Reply to Yuri Tolkach, Markus Kuczyk, Florian Imkamp's letter to the editor re: Eric A. Klein, Matthew R. Cooperberg, Cristina Magi-Galluzzi, et al. A 17-gene assay to predict prostate cancer aggressiveness in the context of gleason grade heterogeneity, tumor multifocality, and biopsy undersampling. Eur urol 2014;66:550-60.

EUROPEAN UROLOGY 66 (2014) e117–e118 available at www.sciencedirect.com journal homepage: www.europeanurology.com Letter to the Editor Reply to Yuri Tolkach, Markus Kuczyk, Florian Imkamp’s Letter to the Editor re: Eric A. Klein, Matthew R. Cooperberg, Cristina Magi-Galluzzi, et al. A 17-gene Assay to Predict Prostate Cancer Aggressiveness in the Context of Gleason Grade Heterogeneity, Tumor Multi- focality, and Biopsy Undersampling. Eur Urol We appreciate the interest in our article and have the following responses. In regard to the selection of the prostatectomy cohort, as we describe in detail in the paper [1], we used an established stratified cohort sampling method (as described in references 23 and 24) in which all patients with clinical recurrence were selected, along with a 1:3 ratio of nonrecurrent patients. This does not mean that one-quarter of all patients in the total cohort failed but rather that the study cohort was enriched for failures to ensure that an adequate number of events were available for the analysis. Next, with regard to the clinical utility of the Genomic Prostate Score (GPS), all of the analyses in the paper [1] (receiver operating characteristic curve, decision analysis, and net reclassification index) demonstrate unequivocally that adding GPS to standard clinical parameters more accurately classifies individual risk for clinical recurrence (prostatectomy study) or adverse pathology (biopsy and validation studies). The clinical utility of this information varies according to patient and clinician attitudes about surveillance and, it is important to note, adds to but does not replace the usual criteria that may lead to the decision that surveillance is a reasonable option. In our experience, a major hurdle to the underuse of surveillance is patient and clinician uncertainty about the biologic potential of a given tumor. GPS and other tools like it are the first to address this issue based on the small amount of tumor material that is available on biopsy. The clinical utility of identifying a high risk of adverse pathology for a young patient with long life expectancy and clinically low-risk disease—for whom the decision may be made to forgo surveillance—is obvious. Less obvious, but still useful, are GPS scores that reaffirm a correct categorization of low-risk disease so that both patient and clinician can be reassured that more aggressive disease is not present at baseline and that an initial decision for surveillance is safe. Beyond choosing an initial management strategy, potential benefits of using a biologic marker such as GPS to assess aggressiveness include (1) tailoring the intensity of follow-up evaluations with imaging or rebiopsy (less intense for patients with more favorable scores, and more intense for patients with higher scores) and (2) serial biologic monitoring to address another unmet need in surveillance, namely, helping to decide when curative intent intervention is necessary. Successful deployment of both these strategies will require a baseline assessment of biologic potential. The way the authors phrase their question about what GPS dictates treatment suggests an impression that the GPS score has a threshold value above or below which adverse pathology is present. In fact, the GPS score is a continuous variable and should not be categorized for a yes or no prediction any more than prostate-specific antigen (PSA) should be used for screening with a threshold of 4 ng/ml. It is important to emphasize that any biologic marker should not by itself be used to make a decision on surveillance; the biological marker should always be interpreted in the context of grade, stage, extent of biopsy involvement, and PSA as well as individual clinical circumstances and, most important, the patient’s preferences. Thus, the answer depends entirely on the details of an individual patient’s desire, risk tolerance, comorbidities, and life expectancy. For a 70-yr-old with a life expectancy of 15 yr, a 20% risk of adverse pathology may be sufficiently low to make him comfortable with surveillance; this is not necessarily so for a 50-yr-old with a 35-yr life expectancy. In our clinical experience with this test (it has been available commer- cially in the United States since May 2013), the same score can—appropriately—result in different decisions for indi- vidual patients. The question the authors raise about the issue of upgrading is not entirely clear from their letter. We believe that the microdissection experiments in the prostatectomy study demonstrate that there is a common underlying biology, as measured by gene expression, that is shared by both primary and secondary Gleason pattern tumors that DOIs of original articles: http://dx.doi.org/10.1016/j.eururo.2014.05.004, http://dx.doi.org/10.1016/j.eururo.2014.08.002. http://dx.doi.org/10.1016/j.eururo.2014.08.001 0302-2838/# 2014 European Association of Urology. Published by Elsevier B.V. All rights reserved.