After radical prostatectomy (RP), 20-40% of patients will experience biochemical recurrence (BCR) within 10 years. Some men experiencing BCR (24-34%) will develop metastatic disease within 15 years and may later progress to castration-resistant prostate cancer (CRPC). Pre-surgical markers predictive for risk of subsequent CRPC will inform the need for adjuvant and multimodal therapy. This study aimed to evaluate Leucine-rich alpha-2-glycoprotein 1 (LRG1) prognostic value to predict CRPC in patients who have undergone RP for localized PCa.
422 patients treated with radical prostatectomy (RP) at the Martini-Klinik were utilized to establish the associations between serum LRG1 and BCR (n=131, 31%). Serum and tissue LRG1 were assessed in an external, Norwegian validation cohort of 145 RP patients from Oslo University Hospital (OUH). Here, 86 (59.3%) underwent second-line therapy, 62 (43.4%) started permanent hormone therapy, and 34 (23.4%) progressed to CRPC. Additionally, LRG1 was analyzed using a tissue microarray (TMA) including tissue from 135 men treated with RP, of which 86 (63.7%) started permanent hormone therapy, and 54 (40.0%) developed CRPC. Serum levels of LRG1 were quantified using ELISA, the expression of LRG1 in tissue was determined by manual scoring of immunohistochemically stained TMA sections by three blinded urological-pathologists. The primary outcomes were BCR and CRPC. Mann-Whitney U test was used to compare continuous variables between groups, whereas the Pearson Chi2 test was employed for categorical variables. Association between LRG1 and BCR or CRPC was analyzed with Cox proportional hazard modeling.
In the Martini-Klinik cohort, low LRG1 was associated with risk factors for BCR. In a multivariable Cox model, high circulating LRG1 was associated with a lowered risk of BCR (EAU-risk adjusted Hazard Ratio (HR) for high LRG1 relative to low LRG1 =0.52, 95% CI;0.35-0.76, p<0.001). In the external validation cohort, LRG1 was also associated with improved outcomes (EAU-risk adjusted HR=0.41, 95% CI;0.18-0.91, p<0.05), hence corroborating results from the Martini Klinik cohort. Next, we found that high LRG1 in serum or tissue were less likely to progress to CRPC (EAU-risk adjusted HR 0.21, 95% CI;0.06-0.61,p<0.01).
High levels of LRG1, assessed both by serum and prostate tissue, are favorable in patients undergoing prostatectomy and predict a reduced risk of BCR and CRPC. More studies are warranted to show the clinical utility of adding LRG1 on top of established, clinically applied risk criteria.