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Prognostic relevance and performance characteristics of serum IGFBP‐2 and PAPP‐A in women with breast cancer: a long‐term Danish cohort study

Measurement of circulating insulin‐like growth factors (IGFs), in particular IGF‐binding protein (IGFBP)‐2, at the time of diagnosis, is independently prognostic in many cancers, but its clinical performance against other routinely determined prognosticators has not been examined. We measured IGF‐I,...

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Autores principales: Espelund, Ulrick, Renehan, Andrew G., Cold, Søren, Oxvig, Claus, Lancashire, Lee, Su, Zhenqiang, Flyvbjerg, Allan, Frystyk, Jan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6010701/
https://www.ncbi.nlm.nih.gov/pubmed/29722920
http://dx.doi.org/10.1002/cam4.1504
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author Espelund, Ulrick
Renehan, Andrew G.
Cold, Søren
Oxvig, Claus
Lancashire, Lee
Su, Zhenqiang
Flyvbjerg, Allan
Frystyk, Jan
author_facet Espelund, Ulrick
Renehan, Andrew G.
Cold, Søren
Oxvig, Claus
Lancashire, Lee
Su, Zhenqiang
Flyvbjerg, Allan
Frystyk, Jan
author_sort Espelund, Ulrick
collection PubMed
description Measurement of circulating insulin‐like growth factors (IGFs), in particular IGF‐binding protein (IGFBP)‐2, at the time of diagnosis, is independently prognostic in many cancers, but its clinical performance against other routinely determined prognosticators has not been examined. We measured IGF‐I, IGF‐II, pro‐IGF‐II, IGF bioactivity, IGFBP‐2, ‐3, and pregnancy‐associated plasma protein A (PAPP‐A), an IGFBP regulator, in baseline samples of 301 women with breast cancer treated on four protocols (Odense, Denmark: 1993–1998). We evaluated performance characteristics (expressed as area under the curve, AUC) using Cox regression models to derive hazard ratios (HR) with 95% confidence intervals (CIs) for 10‐year recurrence‐free survival (RFS) and overall survival (OS), and compared those against the clinically used Nottingham Prognostic Index (NPI). We measured the same biomarkers in 531 noncancer individuals to assess multidimensional relationships (MDR), and evaluated additional prognostic models using survival artificial neural network (SANN) and survival support vector machines (SSVM), as these enhance capture of MDRs. For RFS, increasing concentrations of circulating IGFBP‐2 and PAPP‐A were independently prognostic [HR (biomarker doubling): 1.474 (95% CIs: 1.160, 1.875, P = 0.002) and 1.952 (95% CIs: 1.364, 2.792, P < 0.001), respectively]. The AUC(RFS) for NPI was 0.626 (Cox model), improving to 0.694 (P = 0.012) with the addition of IGFBP‐2 plus PAPP‐A. Derived AUC(RFS) using SANN and SSVM did not perform superiorly. Similar patterns were observed for OS. These findings illustrate an important principle in biomarker qualification—measured circulating biomarkers may demonstrate independent prognostication, but this does not necessarily translate into substantial improvement in clinical performance.
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spelling pubmed-60107012018-06-27 Prognostic relevance and performance characteristics of serum IGFBP‐2 and PAPP‐A in women with breast cancer: a long‐term Danish cohort study Espelund, Ulrick Renehan, Andrew G. Cold, Søren Oxvig, Claus Lancashire, Lee Su, Zhenqiang Flyvbjerg, Allan Frystyk, Jan Cancer Med Clinical Cancer Research Measurement of circulating insulin‐like growth factors (IGFs), in particular IGF‐binding protein (IGFBP)‐2, at the time of diagnosis, is independently prognostic in many cancers, but its clinical performance against other routinely determined prognosticators has not been examined. We measured IGF‐I, IGF‐II, pro‐IGF‐II, IGF bioactivity, IGFBP‐2, ‐3, and pregnancy‐associated plasma protein A (PAPP‐A), an IGFBP regulator, in baseline samples of 301 women with breast cancer treated on four protocols (Odense, Denmark: 1993–1998). We evaluated performance characteristics (expressed as area under the curve, AUC) using Cox regression models to derive hazard ratios (HR) with 95% confidence intervals (CIs) for 10‐year recurrence‐free survival (RFS) and overall survival (OS), and compared those against the clinically used Nottingham Prognostic Index (NPI). We measured the same biomarkers in 531 noncancer individuals to assess multidimensional relationships (MDR), and evaluated additional prognostic models using survival artificial neural network (SANN) and survival support vector machines (SSVM), as these enhance capture of MDRs. For RFS, increasing concentrations of circulating IGFBP‐2 and PAPP‐A were independently prognostic [HR (biomarker doubling): 1.474 (95% CIs: 1.160, 1.875, P = 0.002) and 1.952 (95% CIs: 1.364, 2.792, P < 0.001), respectively]. The AUC(RFS) for NPI was 0.626 (Cox model), improving to 0.694 (P = 0.012) with the addition of IGFBP‐2 plus PAPP‐A. Derived AUC(RFS) using SANN and SSVM did not perform superiorly. Similar patterns were observed for OS. These findings illustrate an important principle in biomarker qualification—measured circulating biomarkers may demonstrate independent prognostication, but this does not necessarily translate into substantial improvement in clinical performance. John Wiley and Sons Inc. 2018-05-03 /pmc/articles/PMC6010701/ /pubmed/29722920 http://dx.doi.org/10.1002/cam4.1504 Text en © 2018 The Authors. Cancer Medicine published by John Wiley & Sons Ltd. This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Clinical Cancer Research
Espelund, Ulrick
Renehan, Andrew G.
Cold, Søren
Oxvig, Claus
Lancashire, Lee
Su, Zhenqiang
Flyvbjerg, Allan
Frystyk, Jan
Prognostic relevance and performance characteristics of serum IGFBP‐2 and PAPP‐A in women with breast cancer: a long‐term Danish cohort study
title Prognostic relevance and performance characteristics of serum IGFBP‐2 and PAPP‐A in women with breast cancer: a long‐term Danish cohort study
title_full Prognostic relevance and performance characteristics of serum IGFBP‐2 and PAPP‐A in women with breast cancer: a long‐term Danish cohort study
title_fullStr Prognostic relevance and performance characteristics of serum IGFBP‐2 and PAPP‐A in women with breast cancer: a long‐term Danish cohort study
title_full_unstemmed Prognostic relevance and performance characteristics of serum IGFBP‐2 and PAPP‐A in women with breast cancer: a long‐term Danish cohort study
title_short Prognostic relevance and performance characteristics of serum IGFBP‐2 and PAPP‐A in women with breast cancer: a long‐term Danish cohort study
title_sort prognostic relevance and performance characteristics of serum igfbp‐2 and papp‐a in women with breast cancer: a long‐term danish cohort study
topic Clinical Cancer Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6010701/
https://www.ncbi.nlm.nih.gov/pubmed/29722920
http://dx.doi.org/10.1002/cam4.1504
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