title: Epidermal growth factor receptor gene polymorphisms are associated with prognostic features of breast cancer.
abstract: BACKGROUND
  The epidermal growth factor receptor (EGFR) is differently expressed in breast cancer, and its presence may favor cancer progression. We hypothesized that two EGFR functional polymorphisms, a (CA)n repeat in intron 1, and a single nucleotide polymorphism, R497K, may affect EGFR expression and breast cancer clinical profile.
  
  
  METHODS
  The study population consisted of 508 Brazilian women with unilateral breast cancer, and no distant metastases. Patients were genotyped for the (CA)n and R497K polymorphisms, and the associations between (CA)n polymorphism and EGFR transcript levels (n = 129), or between either polymorphism and histopathological features (n = 505) were evaluated. The REMARK criteria of tumor marker evaluation were followed.
  
  
  RESULTS
  (CA)n lengths ranged from 14 to 24 repeats, comprehending 11 alleles and 37 genotypes. The most frequent allele was (CA)16 (0.43; 95% CI = 0.40-0.46), which was set as the cut-off length to define the Short allele. Variant (CA)n genotypes had no significant effect in tumoral EGFR mRNA levels, but patients with two (CA)n Long alleles showed lower chances of being negative for progesterone receptor (ORadjusted = 0.42; 95% CI = 0.19-0.91). The evaluation of R497K polymorphism indicated a frequency of 0.21 (95% CI = 0.19 - 0.24) for the variant (Lys) allele. Patients with variant R497K genotypes presented lower proportion of worse lymph node status (pN2 or pN3) when compared to the reference genotype Arg/Arg (ORadjusted = 0.32; 95% CI = 0.17-0.59), which resulted in lower tumor staging (ORadjusted = 0.34; 95% CI = 0.19-0.63), and lower estimated recurrence risk (OR = 0.50; 95% CI = 0.30-0.81). The combined presence of both EGFR polymorphisms (Lys allele of R497K and Long/Long (CA)n) resulted in lower TNM status (ORadjusted = 0.22; 95% CI = 0.07-0.75) and lower ERR (OR = 0.25; 95% CI = 0.09-0.71). When tumors were stratified according to biological classification, the favorable effects of variant EGFR polymorphisms were preserved for luminal A tumors, but not for other subtypes.
  
  
  CONCLUSIONS
  The data suggest that the presence of the variant forms of EGFR polymorphisms may lead to better prognosis in breast cancer, especially in patients with luminal A tumors.
authors.forename: Marcelo Sobral
authors.initials: MS
authors.lastname: Leite
authors.forename: Letícia Carlos
authors.initials: LC
authors.lastname: Giacomin
authors.forename: Diogo Nascimento
authors.initials: DN
authors.lastname: Piranda
authors.forename: Juliana Simões
authors.initials: JS
authors.lastname: Festa-Vasconcellos
authors.forename: Vanessa
authors.initials: V
authors.lastname: Indio-do-Brasil
authors.forename: Sérgio
authors.initials: S
authors.lastname: Koifman
authors.forename: Rodrigo Soares
authors.initials: RS
authors.lastname: de Moura-Neto
authors.forename: Marcelo Alex
authors.initials: MA
authors.lastname: de Carvalho
authors.affiliation: Programa de Farmacologia, Coordenação de Pesquisa, Instituto Nacional do Câncer, Rua André Cavalcanti, 37, 3° andar CEP: 20231-050, Rio de Janeiro, RJ, Brazil. farmaco@inca.gov.br.
authors.forename: Rosane
authors.initials: R
authors.lastname: Vianna-Jorge
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001938:Brazil / Q000453:epidemiology; D001943:Breast Neoplasms / Q000175:diagnosis* / Q000453:epidemiology / Q000235:genetics*; D015331:Cohort Studies; D066246:ErbB Receptors / Q000235:genetics*; D005260:Female; D014644:Genetic Variation; D006801:Humans; D008875:Middle Aged; D011110:Polymorphism, Genetic / Q000235:genetics*; D011379:Prognosis; D011446:Prospective Studies
chemical_list: C512478:EGFR protein, human; D066246:ErbB Receptors