Prostate CancerEvaluating the Four Kallikrein Panel of the 4Kscore for Prediction of High-grade Prostate Cancer in Men in the Canary Prostate Active Surveillance Study
Introduction
Active surveillance is a management strategy for low-grade, localized prostate cancer that allows men to delay or be spared the potential morbidities of treatment. Cancers that appear to be low-risk at diagnosis are monitored, typically with serial prostate-specific antigen (PSA) measurements, clinical examinations, and repeat prostate biopsies. Intervention is recommended on evidence of a more aggressive tumor, usually based on changes in biopsy characteristics.
However, fear of occult high-grade cancer, in part because of the known undersampling of systematic prostate biopsies, has tempered widespread adoption of active surveillance. Even with emerging magnetic resonance imaging (MRI)–based biopsy protocols, there remains uncertainty surrounding the presence of more aggressive disease against a background of apparently low-risk cancer. In addition, the optimal surveillance schedule and triggers for intervention have not been established, resulting in substantial variations in the practice of active surveillance. Prostate biopsy can be painful, anxiety-provoking, expensive, and potentially morbid, so avoiding unnecessary surveillance biopsies is attractive. Methods to reduce the number of biopsies in active surveillance regimens, while maximizing the identification of high-grade cancers that may benefit from treatment, would have substantial clinical utility.
A promising approach to determine active surveillance candidacy and surveillance regimens (eg, more intensive vs less intensive biopsy schedules) involves the addition of biomarker panels to prediction models based on known clinical and demographic variables [1]. Among men suspected of having prostate cancer, a panel of four kallikreins (total PSA [tPSA], free PSA [fPSA], intact PSA [iPSA], and human kallikrein 2 [hK2]) combined with age using a mathematical algorithm improves the prediction of high-grade cancers compared to the PCPT risk calculator or models using tPSA alone [2], [3]. Here, we explore the utility of prediction models incorporating the predefined four kallikrein panel algorithm (4Kpanel) to predict the presence of occult high-grade disease in men already diagnosed with Gleason 6 cancer and on active surveillance. We use plasma specimens and data from the prospective, multi-institutional Canary Prostate Active Surveillance Study (PASS).
Section snippets
Study cohort
This study included men from Canary PASS, a multicenter, prospective study enrolling men on active surveillance [4]. Participants in PASS consented to specimen collection as part of the PASS protocol (clinicaltrials.gov NCT00756665), which was approved by institutional review boards at participating sites. The PASS protocol includes monitoring at clinic visits every 6 mo, with the first ≥10-core prostate needle biopsy at 6–12 mo, the second at 24 mo after cancer diagnosis, and subsequent
Results
Of the 718 men in this study, there were 478 participants in the initial biopsy group for whom kallikreins were assayed: 319 in the training set (60 [18.8%] with Gleason ≥7) and 159 in the test set (34 [21.4%] with Gleason ≥7; Table 1). In bivariate analyses, prostate volume, ratio of positive to total cores, and the 4Kpanel were significantly associated with grade reclassification. There were 444 participants (of whom 204 were also in the initial biopsy group) with 633 subsequent surveillance
Discussion
In this study using a prospectively enrolled multi-institutional cohort of men on active surveillance, we show that addition of a panel of four kallikrein markers to a model that includes clinical information can significantly improve prediction of the outcome in the first surveillance biopsy. Both models performed comparably for prediction of reclassification in subsequent biopsies. Importantly, in DCA both models showed a higher net benefit compared to biopsy-all and biopsy-none strategies.
Conclusions
The 4Kpanel was significantly associated with reclassification at the first surveillance biopsy, providing incremental value over routine clinical information, and the 4K model performed significantly better than the base model in this group. The 4Kpanel did not add predictive value to a PSA clinical model for biopsy decision-making for men at subsequent surveillance biopsies. This work aims to provide clinical validation of a biomarker that will help determine those men who have or will
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Modern Active Surveillance in Prostate Cancer: A Narrative Review
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