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 C. Mack; Catherine Tangen; Erik Gertz; Przemyslaw W. Twardowski; Amir Goldkorn; Maha Hussain; Nicholas J. Vogelzang; Ian M. Thompson; Marta D. Van Loan

doi:10.1093/jnci/dju013

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 C. Mack, Catherine Tangen, Erik Gertz, Przemyslaw W. Twardowski, Amir Goldkorn, Maha Hussain, Nicholas J. Vogelzang, Ian M. Thompson, Marta D. Van Loan

^*Corresponding author for this work

Medicine, Hematology Oncology Division

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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.

Original language	English (US)
Journal	Journal of the National Cancer Institute
Volume	106
Issue number	4
DOIs	https://doi.org/10.1093/jnci/dju013
State	Published - Apr 2014

Funding

This investigation was supported by National Institutes of Health/National Cancer Institute grant 5R01-CA120469 and in part by the following Public Health Service or PHS Cooperative Agreement grant numbers awarded by the National Cancer Institute: CA32102, CA38926. The parent trial (S0421) had accrual participation from other US Cooperative Groups (Eastern Cooperative Oncology Group and Cancer and Leukemia Group B). ClinicalTrials.gov: NCT00134056.

ASJC Scopus subject areas

Oncology
Cancer Research

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1093/jnci/dju013

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Lara, P. N., Ely, B., Quinn, D. I., Mack, P. C., Tangen, C., Gertz, E., 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: Results from SWOG 0421. Journal of the National Cancer Institute, 106(4). https://doi.org/10.1093/jnci/dju013

@article{ef6914dfb3ff4f4a8e9ec3dc9f7f1136,

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 Mack, {Philip C.} 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.}",

note = "Funding Information: This investigation was supported by National Institutes of Health/National Cancer Institute grant 5R01-CA120469 and in part by the following Public Health Service or PHS Cooperative Agreement grant numbers awarded by the National Cancer Institute: CA32102, CA38926. The parent trial (S0421) had accrual participation from other US Cooperative Groups (Eastern Cooperative Oncology Group and Cancer and Leukemia Group B). ClinicalTrials.gov: NCT00134056.",

year = "2014",

month = apr,

doi = "10.1093/jnci/dju013",

language = "English (US)",

volume = "106",

journal = "Journal of the National Cancer Institute",

issn = "0027-8874",

publisher = "Oxford University Press",

number = "4",

}

Lara, PN, Ely, B, Quinn, DI, Mack, PC, 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. https://doi.org/10.1093/jnci/dju013

TY - JOUR

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 C.

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.

N1 - Funding Information: This investigation was supported by National Institutes of Health/National Cancer Institute grant 5R01-CA120469 and in part by the following Public Health Service or PHS Cooperative Agreement grant numbers awarded by the National Cancer Institute: CA32102, CA38926. The parent trial (S0421) had accrual participation from other US Cooperative Groups (Eastern Cooperative Oncology Group and Cancer and Leukemia Group B). ClinicalTrials.gov: NCT00134056.

PY - 2014/4

Y1 - 2014/4

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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U2 - 10.1093/jnci/dju013

DO - 10.1093/jnci/dju013

M3 - Article

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AN - SCOPUS:84898885627

SN - 0027-8874

VL - 106

JO - Journal of the National Cancer Institute

JF - Journal of the National Cancer Institute

IS - 4

ER -

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

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UN SDGs

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