TY - JOUR
T1 - Prognostic relevance and performance characteristics of serum IGFBP-2 and PAPP-A in women with breast cancer: a long-term Danish cohort study
AU - Espelund, Ulrick
AU - Renehan, Andrew G
AU - Cold, Søren
AU - Oxvig, Claus
AU - Lancashire, Lee
AU - Su, Zhenqiang
AU - Flyvbjerg, Allan
AU - Frystyk, Jan
N1 - © 2018 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.
PY - 2018/6
Y1 - 2018/6
N2 - 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.
AB - 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.
KW - Breast neoplasms
KW - insulin-like growth factor-binding protein 2
KW - pregnancy-associated plasma protein A
UR - http://www.scopus.com/inward/record.url?scp=85046263571&partnerID=8YFLogxK
U2 - 10.1002/cam4.1504
DO - 10.1002/cam4.1504
M3 - Journal article
C2 - 29722920
SN - 2045-7634
VL - 7
SP - 2391
EP - 2404
JO - Cancer Medicine
JF - Cancer Medicine
IS - 6
ER -