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

Primo N Lara, Benjamin Ely, David I. Quinn, Philip Mack, Catherine Tangen, Erik Gertz, Przemyslaw W. Twardowski, Amir Goldkorn, Maha Hussain, Nicholas J. Vogelzang, Ian M. Thompson, Marta D. Van Loan

Research output: Contribution to journalArticle

21 Citations (Scopus)

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]; Pinteraction =. 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.

Original languageEnglish (US)
Article numberdju013
JournalJournal of the National Cancer Institute
Volume106
Issue number4
DOIs
StatePublished - 2014

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Castration
Prostatic Neoplasms
Biomarkers
Neoplasm Metastasis
Bone and Bones
Survival
Serum
Bone Remodeling
docetaxel
bis(2,3,3,3-tetrachloropropyl) ether
Placebos
Confidence Intervals
Therapeutics
Bone Resorption
Proportional Hazards Models
Alkaline Phosphatase
Collagen
atrasentan

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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Serum biomarkers of bone metabolism in castration-resistant prostate cancer patients with skeletal metastases : Results from SWOG 0421. / Lara, Primo N; Ely, Benjamin; Quinn, David I.; Mack, Philip; Tangen, Catherine; Gertz, Erik; Twardowski, Przemyslaw W.; Goldkorn, Amir; Hussain, Maha; Vogelzang, Nicholas J.; Thompson, Ian M.; Van Loan, Marta D.

In: Journal of the National Cancer Institute, Vol. 106, No. 4, dju013, 2014.

Research output: Contribution to journalArticle

Lara, PN, Ely, B, Quinn, DI, Mack, P, Tangen, C, Gertz, E, Twardowski, PW, Goldkorn, A, Hussain, M, Vogelzang, NJ, Thompson, IM & Van Loan, MD 2014, 'Serum biomarkers of bone metabolism in castration-resistant prostate cancer patients with skeletal metastases: Results from SWOG 0421', Journal of the National Cancer Institute, vol. 106, no. 4, dju013. https://doi.org/10.1093/jnci/dju013
Lara, Primo N ; Ely, Benjamin ; Quinn, David I. ; Mack, Philip ; Tangen, Catherine ; Gertz, Erik ; Twardowski, Przemyslaw W. ; Goldkorn, Amir ; Hussain, Maha ; Vogelzang, Nicholas J. ; Thompson, Ian M. ; Van Loan, Marta D. / Serum biomarkers of bone metabolism in castration-resistant prostate cancer patients with skeletal metastases : Results from SWOG 0421. In: Journal of the National Cancer Institute. 2014 ; Vol. 106, No. 4.
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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]; Pinteraction =. 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.",
author = "Lara, {Primo N} and Benjamin Ely and Quinn, {David I.} and Philip Mack and Catherine Tangen and Erik Gertz and Twardowski, {Przemyslaw W.} and Amir Goldkorn and Maha Hussain and Vogelzang, {Nicholas J.} and Thompson, {Ian M.} and {Van Loan}, {Marta D.}",
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T1 - Serum biomarkers of bone metabolism in castration-resistant prostate cancer patients with skeletal metastases

T2 - Results from SWOG 0421

AU - Lara, Primo N

AU - Ely, Benjamin

AU - Quinn, David I.

AU - Mack, Philip

AU - Tangen, Catherine

AU - Gertz, Erik

AU - Twardowski, Przemyslaw W.

AU - Goldkorn, Amir

AU - Hussain, Maha

AU - Vogelzang, Nicholas J.

AU - Thompson, Ian M.

AU - Van Loan, Marta D.

PY - 2014

Y1 - 2014

N2 - 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]; Pinteraction =. 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.

AB - 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]; Pinteraction =. 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.

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