title: Serum biomarkers of bone metabolism in castration-resistant prostate cancer patients with skeletal metastases: results from SWOG 0421.
abstract: BACKGROUND
  Prior studies suggest that elevated markers of bone turnover are prognostic for poor survival in castration-resistant prostate cancer (CRPC). The predictive role of these markers relative to bone-targeted therapy is unknown. We prospectively evaluated the prognostic and predictive value of bone biomarkers in sera from CRPC patients treated on a placebo-controlled phase III trial of docetaxel with or without the bone targeted endothelin-A receptor antagonist atrasentan (SWOG S0421).
  
  
  METHODS
  Markers for bone resorption (N-telopeptide and pyridinoline) and formation (C-terminal collagen propeptide and bone alkaline phosphatase) were assayed in pretreatment and serial sera. Cox proportional hazards regression models were fit for overall survival. Models were fit with main effects for marker levels and with/without terms for marker-treatment interaction, adjusted for clinical variables, to assess the prognostic and predictive value of atrasentan. Analysis was adjusted for multiple comparisons. Two-sided P values were calculated using the Wald test.
  
  
  RESULTS
  Sera from 778 patients were analyzed. Elevated baseline levels of each of the markers were associated with worse survival (P < .001). Increasing marker levels by week nine of therapy were also associated with subsequent poor survival (P < .001). Patients with the highest marker levels (upper 25th percentile for all markers) not only had a poor prognosis (hazard ratio [HR] = 4.3; 95% confidence interval [CI] = 2.41 to 7.65; P < .001) but also had a survival benefit from atrasentan (HR = 0.33; 95% CI = 0.15 to 0.71; median survival = 13 [atrasentan] vs 5 months [placebo]; P interaction = .005).
  
  
  CONCLUSIONS
  Serum bone metabolism markers have statistically significant independent prognostic value in CRPC. Importantly, a small group of patients (6%) with highly elevated markers of bone turnover appear to preferentially benefit from atrasentan therapy.
authors.affiliation: Affiliations of authors: University of California Davis Comprehensive Cancer Center, Sacramento, CA (PNL, PCM); Southwest Oncology Group Statistical Center, Seattle, WA (BE, CT); University of Southern California Norris Cancer Center, Los Angeles, CA (DIQ, AG); USDA Western Human Nutrition Center at University of California Davis, Davis, CA (EG, MVL); City of Hope, Duarte, CA (PT); University of Michigan, Ann Arbor, MI (MH), US Oncology, Las Vegas, NV (NJV); Cancer Treatment and Research Center, University of Texas, San Antonio, TX (IT).
authors.forename: Primo N
authors.initials: PN
authors.lastname: Lara
authors.forename: Benjamin
authors.initials: B
authors.lastname: Ely
authors.forename: David I
authors.initials: DI
authors.lastname: Quinn
authors.forename: Philip C
authors.initials: PC
authors.lastname: Mack
authors.forename: Catherine
authors.initials: C
authors.lastname: Tangen
authors.forename: Erik
authors.initials: E
authors.lastname: Gertz
authors.forename: Przemyslaw W
authors.initials: PW
authors.lastname: Twardowski
authors.forename: Amir
authors.initials: A
authors.lastname: Goldkorn
authors.forename: Maha
authors.initials: M
authors.lastname: Hussain
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Vogelzang
authors.forename: Ian M
authors.initials: IM
authors.lastname: Thompson
authors.forename: Marta D
authors.initials: MD
authors.lastname: Van Loan
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000469:Alkaline Phosphatase / Q000097:blood; D000596:Amino Acids / Q000097:blood; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D000077868:Atrasentan; D014408:Biomarkers, Tumor / Q000097:blood*; D001859:Bone Neoplasms / Q000097:blood* / Q000556:secondary; D016723:Bone Remodeling; D024042:Collagen Type I / Q000097:blood; D018572:Disease-Free Survival; D000077143:Docetaxel; D004311:Double-Blind Method; D065130:Endothelin A Receptor Antagonists; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D010446:Peptide Fragments / Q000097:blood; D010455:Peptides / Q000097:blood; D011237:Predictive Value of Tests; D011347:Procollagen / Q000097:blood; D011379:Prognosis; D016016:Proportional Hazards Models; D011446:Prospective Studies; D064129:Prostatic Neoplasms, Castration-Resistant / Q000097:blood* / Q000188:drug therapy / Q000473:pathology*; D011759:Pyrrolidines / Q000627:therapeutic use*; D012372:ROC Curve; D043823:Taxoids / Q000627:therapeutic use*; D017211:Treatment Failure
chemical_list: D000596:Amino Acids; D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D024042:Collagen Type I; D065130:Endothelin A Receptor Antagonists; D010446:Peptide Fragments; D010455:Peptides; D011347:Procollagen; D011759:Pyrrolidines; D043823:Taxoids; C052929:collagen type I trimeric cross-linked peptide; C042813:procollagen type I carboxy terminal peptide; D000077143:Docetaxel; C015484:pyridinoline; D000469:Alkaline Phosphatase; D000077868:Atrasentan