title: Mutational analyses of epidermal growth factor receptor and downstream pathways in adrenocortical carcinoma.
abstract: BACKGROUND
  Adrenocortical carcinoma (ACC) is a rare disease with a poor prognosis and limited therapeutic options. Mitotane is considered the standard first-line therapy with only 30% of the patients showing objective tumour response. Defining predictive factors for response is therefore of clinical importance. The epidermal growth factor receptor (EGFR) has been implicated in the development of one-third of all malignancies. EGFR pathway members in ACC have been investigated, however, without available clinical data and relation to survival.
  
  
  METHODS
  In this study, mutation status of EGFR and downstream signalling pathways was evaluated in 47 ACC patients on mitotane using direct sequencing, a TaqMan allele-specific assay and immunohistochemistry. Archival formalin-fixed paraffin-embedded tumour tissue was used for all analyses. Patient data were obtained anonymously, after coupling with the collected tumour tissue.
  
  
  RESULTS
  One BRAF, two EGFR TK domain (c.2590> A, p.864A>T) and 11 TP53, but no PIK3CA or KRAS, mutations were found. No relationship was found between mutation status, immunostaining and mitotane response or survival.
  
  
  CONCLUSIONS
  In conclusion, our data suggest that the role of EGFR tyrosine kinase inhibitors in ACC is limited. Treatment with EGFR monoclonal antibodies on the other hand might be beneficial for a larger group of patients. The possible efficacy of this therapy in ACC should be evaluated in future trials.
authors.affiliation: Department of Internal Medicine, Máxima Medical Centre, PO Box 90052, 5600 PD Eindhoven, The Netherlands. ilsehermsen@gmail.com
authors.forename: Ilse G C
authors.initials: IG
authors.lastname: Hermsen
authors.forename: Harm R
authors.initials: HR
authors.lastname: Haak
authors.forename: Ronald R
authors.initials: RR
authors.lastname: de Krijger
authors.forename: Thomas M A
authors.initials: TM
authors.lastname: Kerkhofs
authors.forename: Richard A
authors.initials: RA
authors.lastname: Feelders
authors.forename: Wouter W
authors.initials: WW
authors.lastname: de Herder
authors.forename: Hanneke
authors.initials: H
authors.lastname: Wilmink
authors.forename: Jan W A
authors.initials: JW
authors.lastname: Smit
authors.forename: Hans
authors.initials: H
authors.lastname: Gelderblom
authors.forename: Noel F C C
authors.initials: NF
authors.lastname: de Miranda
authors.forename: Ronald
authors.initials: R
authors.lastname: van Eijk
authors.forename: Tom
authors.initials: T
authors.lastname: van Wezel
authors.forename: Hans
authors.initials: H
authors.lastname: Morreau
mesh_terms: D000306:Adrenal Cortex Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D018268:Adrenocortical Carcinoma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use*; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D066246:ErbB Receptors / Q000235:genetics* / Q000276:immunology; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D020935:MAP Kinase Signaling System; D008297:Male; D008875:Middle Aged; D008939:Mitotane / Q000627:therapeutic use*; D009367:Neoplasm Staging; D009426:Netherlands; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D011237:Predictive Value of Tests; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction; D016896:Treatment Outcome; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D051176:beta Catenin / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal; D018931:Antineoplastic Agents, Hormonal; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D051176:beta Catenin; D008939:Mitotane; C512478:EGFR protein, human; D066246:ErbB Receptors; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase