Reducing Unnecessary Biopsy During Prostate Cancer Screening Using a Four-Kallikrein Panel: An Independent Replication

Abstract

PurposeWe previously reported that a panel of four kallikrein forms in blood—total, free, and intact prostate-specific antigen (PSA) and kallikrein-related peptidase 2 (hK2)—can reduce unnecessary biopsy in previously unscreened men with elevated total PSA. We aimed to replicate our findings in a large, independent, representative, population-based cohort.Patients and MethodsThe study cohort included 2,914 previously unscreened men undergoing biopsy as a result of elevated PSA (≥ 3 ng/mL) in the European Randomized Study of Screening for Prostate Cancer, Rotterdam, with 807 prostate cancers (28%) detected. The cohort was randomly divided 1:3 into a training and validation set. Levels of kallikrein markers were compared with biopsy outcome.ResultsAddition of free PSA, intact PSA, and hK2 to a model containing total PSA and age improved the area under the curve from 0.64 to 0.76 and 0.70 to 0.78 for models without and with digital rectal examination results, respectively (P < .001 for both). Application of the panel to 1,000 men with elevated PSA would reduce the number of biopsies by 513 and miss 54 of 177 low-grade cancers and 12 of 100 high-grade cancers. Findings were robust to sensitivity analysis.ConclusionWe have replicated our previously published finding that a panel of four kallikreins can predict the result of biopsy for prostate cancer in men with elevated PSA. Use of this panel would dramatically reduce biopsy rates. A small number of men with cancer would be advised against immediate biopsy, but these men would have predominately low-stage, low-grade disease.

Clinical Utility of Biomarkers in Localized Prostate Cancer

“…A panel of four serum kallikreins (total PSA, free PSA, intact PSA, and human kallikrein protein 2 (hK2) has received extensive evaluation in the pre-biopsy setting and is commercially marketed as the 4Kscore Test (4K, OPKO Lab, Nashville, TN) [19][20][21][22][23]24•]. The algorithm representing these components was initially derived from data based on participants within the European Randomized Study of Prostate Cancer Screening (ERSPC) and Prostate Testing for Cancer and Treatment (ProtecT) studies.…”

Risk-Based Prostate Cancer Screening: Who and How?

“…Vickers and colleagues used four serum kallikrein markers, including total PSA, free PSA, intact PSA, and kallikrein-related peptidase 2 to develop a statistical model to predict prostate biopsy results [81]. This model was successful in predicting the biopsy results in men with elevated PSA, suggesting that biopsy rates could be significantly reduced, while a relatively few men with elevated PSA levels and cancer would be advised not to undergo biopsy, most of whom would have low-grade disease [82].…”

Tumor biomarkers: PSA and beyond

“…Overtreatment is a major problem in patients with early prostate cancer, resulting not only in unnecessary biopsies, but also in treatment being instituted in patients with indolent early prostate cancer, especially the elderly, who may be more threatened by the side effects of therapy rather than by the disease itself. It has been demonstrated that utilization of a panel of biomarkers that includes PSA forms and KLK2 could result in the reduction of biopsy rates (19) .…”