Prostate-specific antigen (PSA) and human kallikrein-related peptidase 2 (hK2) are 237-aa single chain glycoproteins with uniquely different serine proteinase activity and products of two highly homologous primate-lineage specific, androgen receptor-regulated genes (KLK3 and KLK2) with abundant prostate-restricted expression. In blood from healthy middle-aged men not subject to PSA testing, million-fold lower levels of multiple noncatalytic forms of PSA and hK2 are very strongly associated with 20+ year- risk of metastasis or death from prostate cancer (PC), whereas prospective randomized trials in Europe show that early detection by systematic PSA testing reduces PC-specific deaths but remains controversial due to harm from overdiagnosis and overtreatment. Population-based findings of longer lead time at Gleason Grade Group ≥2 (GGG2) versus GGG1 at PC diagnosis provide evidence of grade progression over time. However, our estimates of a ≤6% risk of ≥GGG2-PC by a predefined statistical model based on four kallikrein markers in blood in middle-aged men with modestly elevated PSA is strongly associated with 15-20-year risk of PC death or metastasis below population average. By contrast, a smaller subset of these middle-aged men with modestly elevated PSA and a ≥6% four kallikrein risk-score have 15-20-year risk of PC death or metastasis that is multiple folds higher than the population average. Although evidence exists that mutations in germline DNA are associated with PC-death or metastasis, it is currently unclear how we could integrate these findings in programs aimed at early specific detection of lethal PC.

Citation Format: Hans Lilja. Early, highly specific risk stratification for lethal prostate cancer using a prespecified statistical model based on four kallikrein markers in blood [abstract]. In: Proceedings of the AACR Special Conference: Prostate Cancer: Advances in Basic, Translational, and Clinical Research; 2017 Dec 2-5; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(16 Suppl):Abstract nr IA09.