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United States Department of Agriculture

Agricultural Research Service

Research Project: Mineral and Vitamin Interventions for At-risk Populations

Location: Obesity and Metabolism Research Unit

Title: Serum biomarkers of bone metabolism in castration resistant prostate cancer patients with skeletal metastases

Authors
item Lara, Primo -
item Ely, Benjamin -
item Quinn, David -
item Mack, Philip -
item Tangen, Cathy -
item Gertz, Erik
item Twardowski, Przemyslaw -
item Goldkorn, Amir -
item Hussain, Maha -
item Vogelzang, Nicholas -
item Thompson, Ian -
item Van Loan, Marta

Submitted to: Journal of the National Cancer Institute
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: December 30, 2013
Publication Date: March 10, 2014
Citation: Lara, P.N., Ely, B., Quinn, D.L., Mack, P.C., Tangen, C.M., Gertz, E.R., Twardowski, P.W., Goldkorn, A., Hussain, M., Vogelzang, N.J., Thompson, I.M., Van Loan, M.D. 2014. Serum biomarkers of bone metabolism in castration resistant prostate cancer patients with skeletal metastases. Journal of the National Cancer Institute. 106(4):1-9. DOI: 10.1093/jnci/dju013.

Interpretive Summary: Prostate cancer occurs in 1 out of 6 men in the U.S. Traditional treatment includes prostate surgery and in more advanced case chemotherapy. Some patients do not respond to these therapeutic approaches and require more advanced and even experimental pharmacological interventions. However, methods to predict which patients will respond to the therapy and thereby have the greatest likelihood of survival are limited. Often times in advanced prostate cancer, cancer cells invade bone, known as bone metastases, and disrupt normal bone metabolism. Therefore, we examined changes in bone metabolism and its relationship to length of survival in approximately 800 men taking atrsentan, a prostate cancer drug, to determine if biochemical markers of bone metabolism could be predictive of survival. We found that if blood levels of bone metabolism were elevated at the time of initial treatment length of survival time was shortened. Additionally, if bone markers continued to increase during treatment time of survival was less. These results have clearly demonstrated that blood markers of bone metabolism can serve as an independent measure for prostate cancer prognosis and therefore, serve as a clinical tool for evaluation of treatment therapy.

Technical 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 metabolism markers 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 pre-treatment and serial sera. Cox regression models for survival based on marker levels adjusted for clinical variables were developed. A Cox model was fitted with main effects and marker treatment interaction, adjusted for clinical variables, to assess predictive value of atrasentan on survival. Analysis was adjusted for multiple comparisons. Results. Analyzable serum was available from 778 patients. Elevated baseline levels of each of the markers was associated with worse survival (p<0.001). Increasing marker levels by week nine of therapy were also associated with subsequent poor survival (p<0.001). Patients with the highest marker levels (upper 25th percentile) not only had a poor prognosis (hazard ratio [HR] = 4.3, p<0.001) but had a survival benefit from atrasentan (HR=0.33, median survival = 13 vs. 5 months; interaction p=0.005). Conclusions. Serum bone metabolism markers have significant independent prognostic value in CRPC. Importantly, a group of CRPC patients with highly elevated markers of bone turnover were identified that preferentially benefits from bone-targeted therapy.

Last Modified: 10/22/2014
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