Prognostic relevance and performance characteristics of serum IGFBP‐2 and PAPP‐A in women with breast cancer: a long‐term Danish cohort study
Abstract 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 measur...
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Wiley
2018-06-01
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| Series: | Cancer Medicine |
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| Online Access: | https://doi.org/10.1002/cam4.1504 |
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| author | Ulrick Espelund Andrew G. Renehan Søren Cold Claus Oxvig Lee Lancashire Zhenqiang Su Allan Flyvbjerg Jan Frystyk |
| author_facet | Ulrick Espelund Andrew G. Renehan Søren Cold Claus Oxvig Lee Lancashire Zhenqiang Su Allan Flyvbjerg Jan Frystyk |
| author_sort | Ulrick Espelund |
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| description | Abstract 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 [HRbiomarker 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 AUCRFS for NPI was 0.626 (Cox model), improving to 0.694 (P = 0.012) with the addition of IGFBP‐2 plus PAPP‐A. Derived AUCRFS 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. |
| format | Article |
| id | doaj-art-2c5a5bc59aae464fb2bbd784e088cf3d |
| institution | OA Journals |
| issn | 2045-7634 |
| language | English |
| publishDate | 2018-06-01 |
| publisher | Wiley |
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| series | Cancer Medicine |
| spelling | doaj-art-2c5a5bc59aae464fb2bbd784e088cf3d2025-08-20T02:38:17ZengWileyCancer Medicine2045-76342018-06-01762391240410.1002/cam4.1504Prognostic relevance and performance characteristics of serum IGFBP‐2 and PAPP‐A in women with breast cancer: a long‐term Danish cohort studyUlrick Espelund0Andrew G. Renehan1Søren Cold2Claus Oxvig3Lee Lancashire4Zhenqiang Su5Allan Flyvbjerg6Jan Frystyk7Medical Research Laboratory Department of Clinical Medicine, Health Aarhus University Aarhus DenmarkThe Christie NHS Foundation Trust Division of Molecular and Clinical Cancer Sciences School of Medical Sciences Faculty of Biology, Medicine and Health University of Manchester Manchester Academic Health Science Centre Manchester UKDepartment of Oncology Odense University Hospital Odense DenmarkDepartment of Molecular Biology and Genetics, Science and Technology Aarhus University Aarhus DenmarkClarivate Analytics London UKClarivate Analytics London UKMedical Research Laboratory Department of Clinical Medicine, Health Aarhus University Aarhus DenmarkMedical Research Laboratory Department of Clinical Medicine, Health Aarhus University Aarhus DenmarkAbstract 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 [HRbiomarker 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 AUCRFS for NPI was 0.626 (Cox model), improving to 0.694 (P = 0.012) with the addition of IGFBP‐2 plus PAPP‐A. Derived AUCRFS 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.https://doi.org/10.1002/cam4.1504Breast neoplasmsinsulin‐like growth factor‐binding protein 2pregnancy‐associated plasma protein A |
| spellingShingle | Ulrick Espelund Andrew G. Renehan Søren Cold Claus Oxvig Lee Lancashire Zhenqiang Su Allan Flyvbjerg Jan Frystyk Prognostic relevance and performance characteristics of serum IGFBP‐2 and PAPP‐A in women with breast cancer: a long‐term Danish cohort study Cancer Medicine Breast neoplasms insulin‐like growth factor‐binding protein 2 pregnancy‐associated plasma protein A |
| 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 | Breast neoplasms insulin‐like growth factor‐binding protein 2 pregnancy‐associated plasma protein A |
| url | https://doi.org/10.1002/cam4.1504 |
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