Clinical-Genomic Characterization Unveils More Aggressive Disease Features in Elderly Prostate Cancer Patients with Low-Grade Disease - Beyond the Abstract

Prostate cancer is a disease more prevalent in aging men with more than 50% of newly diagnosed men being older than 65.1 The currently reported life expectancy of an average male in the US is 76.1,2 while in the European Union it is 78.3.3 However, data show that men reaching the age of 75 years may live an additional 10.6 years at minimum.1 Despite these rapidly evolving data, various current established guidelines recommend against prostate cancer screening in men 75 or older.4,5 Moreover, patients over the age of 75 are less likely to be offered optimal curative prostate cancer management.6

It is important to note that current expert guidelines for the treatment of localized prostate carcinoma recommend potentially curative therapy for patients whose life expectancy is at least 10 years.7,8 Patients with limited life expectancy are more likely to die from health conditions other than prostate cancer. This 10-year rule is widely accepted by most urologists and radiation oncologists.9 Additionally, most studies investigating optimal treatment approaches have focused on patients  younger than 75 years,6 despite existing evidence showing a clear therapeutic benefit of radical treatments in healthy elderly men.10

There is a growing body of evidence demonstrating that older men with prostate cancer have worse oncological outcomes compared to their younger counterparts.11 Unfortunately, older healthy men with prostate cancer with a life expectancy of more than 10 years are still most commonly offered conservative management.

In this study, we used the Decipher test (Decipher Biosciences, Vancouver, BC, Canada) and the PAM50 molecular subtypes in a large biopsy and radical prostatectomy cohort of patients. Our aim was to identify high-risk prostate cancer among men of all ages. Decipher is a prognostic 22-gene genomic classifier that captures multiple biological pathways occurring in aggressive prostate cancer.12 PAM50 is a gene expression biomarker that subtypes patients into luminal (A or B) and basal tumors. This molecular subtype method is prognostic and predicts response to androgen deprivation therapy and captures important cancer data.13

Our hypothesis was that these molecular biomarkers could demonstrate the important association that age has with aggressive disease features of prostate cancer.

A total of 25,721 patients were analyzed in the study (9434 in the biopsy cohort, and 16,287 in the radical prostatectomy cohort). Overall 18.5% of the patients in the biopsy cohort were older than 75 years, compared with only 4.5% in the radical prostatectomy cohort. Looking at their basic clinical data, both in the biopsy and radical prostatectomy cohorts, older age was associated with worse clinical parameters, more aggressive biopsy and radical prostatectomy results.

Our analyses demonstrated that in patients with low-grade prostate cancer (ISUP grade group 1–2), older patients were more likely to have a genomically defined high-risk disease, translating to a high Decipher score. Age was also positively associated with a higher genomic risk score in univariable and multivariable analyses. Moreover, supporting our findings with Decipher risk score, elderly patients exhibited a higher prevalence of luminal B subtype (which is associated with worse prognosis). This was more evident in the subgroup with low ISUP grade group (1 and 2) both in the biopsy and in the radical prostatectomy cohort.

As mentioned in the actual paper, the European Association of Urology supports the endorsement by the International Society of Geriatric Oncology that elderly men should be treated according to their health status and biological age, rather than their chronological age.14 Despite this, most fit and healthy elderly men with curable localized prostate cancer are commonly managed conservatively and less likely to undergo definitive treatment, which is substantially underutilized in the elderly population.

Our study has some important limitations that need to be mentioned. These include the possible selection bias due to the retrospective nature of this work. Clearly, the healthier and fitter older patients were referred for a biopsy and even more so for surgery. Additionally, it is reasonable to assume that sicker patients with more aggressive disease were referred for surgery, so it should not surprise us that they had a higher risk of genomically defined disease. Lastly, we lacked data on the long-term follow-up of these patients, limiting our ability to validate the prognostic performance of these biomarkers.

Nevertheless, this study provides clear evidence of the benefit of using clinical-genomic characterization of elderly patients for individual treatment decisions. Our results suggest that older patients with assumed favorable pathology (ISUP grade group 1+2) could potentially be harboring a much more aggressive disease than originally thought, especially when compared to their younger counterparts. This does not contradict the well-known fact that low-grade disease will most likely not decrease the life expectancy of elderly patients (older than 75 years) and will most likely not be the cause of their death. As opposed to chronological age, biological age should be one of the main factors affecting treatment decisions. In fact, older fit healthy patients might need a more aggressive treatment plan, if they are shown to be harboring a more high-risk disease than originally thought.

Written by: Hanan Goldberg, MD, MSc, Urology department, SUNY Upstate Medical University, Syracuse, New York, Twitter: @Goldberghanan


1. Weiner, Adam B., Sanjay G. Patel, Ruth Etzioni, and Scott E. Eggener. "National trends in the management of low and intermediate risk prostate cancer in the United States." The Journal of urology 193, no. 1 (2015): 95-102.
2. Statistics NCfH. Mortality in the United States htm. 2018.
3. (INED) TFIfDS. Life expectancy at birth. 2017.
4. Grossman, David C., Susan J. Curry, Douglas K. Owens, Kirsten Bibbins-Domingo, Aaron B. Caughey, Karina W. Davidson, Chyke A. Doubeni et al. "Screening for prostate cancer: US Preventive Services Task Force recommendation statement." Jama 319, no. 18 (2018): 1901-1913.
5. Moyer, Virginia A. "Screening for prostate cancer: US Preventive Services Task Force recommendation statement." Annals of internal medicine 157, no. 2 (2012): 120-134.6. Bechis SK, Carroll PR, Cooperberg MR. Impact of age at diagnosis on prostate cancer treatment and survival. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2011; 29(2): 235-41.
7. Chodak, Gerald W., Ronald A. Thisted, Glenn S. Gerber, Jan-Erik Johansson, Jan Adolfsson, George W. Jones, Geoff D. Chisholm, Boaz Moskovitz, Pinhas M. Livne, and John Warner. "Results of conservative management of clinically localized prostate cancer." New England Journal of Medicine 330, no. 4 (1994): 242-248.
8. Albertsen, Peter C., James A. Hanley, and Judith Fine. "20-year outcomes following conservative management of clinically localized prostate cancer." Jama 293, no. 17 (2005): 2095-2101.
9. Krahn, Murray D., Karen E. Bremner, Jamil Asaria, Shabbir MH Alibhai, Robert Nam, George Tomlinson, Michael AS Jewett, Padraig Warde, and Gary Naglie. "The ten-year rule revisited: accuracy of clinicians’ estimates of life expectancy in patients with localized prostate cancer." Urology 60, no. 2 (2002): 258-263.
10. Alibhai, Shabbir MH, Gary Naglie, Robert Nam, John Trachtenberg, and Murray D. Krahn. "Do older men benefit from curative therapy of localized prostate cancer?." Journal of clinical oncology 21, no. 17 (2003): 3318-3327.
11. Hamdy, Freddie C., Jenny L. Donovan, J. Lane, Malcolm Mason, Chris Metcalfe, Peter Holding, Michael Davis et al. "10-year outcomes after monitoring, surgery, or radiotherapy for localized prostate cancer." N Engl J Med 375 (2016): 1415-1424.
12. Erho, Nicholas, Anamaria Crisan, Ismael A. Vergara, Anirban P. Mitra, Mercedeh Ghadessi, Christine Buerki, Eric J. Bergstralh et al. "Discovery and validation of a prostate cancer genomic classifier that predicts early metastasis following radical prostatectomy." PloS one 8, no. 6 (2013).
13. Zhao, Shuang G., S. Laura Chang, Nicholas Erho, Menggang Yu, Jonathan Lehrer, Mohammed Alshalalfa, Corey Speers et al. "Associations of luminal and basal subtyping of prostate cancer with prognosis and response to androgen deprivation therapy." JAMA oncology 3, no. 12 (2017): 1663-1672.
14. Droz, Jean-Pierre, Matti Aapro, Lodovico Balducci, Helen Boyle, Thomas Van den Broeck, Paul Cathcart, Louise Dickinson et al. "Management of prostate cancer in older patients: updated recommendations of a working group of the International Society of Geriatric Oncology." The Lancet Oncology 15, no. 9 (2014): e404-e414.

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