title: Alterations of the genes involved in the PI3K and estrogen-receptor pathways influence outcome in human epidermal growth factor receptor 2-positive and hormone receptor-positive breast cancer patients treated with trastuzumab-containing neoadjuvant chemotherapy.
abstract: BACKGROUND
  Chemotherapy with trastuzumab is widely used for patients with human epidermal growth factor receptor 2-positive (HER2+) breast cancer, but a significant number of patients with the tumor fail to respond, or relapse. The mechanisms of recurrence and biomarkers that indicate the response to the chemotherapy and outcome are not fully investigated.
  
  
  METHODS
  Genomic alterations were analyzed using single-nucleotide polymorphism arrays in 46 HER2 immunohistochemistry (IHC) 3+ or 2+/fluorescent in situ hybridization (FISH)+ breast cancers that were treated with neoadjuvant chemotherapy with paclitaxel, cyclophosphamid, epirubicin, fluorouracil, and trastuzumab. Patients were classified into two groups based on presence or absence of alterations of 65 cancer-associated genes, and the two groups were further classified into four groups based on genomic HER2 copy numbers or hormone receptor status (HR+/-). Pathological complete response (pCR) and relapse-free survival (RFS) rates were compared between any two of the groups.
  
  
  CONCLUSIONS
  The pCR rate was 54% in 37 patients, and the RFS rate at 3 years was 72% (95% CI, 0.55-0.89) in 42 patients. The analysis disclosed 8 tumors with nonamplified HER2 and 38 tumors with HER2 amplification, indicating the presence of discordance in tumors diagnosed using current HER2 testing. The 8 patients showed more difficulty in achieving pCR (P=0.019), more frequent relapse (P=0.018), and more frequent alterations of genes in the PI3K pathway (P=0.009) than the patients with HER2 amplification. The alterations of the PI3K and estrogen receptor (ER) pathway genes generally indicated worse RFS rates. The prognostic significance of the alterations was shown in patients with a HR+ tumor, but not in patients with a HR- tumor when divided. Alterations of the PI3K and ER pathway genes found in patients with a HR+ tumor with poor outcome suggested that crosstalk between the two pathways may be involved in resistance to the current chemotherapy with trastuzumab.
  
  
  CONCLUSIONS
  We recommend FISH analysis as a primary HER2 testing because patients with IHC 2+/3+ and nonamplified HER2 had poor outcome. We also support concurrent use of trastuzumab, lapatinib, and cytotoxic and anti-hormonal agents for patients having HR+ tumors with alterations of the PI3K and ER pathway genes.
authors.affiliation: Department of Cancer Diagnosis, Research Institute for Clinical Oncology, Saitama Cancer Center, 818 Komuro, Ina, Saitama, 362-0806, Japan.
authors.forename: Mamoru
authors.initials: M
authors.lastname: Takada
authors.forename: Toru
authors.initials: T
authors.lastname: Higuchi
authors.forename: Katsunori
authors.initials: K
authors.lastname: Tozuka
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Takei
authors.forename: Masayuki
authors.initials: M
authors.lastname: Haruta
authors.forename: Junko
authors.initials: J
authors.lastname: Watanabe
authors.forename: Fumio
authors.initials: F
authors.lastname: Kasai
authors.forename: Kenichi
authors.initials: K
authors.lastname: Inoue
authors.forename: Masafumi
authors.initials: M
authors.lastname: Kurosumi
authors.forename: Masaru
authors.initials: M
authors.lastname: Miyazaki
authors.forename: Aiko
authors.initials: A
authors.lastname: Sato-Otsubo
authors.forename: Seishi
authors.initials: S
authors.lastname: Ogawa
authors.forename: Yasuhiko
authors.initials: Y
authors.lastname: Kaneko
mesh_terms: D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000628:therapy*; D017024:Chemotherapy, Adjuvant; D002869:Chromosome Aberrations; D003520:Cyclophosphamide / Q000008:administration & dosage; D018572:Disease-Free Survival; D015251:Epirubicin / Q000008:administration & dosage; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D018628:Gene Dosage; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D053208:Kaplan-Meier Estimate; D020360:Neoadjuvant Therapy; D020411:Oligonucleotide Array Sequence Analysis; D017239:Paclitaxel / Q000008:administration & dosage; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D020641:Polymorphism, Single Nucleotide; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics* / Q000378:metabolism; D011960:Receptors, Estrogen / Q000378:metabolism*; D011980:Receptors, Progesterone / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics*; D015996:Survival Rate; D000068878:Trastuzumab
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D003520:Cyclophosphamide; D015251:Epirubicin; D005472:Fluorouracil; D017239:Paclitaxel; D019869:Phosphatidylinositol 3-Kinases; D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D000068878:Trastuzumab; C508053:ERBB2 protein, human