title: Mutations in the epidermal growth factor receptor (EGFR) gene in triple negative breast cancer: possible implications for targeted therapy.
abstract: BACKGROUND
  Triple negative breast cancer is associated with poorer prognosis and unresponsiveness to endocrine and anti-HER2 directed agents. Despite emerging data supporting the use of polyADP-ribose polymerase (PARP) inhibitors, complete and durable responses are rare and exploration of additional targeted therapies is needed. Epidermal growth factor receptor (EGFR) is expressed in triple negative breast cancer and several clinical trials are testing the role of anti-EGFR directed therapy. However, the rate of EGFR mutations is poorly defined. We, therefore, sought to characterize EGFR mutations in triple negative breast cancers.
  
  
  METHODS
  Seventy samples were randomly chosen from a cohort of 653 triple negative breast tumours for EGFR mutation analysis. These samples were immunostained for EGFR protein expression and consisted of negatively stained and positively stained cases. DNA was extracted from paraffin blocks and polymerase chain reaction was performed to amplify exon regions 18 to 21 of the EGFR gene. Direct sequencing of the purified PCR products was performed.
  
  
  RESULTS
  EGFR mutations were found in 8 of 70 samples (11.4%). Mutations were predominantly exon 19 deletions (4 of 70 samples, 5.7%), which clustered in the region spanning codons 746 to 759 within the kinase domain of EGFR. Two types of exon 19 deletions were seen: a 15 nucleotide deletion (del E746-A750) (2 of 70 samples) and a 24 nucleotide deletion (del S752 - I759) (2 of 70 samples). Other exon 19 mutations observed were the inversion of the complementary strand (1 of 70 samples). Exon 21 mutations included missense substitution, L858R (1 of 70 samples) and T847I (2 of 70 samples). Mutations observed were independent of EGFR protein expression determined by immunohistochemical staining.
  
  
  CONCLUSIONS
  This study is among the first to document the presence and estimate the prevalence of EGFR mutations in triple negative breast cancer. These findings have potential implications for the design of clinical trials involving anti-EGFR directed therapy which currently do not select for patients based on presence of activating EGFR mutations, which may hence be underpowered to detect significant benefit in unselected populations. More complete sampling of EGFR mutation status in triple negative breast cancer is needed to determine the true mutation rate.
authors: Department of Pathology, Singapore General Hospital, Outram Road, Singapore 169608, Singapore.
authors: Yvonne Hui-Fang
authors: YH
authors: Teng
authors: Wai-Jin
authors: WJ
authors: Tan
authors: Aye-Aye
authors: AA
authors: Thike
authors: Poh-Yian
authors: PY
authors: Cheok
authors: Gary Man-Kit
authors: GM
authors: Tse
authors: Nan-Soon
authors: NS
authors: Wong
authors: George Wai-Cheong
authors: GW
authors: Yip
authors: Boon-Huat
authors: BH
authors: Bay
authors: Puay-Hoon
authors: PH
authors: Tan
mesh_terms: D000328:Adult; D000368:Aged; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D004273:DNA, Neoplasm / Q000032:analysis* / Q000235:genetics; D066246:ErbB Receptors / Q000096:biosynthesis; D005260:Female; D018773:Genes, erbB-1; D006801:Humans; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D009154:Mutation; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D011960:Receptors, Estrogen / Q000378:metabolism; D011980:Receptors, Progesterone / Q000172:deficiency / Q000378:metabolism
chemical_list: D004273:DNA, Neoplasm; D066246:ErbB Receptors; D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone