Reply to A. Azad et al.

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Carter HB, Partin AW, Walsh PC, et al: Gleason score 6 adenocarcinoma: Should it be labeled as cancer? J Clin Oncol 30:4294-4296, 2012 16. Cooperberg MR, Broering JM, Carroll PR: Time trends and local variation in primary treatment of localized prostate cancer. J Clin Oncol 28:1117-1123, 2010 17. Barocas DA, Cowan JE, Smith JA Jr, et al: What percentage of patients with newly diagnosed carcinoma of the prostate are candidates for surveillance? An analysis of the CaPSURE database. J Urol 180:1330-1334, 2008 18. Lawrentschuk N, Klotz L: Active surveillance for low-risk prostate cancer: An update. Nat Rev Urol 8:312-320, 2011 19. Tran B, Dancey JE, Kamel-Reid S, et al: Cancer genomics: Technology, discovery, and translation. J Clin Oncol 30:647-660, 2012 20. Nagrath S, Sequist LV, Maheswaran S, et al: Isolation of rare circulating tumour cells in cancer patients by microchip technology. Nature 450:1235-1239, 2007 21. Stott SL, Lee RJ, Nagrath S, et al: Isolation and characterization of circulating tumor cells from patients with localized and metastatic prostate cancer. Sci Transl Med 2:25ra23, 2010 22. Fendler A, Jung M, Stephan C, et al: miRNAs can predict prostate cancer biochemical relapse and are involved in tumor progression. Int J Oncol 39:1183- 23. Martens-Uzunova ES, Jalava SE, Dits NF, et al: Diagnostic and prognostic signatures from the small non-coding RNA transcriptome in prostate cancer. Oncogene 31:978-991, 2012 24. Schaefer A, Jung M, Mollenkopf HJ, et al: Diagnostic and prognostic implications of microRNA profiling in prostate carcinoma. Int J Cancer 126:1166- 25. Mullins JK, Bonekamp D, Landis P, et al: Multiparametric magnetic resonance imaging findings in men with low-risk prostate cancer followed using active surveillance. BJU Int 111:1037-1045, 2013 DOI: 10.1200/JCO.2013.51.0420; published online ahead of print at www.jco.org on August 12, 2013 Reply to A. Azad et al We appreciate Azad et al’s comments, 1 which center on questions regardingtheclinicalapplicationofthecellcycleprogression(CCP)score. We would stress that the purpose of our article 2 was to validate the score’s accuracy in a contemporary prostatectomy cohort. To this end, we dem- onstrated that the score does in fact yield additional, independent infor- mation about progression risk, independent of all standard clinical and pathologic information. Our study was not designed to determine the optimal use of the score in clinical practice; answering this question will require additional research, ongoing at our institution and elsewhere. To address the specific points Azad et al raise 1 : first, we agree that most tumors with pathologic Gleason score 6 typically do not progress to metastasis or mortality after surgery, and we certainly do not advocate indiscriminate use of any adjunct testing for all men with these tumors. However,itshouldbestressedthatweexploredinteractionsbetweenCCP score and clinical/pathologic risk, as determined by the Cancer of the Prostate Risk Assessment Post-Surgical (CAPRA-S) score, and found that the CCP score was predictive across the range of CAPRA-S scores. Furthermore, Gleason score should not be interpreted in a vacuum; some Gleason 6 scores are associated with other higher risk characteristics (high preoperative prostate-specific antigen, higher stage, positive mar- gins, and so on). Conversely, some Gleason 7 tumors with minimal rep- resentation of pattern 4 and no other adverse risk characteristics behave no differently from Gleason 6 tumors. 3 Ultimately, risk assessment must consider all available information and identifying which tumors with one ormorehigh-riskfeaturesmightbenefitfromadditionaltreatmentwould be potentially beneficial. We agree entirely that active surveillance is under-used for low- risk disease in the United States and have repeatedly made this argu- ment in prior publications. 4,5 Azad et al’s first point was that the CCP score may be more useful for tumors with adverse risk factors such as Gleason 7. So, if anything, the score should be more useful in the setting of clinical cohorts with higher average progression risk. With respect to the question of postoperative radiation selection and timing, we did not claim that the CCP score would settle the question of adjuvant versus early-salvage radiation. We agree studies in cohorts re- © 2013 by American Society of Clinical Oncology ceivingradiationareneeded,andthesestudiesareongoing.Intheinterim, the score should be interpreted only as providing additional information about progression risk, which can help inform a clinical decision; we have not proposed an algorithm to determine which men should get radiation based the CCP score, either alone or together with the CAPRA-S. Finally, we agree that the number of options for additional testing among men with prostate cancer is obviously growing rapidly. However, most of these tests—including the ones referenced in Azad et al’s 1 letter— have not been validated to date nearly as rigorously as the CCP score. Determining the relative merits of the CCP score in relation to these other tests was well beyond the intended scope of our validation study but, again, is the focus of ongoing research. Specifically with respect to mul- tiparametric magnetic resonance imaging, we agree this modality is likely to have a future role in helping improve active surveillance protocols. 6 This modality still depends on very experienced radiologists with a high degree of prostate expertise, and—at least in the United States—is ex- tremely expensive relative to other emerging tests. Ourvalidationstudy 2 ontheCCPscoreisclearlynotpresentedasthe end of the story for improved risk stratification, nor is it even the begin- ning of the end. 7 We are only starting to learn how best to use cancer genomic assays 7 and other emerging tests to help improve decision- making for men with prostate cancer. However, there is no question that innovative tests like this one will be essential to help effect the needed paradigm shift in prostate cancer screening, diagnosis, and management—to one in which decisions at all time points reflect full use of the maximal information available. Matthew R. Cooperberg, Janet E. Cowan, and Peter R. Carroll University of California, San Francisco, Helen Diller Family Comprehensive Cancer Center, San Francisco, CA AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST Although all authors completed the disclosure declaration, the following author(s) and/or an author’s immediate family member(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a “U” are those for which no compensation was received; those relationships marked with a “C” were compensated. For a detailed description of the disclosure categories, or for more information about ASCO’s J OURNAL OF C LINICAL O NCOLOGY Information downloaded from jco.ascopubs.org and provided by at CONS CALIFORNIA DIG LIB on July 14, 2016 from Copyright © 2013 American Society of Clinical Oncology. All rights reserved.