hormone receptor-positive BC.
authors.affiliation: Medical Oncology, Regina Elena Cancer Institute, Rome, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Fabi
authors.forename: Anna
authors.initials: A
authors.lastname: Di Benedetto
authors.forename: Giulio
authors.initials: G
authors.lastname: Metro
authors.forename: Letizia
authors.initials: L
authors.lastname: Perracchio
authors.forename: Cecilia
authors.initials: C
authors.lastname: Nisticò
authors.forename: Franco
authors.initials: F
authors.lastname: Di Filippo
authors.forename: Cristiana
authors.initials: C
authors.lastname: Ercolani
authors.forename: Gianluigi
authors.initials: G
authors.lastname: Ferretti
authors.forename: Elisa
authors.initials: E
authors.lastname: Melucci
authors.forename: Simonetta
authors.initials: S
authors.lastname: Buglioni
authors.forename: Isabella
authors.initials: I
authors.lastname: Sperduti
authors.forename: Paola
authors.initials: P
authors.lastname: Papaldo
authors.forename: Francesco
authors.initials: F
authors.lastname: Cognetti
authors.forename: Marcella
authors.initials: M
authors.lastname: Mottolese
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy / Q000473:pathology* / Q000556:secondary*; D002886:Chromosomes, Human, Pair 17 / Q000235:genetics; D056915:DNA Copy Number Variations; D018572:Disease-Free Survival; D005260:Female; D005784:Gene Amplification; D006801:Humans; D017403:In Situ Hybridization; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D009362:Neoplasm Metastasis; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics* / Q000378:metabolism; D000068878:Trastuzumab; D016896:Treatment Outcome
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; C508053:ERBB2 protein, human