Identification and Validation of Leucine-rich α-2-glycoprotein 1 as a Noninvasive Biomarker for Improved Precision in Prostate Cancer Risk Stratification

Ingrid J Guldvik; Verena Zuber; Peder R Braadland; Helene H Grytli; Håkon Ramberg; Wolfgang Lilleby; Bernd Thiede; Manuela Zucknick; Fahri Saatcioglu; Randi Gislefoss; Rune Kvåle; Anne George; Henrik Grönberg; Fredrik Wiklund; David E Neal; Vincent J Gnanapragasam; Kristin A Taskén; Ian G Mills

doi:10.1016/j.euros.2020.08.007

Identification and Validation of Leucine-rich α-2-glycoprotein 1 as a Noninvasive Biomarker for Improved Precision in Prostate Cancer Risk Stratification

Eur Urol Open Sci. 2020 Oct 13:21:51-60. doi: 10.1016/j.euros.2020.08.007. eCollection 2020 Oct.

Authors

Ingrid J Guldvik^{1

2}, Verena Zuber^{3

4}, Peder R Braadland², Helene H Grytli², Håkon Ramberg², Wolfgang Lilleby⁵, Bernd Thiede^{6

7}, Manuela Zucknick⁸, Fahri Saatcioglu⁷, Randi Gislefoss⁹, Rune Kvåle^{9

10

11}, Anne George^{12

13

14}, Henrik Grönberg¹⁵, Fredrik Wiklund¹⁵, David E Neal¹⁶, Vincent J Gnanapragasam^{12

13

14}, Kristin A Taskén^{2

17}, Ian G Mills^{1

12

16

18

19

20}

Affiliations

¹ Prostate Cancer Research Group, Centre for Molecular Medicine Norway, University of Oslo and Oslo University Hospital, Oslo, Norway.
² Department of Tumour Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway.
³ MRC Biostatistics Unit, Cambridge University, Cambridgeshire, UK.
⁴ Department of Epidemiology and Biostatistics, Imperial College London, London, UK.
⁵ Department of Oncology, Oslo University Hospital, Oslo, Norway.
⁶ Biotechnology Centre of Oslo, University of Oslo, Oslo, Norway.
⁷ Department of Biosciences, University of Oslo, Oslo, Norway.
⁸ Department of Biostatistics, Oslo Centre for Biostatistics and Epidemiology, University of Oslo, Oslo, Norway.
⁹ Cancer Registry of Norway, Institute of Population-Based Cancer Research, Oslo, Norway.
¹⁰ Department of Oncology, Haukeland University Hospital, Bergen, Norway.
¹¹ Department of Health Registry Research and Development, Norwegian Institute of Public Health, Bergen, Norway.
¹² Academic Urology Group, Department of Surgery, University of Cambridge, Cambridge, UK.
¹³ Department of Urology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.
¹⁴ Cambridge Urology Translational Research and Clinical Trials, Cambridge, UK.
¹⁵ Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden.
¹⁶ Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK.
¹⁷ Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
¹⁸ Department of Molecular Oncology, Oslo University Hospitals, Oslo, Norway.
¹⁹ Department of Urology, Oslo University Hospitals, Oslo, Norway.
²⁰ Prostate Cancer UK/Movember Centre of Excellence for Prostate Cancer Research, Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, UK.

Abstract

Background: More accurate risk assessments are needed to improve prostate cancer management.

Objective: To identify blood-based protein biomarkers that provided prognostic information for risk stratification.

Design setting and participants: Mass spectrometry was used to identify biomarker candidates from blood, and validation studies were performed in four independent cohorts retrospectively collected between 1988 and 2015.

Outcome measurements and statistical analysis: The primary outcome objectives were progression-free survival, prostate cancer-specific survival (PCSS), and overall survival. Statistical analyses to assess survival and model performance were performed.

Results and limitation: Serum leucine-rich α-2-glycoprotein 1 (LRG1) was found to be elevated in fatal prostate cancer. LRG1 provided prognostic information independent of metastasis and increased the accuracy in predicting PCSS, particularly in the first 3 yr. A high LRG1 level is associated with an average of two-fold higher risk of disease-progression and mortality in both high-risk and metastatic patients. However, our study design, with a retrospective analysis of samples spanning several decades back, limits the assessment of the clinical utility of LRG1 in today's clinical practice. Thus, independent prospective studies are needed to establish LRG1 as a clinically useful biomarker for patient management.

Conclusions: High blood levels of LRG1 are unfavourable in newly diagnosed high-risk and metastatic prostate cancer, and LRG1 increased the accuracy of risk stratification of prostate cancer patients.

Patient summary: High blood levels of leucine-rich α-2-glycoprotein 1 are unfavourable in newly diagnosed high-risk and metastatic prostate cancer.

Keywords: Biomarker; Leucine-rich α-2-glycoprotein 1; Noninvasive; Prostate cancer.