title: Human epidermal growth factor receptor 2-positive breast cancer: heat shock protein 90 overexpression, Ki67 proliferative index, and topoisomerase II-α co-amplification as predictors of pathologic complete response to neoadjuvant chemotherapy with trastuzumab and docetaxel.
abstract: BACKGROUND
  The combination of trastuzumab and chemotherapy is currently considered the standard of care for patients with locally advanced/operable human epidermal growth factor receptor 2 (HER2)-positive breast cancer. The potential correlation between the pathologic complete response (pCR) and the overexpression of heat shock protein 90 (Hsp90), Ki67, and the amplification of topoisomerase II-α (TOPO2A) was investigated in a series of patients who received neoadjuvant treatment.
  
  
  METHODS
  HER2-amplified patients who received neoadjuvant trastuzumab-docetaxel were gathered. Baseline and postsurgical Hsp90 immunoscore, Ki67 proliferation index, and TOPO2A amplification were determined together with classic clinical-pathologic predictors and correlated with pCR and imaging data.
  
  
  RESULTS
  A total of 24 patients were evaluated for response; pCR, clinical, and radiologic response were found in 4 patients (16.7%; 95% confidence interval [CI], 1.7-31.5), 9 patients (37.5%; 95% CI, 18.1-56.8), and 6 patients (25.0%; 95% CI, 7.6-42.3) patients, respectively. pCR was significantly higher in premenopausal (60.0% vs. 5.3%, P = .02) and negative hormonal receptor patients (50.0% vs. 5.6%, P = .03). A trend for patients with high Ki67 and TOPO2A/HER2 co-amplification was found (21.1% vs. none, P = .54; 50.0% vs. 12%, P = .16). pCR was significantly higher in patients with Hsp90 score 3+, in comparison with score 2+ and score 1+ (50.0% vs. 14.3% vs. none, P = .05). After treatment, a statistically significant lower Ki67 staining (30.0% vs. 17.5%, P = .005) and a trend for the decreased expression of high (score 3+) and moderate (score 2+) Hsp90 immunostaining (McNemar P = .25, Wilcoxon-Mann-Whitney P = .08) were found.
  
  
  CONCLUSIONS
  Although underpowered, our data suggest that patients with HER2-positive breast cancer overexpressing Hsp90 should be investigated as a "newer" molecular subtype with a significantly higher chance of pCR when receiving anti-Her2 agents.
authors.affiliation: Medical Oncology, Azienda Ospedaliera Universitaria Integrata, University of Verona, Verona, Italy. Electronic address: emiliobria@yahoo.it.
authors.forename: Emilio
authors.initials: E
authors.lastname: Bria
authors.affiliation: Medical Oncology, Azienda Ospedaliera Universitaria Integrata, University of Verona, Verona, Italy.
authors.forename: Jenny
authors.initials: J
authors.lastname: Furlanetto
authors.affiliation: Medical Oncology, Azienda Ospedaliera Universitaria Integrata, University of Verona, Verona, Italy.
authors.forename: Luisa
authors.initials: L
authors.lastname: Carbognin
authors.affiliation: Department of Pathology and Diagnostic, Azienda Ospedaliera Universitaria Integrata, University of Verona, Verona, Italy.
authors.forename: Matteo
authors.initials: M
authors.lastname: Brunelli
authors.affiliation: Medical Oncology, Azienda Ospedaliera Universitaria Integrata, University of Verona, Verona, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Caliolo
authors.affiliation: Medical Oncology, Azienda Ospedaliera Universitaria Integrata, University of Verona, Verona, Italy.
authors.forename: Rolando
authors.initials: R
authors.lastname: Nortilli
authors.affiliation: Medical Oncology, Azienda Ospedaliera Universitaria Integrata, University of Verona, Verona, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Massari
authors.affiliation: Department of Pathology and Diagnostic, Azienda Ospedaliera Universitaria Integrata, University of Verona, Verona, Italy.
authors.forename: Serena
authors.initials: S
authors.lastname: Pedron
authors.affiliation: Department of Pathology and Diagnostic, Azienda Ospedaliera Universitaria Integrata, University of Verona, Verona, Italy.
authors.forename: Erminia
authors.initials: E
authors.lastname: Manfrin
authors.affiliation: Chirurgia 'A', Department of Surgery and Oncology, Azienda Ospedaliera Universitaria Integrata, University of Verona, Verona, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Pellini
authors.affiliation: Department of Pathology and Diagnostic, Azienda Ospedaliera Universitaria Integrata, University of Verona, Verona, Italy.
authors.forename: Franco
authors.initials: F
authors.lastname: Bonetti
authors.affiliation: Biostatistics, Regina Elena National Cancer Institute, Roma, Italy.
authors.forename: Isabella
authors.initials: I
authors.lastname: Sperduti
authors.affiliation: Chirurgia 'A', Department of Surgery and Oncology, Azienda Ospedaliera Universitaria Integrata, University of Verona, Verona, Italy.
authors.forename: Giovanni Paolo
authors.initials: GP
authors.lastname: Pollini
authors.affiliation: Department of Pathology and Diagnostic, Azienda Ospedaliera Universitaria Integrata, University of Verona, Verona, Italy.
authors.forename: Aldo
authors.initials: A
authors.lastname: Scarpa
authors.affiliation: Medical Oncology, Azienda Ospedaliera Universitaria Integrata, University of Verona, Verona, Italy.
authors.forename: Giampaolo
authors.initials: G
authors.lastname: Tortora
mesh_terms: D000328:Adult; D000368:Aged; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage; D000951:Antigens, Neoplasm / Q000235:genetics*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000453:epidemiology / Q000378:metabolism / Q000473:pathology; D018270:Carcinoma, Ductal, Breast / Q000188:drug therapy / Q000453:epidemiology / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation; D004250:DNA Topoisomerases, Type II / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics*; D000077143:Docetaxel; D005260:Female; D005784:Gene Amplification; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism*; D006801:Humans; D019394:Ki-67 Antigen / Q000378:metabolism*; D008875:Middle Aged; D008940:Mitotic Index; D020360:Neoadjuvant Therapy; D011379:Prognosis; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D012074:Remission Induction; D012189:Retrospective Studies; D043823:Taxoids / Q000008:administration & dosage; D000068878:Trastuzumab; D016896:Treatment Outcome
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000951:Antigens, Neoplasm; D004250:DNA Topoisomerases, Type II; D004268:DNA-Binding Proteins; D000077143:Docetaxel; D018841:HSP90 Heat-Shock Proteins; D019394:Ki-67 Antigen; D018719:Erb-b2 Receptor Tyrosine Kinases; D043823:Taxoids; D000068878:Trastuzumab; C508053:ERBB2 protein, human
keywords: Breast cancer; HER2; Hsp90; Ki67; TOPO2A