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Predictive Value of AZGP1 Following Radical Original article J Clin Pathol: first published as 10.1136/jclinpath-2019-205940 on 22 July 2019. Downloaded from Predictive value of AZGP1 following radical prostatectomy for prostate cancer: a cohort study and meta-analysis Gitte Kristensen, 1 Kasper Drimer Berg,1 Birgitte Grønkær Toft,2 Hein Vincent Stroomberg,1 Rosalie Nolley,3 James D Brooks,3 Klaus Brasso,1 Martin Andreas Roder1,4 ► Additional material is ABSTRact be due to the fact that most biomarkers have been published online only. To view Aims Zinc-alpha 2-glycoprotein (AZGP1) is a promising tested for surrogate endpoints including biochem- please visit the journal online ical failure (BF), whereas long-term endpoints such (http:// dx. doi. org/ 10. 1136/ tissue biomarker to predict outcomes in men undergoing jclinpath- 2019- 205940). treatment for localised prostate cancer (PCa). We as time to metastatic disease and death are rarely aimed to examine the association between AZGP1 investigated. A valid biomarker could change prog- 1Copenhagen Prostate expression and the endpoints: risk of biochemical failure nostication after RP and also define subgroups of Cancer Center, Department (BF), initiating castration-based treatment, developing patients for individualised follow-up or candidates of Urology, Rigshospitalet, Copenhagen University Hospital, castration-resistant PCa (CRPC) and PCa-specific for adjuvant therapies. Copenhagen, Denmark mortality following radical prostatectomy (RP). Zinc-alpha 2-glycoprotein (AZGP1) is a secretory 2Department of Pathology, Methods The study included a prospective cohort protein that is encoded by the AZGP1 gene located Rigshospitalet, Copenhagen of 302 patients who underwent RP for PCa from on chromosome 7q22.1. AZGP1 is important in University Hospital, lipid metabolism, glucose utilisation and regula- Copenhagen, Denmark 2002 to 2005. AZGP1 expression was analysed 3Department of Urology, using immunohistochemistry on tissue microarray RP tion of insulin sensitivity and is found in most body Stanford Medicine, Stanford, specimens and was scored semiquantitively as low or fluids and secretory epithelial cells in several organs, California, USA including the prostate. The production of AZGP1 is 4 high expression. Risk of all endpoints was analysed using Department of Clinical stratified cumulative incidences and cause-specific Cox regulated by different hormones including andro- Medicine, Faculty of Health and 4 Medical Sciences, University regression, and validated with receiver operating curves, gens. Several studies have found that low AZGP1 of Copenhagen, Copenhagen, calibration and discrimination in competing-risk analyses. expression is associated with BF following radical Denmark A meta-analysis was performed including previous prostatectomy (RP).5–11 However, the predictive studies investigating AZGP1 expression and risk of BF value of AZGP1 as a marker for later and more Correspondence to following RP. adverse outcomes has received limited attention. http://jcp.bmj.com/ Dr Gitte Kristensen, Results Median time of follow-up was 14.0 years. The The primary goal of the present study was to Department of Urology, Copenhagen Prostate Cancer cumulative incidence of all endpoints was significantly assess the predictive value of AZGP1 expression Center, Rigshospitalet, higher in patients with low AZGP1 expression compared in tumour tissue for the risk of initiating castra- Kobenhavn 2100, Denmark; with patients with high AZGP1 expression (p<0.001). In tion-based treatment, development of castration-re- gittekristensen01@ gmail. com a multivariate analysis, low AZGP1 expression increases sistant prostate cancer (CRPC) and PCa-specific the risk of BF (HR 2.7; 95% CI 1.9 to 3.8; p<0.0001), mortality following RP. Furthermore, we aimed to Received 30 April 2019 on 13 August 2019 at lane medical library. Protected by copyright. Revised 3 June 2019 castration-based treatment (HR 2.2; 95% CI 1.2 to 4.2; investigate the association between AZGP1 expres- Accepted 7 June 2019 p=0.01) and CRPC (HR 2.3; 95% CI 1.1 to 5.0; p=0.03). sion and BF following RP and compare our results Validation showed a low risk of prediction error and a with previous studies in a meta-analysis. high model performance for all endpoints. In a meta- analysis, low AZGP1 was associated with BF (HR 1.7; MatERIALS AND METHODS 95% CI 1.2 to 2.5). Cohort study Conclusions Low AZGP1 expression is associated with Patients the risk of aggressive time-dependent outcomes in men The study includes a historical consecutive series undergoing RP for localised PCa. of patients who underwent RP for PCa at the Department of Urology, Rigshospitalet, Copen- hagen University Hospital, Denmark between 1 January 2002 and 31 December 2005. We used INTRODUCTION tissue microarrays (TMAs) including malignant and © Author(s) (or their Biomarkers that reflect the malignant potential of benign prostate tissue from the patient’s forma- employer(s)) 2019. No the tumour could refine prognostication of pros- lin-fixed, paraffin-embedded RP specimens. The commercial re-use. See rights and permissions. Published tate cancer (PCa). Currently, a combination of collection of clinicopathological data and produc- by BMJ. clinical, biochemical and pathological variables is tion of the TMAs have been described previously used1–3; however, these variables lack accuracy in in detail.12 The study was approved by the Danish To cite: Kristensen G, predicting PCa outcomes on a patient-based level. National Committee on Health Research Ethics ( Berg KD, Toft BG, et al. J Clin Pathol Epub ahead of Many potential biomarkers for PCa aggressiveness Journal. no. H-6-2014-111) and The Danish Data print: [please include Day have been reported in the literature, but only few Protection Agency (file#2006-1-6256). Month Year]. doi:10.1136/ have entered clinical practice despite a clear clinical RP Gleason Score (GS) was reclassified according jclinpath-2019-205940 need for optimisation of prognostication. This may to the 2005 International Society of Urological Kristensen G, et al. J Clin Pathol 2019;0:1–9. doi:10.1136/jclinpath-2019-205940 1 Original article J Clin Pathol: first published as 10.1136/jclinpath-2019-205940 on 22 July 2019. Downloaded from Figure 1 (A) Flowchart of patients included in the cohort study. (B) Immunohistochemical AZGP1 staining in representative prostate cancer samples showing absent, weak, moderate and strong intensity. (C) AZGP1 score table. CRPC, castration-resistant prostate cancer; IHC, immunohistochemistry; http://jcp.bmj.com/ PCa, prostate cancer; PSA, prostate specific antigen; RP, radical prostatectomy; TMA, tissue microarray. Pathology13 Gleason grading system.13 The study endpoints (BF, Statistics castration-based treatment, CRPC14 and PCa-specific mortality) Association of AZGP1 expression in tumour tissue and clinicopath- were updated in October 2018. Patients were excluded if malig- ological variables was analysed using χ2 test for categorical vari- nant tissue was not present in the TMA for analysis of the ables and Mann-Whitney U test for continuous variables. Median on 13 August 2019 at lane medical library. Protected by copyright. biomarker status (figure 1A). follow-up time was calculated using the reverse Kaplan-Meier method.16 Follow-up was calculated until the latest follow-up date. Immunohistochemistry Cumulative incidences of study endpoints were analysed using TMA tissue sections were used for immunohistochemical (IHC) the Aalen-Johansen method for competing risks. Death before BF, staining of AZGP1 (1:500 dilution, anti-AZGP1: HPA012582; castration-based treatment and CRPC were treated as competing Sigma Aldrich) as described previously.10 The stained slides were events when analysing risk of BF, castration-based treatment digitalised using the Hamamatsu Nano ZoomerXR at a magnifi- and CRPC, respectively. Other cause mortality was treated as a cation equivalent to ×20. Evaluation of the AZGP1-stained slides competing event when analysing risk of PCa-specific mortality. was done by using the Hamamatsu NDP. view V.2.6.13 viewing soft- Gray’s test was used to assess differences in the cumulative inci- ware. Whole field inspection of each core was carried out by one dence of the endpoints between different AZGP1 expression.17 observer (GK) to evaluate the presence of cancer and benign glands Univariate and multivariate cause-specific Cox proportion- as well as AZGP1 immunoreactivity. Each core on the TMA was al-hazards regression models were performed for risk of BF, given a score from 0 to 3 based on the cytoplasmic staining inten- castration-based treatment, CRPC and PCa-specific mortality, with sity (absent, weak, moderate and strong) and the fraction of posi- results presented as HRs and 95% CIs. The analyses included age at tive tumour cells (figure 1B–C).15 The AZGP1 scoring was checked RP, log2-transformed prostate specific antigen, pT-stage, pN-stage, on random cores by an experienced uropathologist (BGT). As each RP GS, margin status and AZGP1 expression. The sensitivity and patient had multiple cores, a mean AZGP1 score (∑score for each specificity of the models with and without AZGP1 expression were core/number of cores) was calculated for each patient. This score analysed using receiver operating characteristic curves and quanti- was then dichotomised, and the patients were classified as having fied using the areas under the curve (AUC) for selected time points. low AZGP1 expression (mean AZGP1 score ≤1.5) or high AZGP1 Changes in the predicted risk of
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