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J Natl Cancer Inst. 2014 Apr;106(4):dju013. doi: 10.1093/jnci/dju013. Epub 2014 Feb 24.

Serum biomarkers of bone metabolism in castration-resistant prostate cancer patients with skeletal metastases: results from SWOG 0421.

Author information

1
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).

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.

TRIAL REGISTRATION:

ClinicalTrials.gov NCT00134056.

PMID:
24565955
PMCID:
PMC3982883
DOI:
10.1093/jnci/dju013
[Indexed for MEDLINE]
Free PMC Article

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