title: Efficacy of cetuximab in metastatic castration-resistant prostate cancer might depend on EGFR and PTEN expression: results from a phase II trial (SAKK 08/07).
abstract: OBJECTIVE
  The EGF receptor (EGFR) is overexpressed in the majority of metastatic castration-resistant prostate cancers (mCRPC) and might represent a valid therapeutic target. The combination of docetaxel and cetuximab, the monoclonal antibody against EGFR, has not been tested in patients with prostate cancer.
  
  
  METHODS
  Patients with mCRPC progressing during or within 90 days after at least 12 weeks of docetaxel were included in this phase II trial. Treatment consisted of docetaxel (75 mg/m(2) every 3 weeks or 35 mg/m(2) on days 1, 8, 15 every 4 weeks) in combination with cetuximab (400 mg/m(2) on day 1 and then 250 mg/m(2) weekly). The primary endpoint was progression-free survival (PFS) at 12 weeks defined as the absence of prostate-specific antigen (PSA), radiographic, or clinical progression. Evaluation of known biomarkers of response and resistance to cetuximab (EGFR, PTEN, amphiregulin, epiregulin) was conducted.
  
  
  RESULTS
  Thirty-eight patients were enrolled at 15 Swiss centers. Median age was 68 years and median PSA was 212 ng/mL. PFS at 12 weeks was 34% [95% confidence interval (CI), 19%-52%], PFS at 24 weeks was 20%, and median overall survival (OS) was 13.3 months (95% CI, 7.3-15.4). Seven patients (20%) had a confirmed ≥ 50% and 11 patients (31%) a confirmed ≥ 30% PSA decline. About 47% of enrolled patients experienced grade 3 and 8% grade 4 toxicities. A significantly improved PFS was found in patients with overexpression of EGFR and persistent activity of PTEN.
  
  
  CONCLUSIONS
  EGFR inhibition with cetuximab might improve the outcome of patients with mCRPC. A potential correlation between EGFR overexpression, persistent expression of PTEN, and EGFR inhibition should be investigated further.
authors.affiliation: Medical Oncology, Kantonsspital Graubünden, Chur, Switzerland. richard.cathomas@ksgr.ch
authors.forename: Richard
authors.initials: R
authors.lastname: Cathomas
authors.forename: Christian
authors.initials: C
authors.lastname: Rothermundt
authors.forename: Dirk
authors.initials: D
authors.lastname: Klingbiel
authors.forename: Lukas
authors.initials: L
authors.lastname: Bubendorf
authors.forename: Rolf
authors.initials: R
authors.lastname: Jaggi
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Betticher
authors.forename: Peter
authors.initials: P
authors.lastname: Brauchli
authors.forename: Denise
authors.initials: D
authors.lastname: Cotting
authors.forename: Cornelia
authors.initials: C
authors.lastname: Droege
authors.forename: Ralph
authors.initials: R
authors.lastname: Winterhalder
authors.forename: Daniele
authors.initials: D
authors.lastname: Siciliano
authors.forename: Dominik R
authors.initials: DR
authors.lastname: Berthold
authors.forename: Miklos
authors.initials: M
authors.lastname: Pless
authors.forename: Ralph
authors.initials: R
authors.lastname: Schiess
authors.forename: Roger
authors.initials: R
authors.lastname: von Moos
authors.forename: Silke
authors.initials: S
authors.lastname: Gillessen
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use; D000068818:Cetuximab; D000077143:Docetaxel; D066246:ErbB Receptors / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009919:Orchiectomy; D051059:PTEN Phosphohydrolase / Q000235:genetics; D017430:Prostate-Specific Antigen / Q000097:blood; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality / Q000473:pathology*; D043823:Taxoids / Q000008:administration & dosage; D057170:Translational Research, Biomedical; D016896:Treatment Outcome
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D043823:Taxoids; D000077143:Docetaxel; D066246:ErbB Receptors; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; D017430:Prostate-Specific Antigen; D000068818:Cetuximab