BERKELEY, CA (UroToday.com) - Prostate cancer is a significant health burden. There will be over 238 590 new diagnoses of prostate cancer this year. Although prostate cancer is the second-greatest cause of cancer death among men and is estimated to account for over 29 000 deaths this year, the majority of newly diagnosed cases are clinically localized and of low grade. The stage migration stemming from widespread use of prostate-specific antigen (PSA) screening and prostate biopsy has resulted in the number of diagnoses of prostate cancer far outnumbering the number of lethal cases, i.e., over-diagnosis of those cancers that would never progress or cause harm to the patient if left untreated.
Despite the indolent natural history of the majority of newly diagnosed prostate cancers, most men still undergo primary curative therapy with associated side effects and costs, i.e., overtreatment. While conservative management for low-risk tumors has increased slightly in recent years, the aggressive treatment of apparently low-risk prostate cancer persists.
Active surveillance – or careful monitoring of the cancer, most often with PSA kinetics and serial biopsy, with selected intervention based on these parameters – is an emerging initial management alternative for prostate cancer that appears unlikely to threaten quality or length of life. Active surveillance is a management strategy for those with low-grade, low-volume malignancy who are followed carefully and treated with curative intent based on apparent progression. “Watchful waiting” withholds treatment, usually in older patients and those with significant co-morbidity, and palliative interventions are offered when symptoms develop. Importantly, active surveillance has been recognized as an accepted treatment option by international consensus panels, and guideline statements cite active surveillance as the primary treatment option for certain subsets of men with low-risk prostate cancer.[3, 4, 5]
Outcomes of men on active surveillance have yielded very few cancer-specific deaths, overall survival is similar to men undergoing early primary treatment, and the recent PIVOT results reinforce the potentially indolent nature of low-risk prostate cancer. However, the use of active surveillance is not widely accepted among physicians and patients. Likely reasons that hamper the acceptance of active surveillance for the management of low-risk disease include physicians’ and patients’ concerns that low-risk cancers could progress rapidly due to the imprecise clinical knowledge of the cancer’s extent and growth rate, and concerns that current monitoring tools are neither sensitive nor specific. If patients and their physicians had a reliable and valid estimate of the risks of disease progression and harm, then more might opt for surveillance, thereby reducing the risks of overtreatment and its attendant substantial costs and morbidity. There is, therefore, urgent need for the development, acceptance, and implementation of a risk-based management strategy, and such a strategy would be greatly enhanced if founded upon accurate biomarkers of disease behavior.
The Canary Prostate Active Surveillance Study (PASS), established in 2008, is the only multi-institutional prospective active surveillance cohort study in North America. Men with clinically localized prostate cancer, who have not received prior treatment for their cancer, and who have chosen to manage their cancer using active surveillance are enrolled, and biospecimens (blood, urine, tissue) and associated clinical data are collected serially with rigorous quality control. Participants enrolled in Canary PASS are followed with serum PSA measurements every 3 months, clinical exam and digital rectal examination (DRE) every 6 months, and serial repeat prostate biopsy 6-12 months after the initial diagnosis, 24 months after the initial diagnosis, and every other year thereafter. The goals of PASS are to establish the first multi-site active surveillance cohort in North America, study the natural history of low-risk prostate cancer in systematic fashion, assemble a repository of high-quality biospecimens suitable for biomarker discovery and validation, and to test biomarkers to distinguish lethal and benign prostate cancer. To date, over 900 participants have been enrolled in PASS at 9 clinical sites.
PCA3 and the TMPRSS2-ERG fusion are two prostate cancer-specific biomarkers that hold promise for stratifying risk in an active surveillance setting. PCA3 is a prostate-specific noncoding mRNA that is significantly over expressed in prostate carcinoma compared to benign prostatic tissue,[9, 10] and the fusion is the most prevalent ETS rearrangement involving the androgen-regulated TMPRSS2 gene with the ERG transcription factor (TMPRSS2:ERG). Both markers have been correlated, in some reports, with aggressive disease. The goal of the present study was to determine whether urinary PCA3 and TMPRSS2:ERG mRNA levels are associated with higher volume or grade prostate cancer at the time of entry into a prospective multi-institutional active surveillance cohort.
Using urine specimens from 387 men, we found that in univariate analyses both markers, especially PCA3, seem to stratify by baseline risk of disease aggressiveness as determined by biopsy Gleason score or tumor volume (% of positive cores). There is a trend toward these markers improving the power over standard metrics (e.g. PSA) to predict high grade or volume disease, although the analysis is hampered by relatively low power. The results presented here are encouraging, but further work is needed to determine their clinical utility for men on active surveillance. The clinically relevant question is how these biomarkers aid in the prediction of the presence of occult aggressive disease or progression to an aggressive phenotype over time. To address these important questions, we are continuing to expand our cohort, collect and analyze longitudinal clinical data and specimens, and follow participants to collect long-term disease status.
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- Cooperberg MR, Broering JM, Carroll PR: Time trends and local variation in primary treatment of localized prostate cancer. J Clin Oncol 28:1117-23, 2010
- Heidenreich A, Bellmunt J, Bolla M, Joniau S, Mason M, Matveev V, Mottet N, Schmid HP, van der Kwast T, Wiegel T, Zattoni F: EAU Guidelines on Prostate Cancer. Part 1: Screening, Diagnosis, and Treatment of Clinically Localised Disease. Eur Urol, 2010
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- Network NCC: NCCN Clinical Practice Guidelines in Oncology: Prostate Cancer, 2013
- Dall'Era MA, Cooperberg MR, Chan JM, Davies BJ, Albertsen PC, Klotz LH, Warlick CA, Holmberg L, Bailey DE, Jr., Wallace ME, Kantoff PW, Carroll PR: Active surveillance for early-stage prostate cancer: review of the current literature. Cancer 112:1650-9, 2008
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- Newcomb LF, Brooks JD, Carroll PR, Feng Z, Gleave ME, Nelson PS, Thompson IM, Lin DW: Canary Prostate Active Surveillance Study: design of a multi-institutional active surveillance cohort and biorepository. Urology 75:407-13, 2010
- Bussemakers MJG, van Bokhoven A, Verhaegh GW, Smit FP, Karthaus HFM, Schalken JA, Debruyne FMJ, Ru N, Isaacs WB: DD3::A New Prostate-specific Gene, Highly Overexpressed in Prostate Cancer. Cancer Res 59:5975-5979, 1999
- Hessels D, Klein Gunnewiek JM, van Oort I, Karthaus HF, van Leenders GJ, van Balken B, Kiemeney LA, Witjes JA, Schalken JA: DD3(PCA3)-based molecular urine analysis for the diagnosis of prostate cancer. Eur Urol 44:8-15; discussion 15-6, 2003
- Tomlins SA, Rhodes DR, Perner S, Dhanasekaran SM, Mehra R, Sun XW, Varambally S, Cao X, Tchinda J, Kuefer R, Lee C, Montie JE, Shah RB, Pienta KJ, Rubin MA, Chinnaiyan AM: Recurrent fusion of TMPRSS2 and ETS transcription factor genes in prostate cancer. Science 310:644-8, 2005
Lisa Newcomb and Daniel W. Lin as part of Beyond the Abstract on UroToday.com. This initiative offers a method of publishing for the professional urology community. Authors are given an opportunity to expand on the circumstances, limitations etc... of their research by referencing the published abstract.
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