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News and Views From the Literature


More Aggressive Prostate Cancer in Elderly Men

Reviewed by Annelies Vellekoop MD, Stacy Loeb, MD
Department of Urology, New York University and the Manhattan Veterans Affairs Hospital, New York, NY
[Rev Urol.2013;15(4):202-204 doi:10.3909/riu0590a]

© 2014 MedReviews®, LLC

 

More than one-fifth of men who are diagnosed with prostate cancer are age ≥ 75 years.1 However, prostate cancer screening and treatment are both controversial in elderly men. In 2008, the US Preventive Services Task Force recommended against prostate-specific antigen (PSA)–based screening in men aged ≥ 75 years. This recommendation, which has been expanded to include all men,2 generated controversy by focusing on chronologic age rather than health status.3, 4 More recently, the American Urological Association issued new guidelines stating that they do not recommend routine PSA screening in men aged > 70  years or those with less than a 10- to 15-year life expectancy, although some older men who are in excellent health may benefit from prostate cancer screening.5 This review describes two recent studies on the tumor features and outcomes of prostate cancer in elderly men.6,7

 

Prostate Cancer in Men Aged 70 Years Old or Older, Indolent or Aggressive: Clinicopathological Analysis and Outcomes  

Brassell SA, Rice KR, Parker PM, et al. 
J Urol. 2011;185:132-137. 

Brassell and colleagues reported on the clinicopathologic features and the survival outcomes in 12,081 men diagnosed with prostate cancer between 1989 and 2009, from the Prostate Disease Research database. The study population was further stratified by age and race. Prediagnosis PSA velocity (PSAV) was defined as rapid for a change > 0.35 ng/mL/year at PSA < 4 ng/mL, or > 0.75 ng/mL/year at PSA > 4 ng/mL. Analysis of radical prostatectomy (RP) specimens was performed by the Armed Forces Institute of Pathology. Biochemical recurrence was defined as a PSA > 0.2 ng/mL after RP and as PSA nadir 12 ng/mL after radiotherapy. Mean overall follow-up was 6.3 years. 

Men aged ≥ 70 years (n = 3350, 30.2%), had a significantly higher clinical stage and biopsy Gleason grade. Older men also had higher prediagnosis PSAV (P < .0001), which has previously been shown to be a marker for more aggressive prostate cancer.8 Among patients aged ≥ 70 years, 49.4% had external beam radiation therapy (EBRT), 24.6% had RP, 18.7% received primary hormonal therapy, 6% had brachytherapy, and 1.2% had cryotherapy. Among patients who underwent RP, pathologic stage, upgrading, and positive surgical margin rates were all significantly higher in older men.

Biochemical recurrence (BCR) occurred in 49.3% of men aged ≥ 70 years, compared with 44.2%, 42.1%, and 29.6% of men aged 60 to 69 years, 50 to 59 years, and < 50 years, respectively (P < .0001). On multivariate analysis age > 70 years was a significant predictor for BCR with hazard ratio 1.45 (confidence interval, 1.115-1.873). Although there was no difference in PSA doubling time at recurrence by age, secondary treatment was significantly more likely in older men compared with younger men (11.6%, 20.9%, 20.8%, and 23.7% for age < 50 years, 50 to 59 years, 60 to 69 years, and > 70 years, respectively).

As expected, among men treated surgically, overall survival was lowest in men aged ≥ 70 years. However, Kaplan-Meier survival analysis showed improved survival for men aged ≥ 70 years who received RP or EBRT compared with expectant management. 

Overall, Brassell and colleagues showed that aggressive disease was more common as men age, even in this heavily prescreened population. Proposed explanations for these findings include the natural progression of undiagnosed prostate cancer or changes in hormones with age9; however, the study did not provide data that could help elucidate the underlying mechanism. Another important limitation was that the study was retrospective, and treatment selection was not randomly assigned. As such, the results suggesting improved survival with definitive treatment in elderly men should be viewed with caution because there are numerous confounding factors. Despite these limitations, the study provides useful information from a large study of men in different age groups showing that elderly men quite frequently have clinically significant prostate cancer, and that some of these men would benefit from definitive therapy.

 

Prostate Cancer in the Elderly: Frequency of Advanced Disease at Presentation and Disease-specific Mortality

Scosyrev E, Messing EM, Mohile S, et al.
Cancer. 2012;118:3062-3070.

Scosyrev and colleagues used the Surveillance, Epidemiology, and End Results database to determine the frequency of metastatic (M1) disease and prostate cancer death in different age groups. A total of 464,918 patients diagnosed with prostate cancer between 1998 and 2007 were categorized into 10 age groups ranging from > 50 years to ≥ 90 years. The largest group was aged 65 to 69 years (n = 87,568).

Information on comorbidities was not included in the analysis. Tumor features, including Gleason score and stage at presentation were recorded, and men were followed for a median of 4.5 years (range, 1-10 years). Expected survival was obtained from the general population, and the Gray method was used to assess the cumulative incidence of death from prostate cancer in different age groups. The frequency of metastatic prostate cancer ranged from 3% (group aged < 75 years) to 17% (group aged ≥ 90 years). Overall, men aged > 75 years represented 52% of all M1 cases.  

Similarly, the 5-year cumulative incidence of death from prostate cancer increased from 3% to 4% at age < 75 years to 30% at age ≥ 90 years. Cumulative incidence of death from other causes also increased with age, from 9% in men aged 65 to 69 years up to 48% in men aged ≥ 90 years. Despite the greater risk of mortality from competing causes, men aged > 75 years still contributed to 47% of prostate cancer deaths. Although older patients did not lose as many years of life as younger patients, men aged > 75 years still lost approximately 75% of their remaining years of life (range, 74% to 78%). Hence, the proportion of remaining life lost in the elderly still was very high. 

The authors suggested less frequent PSA testing and diagnostic evaluation as probable reasons for age-­specific differences in the frequency of aggressive disease and prostate cancer mortality. For example, it is possible that biopsies were performed less frequently to evaluate PSA elevations among elderly men. However, they did not describe the prior screening or biopsy history, precluding the ability to examine the presence and impact of delays in diagnostic evaluation by age. Other limitations of this study include missing data on comorbidities and the use of androgen deprivation therapy, which could also contribute to survival differences.  

 

Discussion

Several differences between the study by Brassell and the study by Scosyrev should be highlighted, including the sample size (12,081 vs 464,918), years of the study (1989 to 2009 vs 1998 to 2007), and age distribution (30.2% vs 44% who were aged ≥ 70 years). Despite these differences, both studies provide the consistent message that elderly men have a greater risk of diagnosis with aggressive prostate cancer.

Nevertheless, Level 1 evidence on routine use of PSA testing in the elderly is lacking because men aged > 75 years were not included in major screening trials.10,11 According to the 2011 US National Vital Statistics, the average man is expected to live an additional 14.3 years at age 70, and 11.0 years at age 75.12 Although overdiagnosis and overtreatment clearly can cause harm in this expanding population, our challenge is to also avoid undue morbidity and mortality from underdiagnosis and undertreatment of elderly men.   

References
  1. National Cancer Institute. SEER Stat Fact Sheet: Prostate cancer. http://seer.cancer.gov/statfacts/html/prost.html#incidence-mortality. Accessed November 28, 2011. 
  2. US Preventive Services Task Force. Screening for prostate cancer: Draft Recommendation Statement. Accessed October 29, 2011. 
  3. Catalona WJ, D’Amico AV, Fitzgibbons WF, et al. What the U.S. Preventive Services Task Force missed in its prostate cancer screening recommendation. Annals Intern Med. 2012;157:137-138.
  4. Caire AA, Sun L, Robertson CN, et al. Public survey and survival data do not support recommendations to discontinue prostate-specific antigen screening in men at age 75. Urology. 2010;75:1122-1127.
  5. American Urological Association. Early detection of prostate cancer: American Urological Association Guideline.  Accessed May 12, 2013. 
  6. Brassell SA, Rice KR, Parker PM, et al. Prostate cancer in men 70 years old or older, indolent or aggressive: clinicopathological analysis and outcomes. J Urol. 2011;185:132-137.
  7. Scosyrev E, Messing EM, Mohile S, et al. Prostate cancer in the elderly: frequency of advanced disease at presentation and disease-specific mortality. Cancer. 2012;118:3062-3070.
  8. D’Amico AV, Chen MH, Roehl KA, Catalona WJ. Preoperative PSA velocity and the risk of death from prostate cancer after radical prostatectomy. N Engl J Med. 2004;351:125-135.
  9. Massengill JC, Sun L, Moul JW, et al. Pretreatment total testosterone level predicts pathological stage in patients with localized prostate cancer treated with radical prostatectomy. J Urol. 2003;169:1670-1675.
  10. Andriole GL, Crawford ED, Grubb RL 3rd, et al. Prostate cancer screening in the randomized Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial: mortality results after 13 years of follow-up. J Natl Cancer Inst. 2012;104:125-132.
  11. Schröder FH, Hugosson J, Roobol MJ, et al. Prostate-cancer mortality at 11 years of follow-up. N Engl J Med. 2012;366:981-990.
  12. Hoyert DL, Xu J. National Vital Statistics Reports. 2012;61:1-52.  Accessed May 12, 2013. 

PSA Velocity in Risk Stratification of Prostate Cancer

Reviewed by Marc A. Bjurlin, MD, Stacy Loeb, MD
Department of Urology, New York University and the Manhattan Veterans Affairs Hospital, New York, NY 
[Rev Urol. 2013;15(4):204-206 doi:10.3909/riu0590b]

© 2014 MedReviews®, LLC

 

Since the introduction of widespread prostate-specific antigen (PSA)–based prostate cancer screening, several markers have been employed to aid in detection of prostate cancer. The change in PSA level over time, PSA velocity (PSAV), is such a marker that may improve specificity; however, its role as an adjunct to PSA is controversial. Some prior studies have shown that a PSAV provides independent predictive information for estimating prostate cancer risk1 and a PSAV threshold of 0.35 to 0.4 ng/mL/year has been associated with the likelihood of insignificant prostate cancer, suggesting that PSAV may increase specificity for identifying patients with clinically significant disease.2,3 Conversely, other studies have shown that PSAV has limited value4 and biopsying men with high PSAV but no other indication would lead to a large number of additional prostate biopsies.5 Recently, Ørsted and colleagues6 and Wallner and associates7 evaluated the value of PSAV as an adjunct marker to PSA, its role in predicting aggressive disease, and improving classification of prostate cancer risk and mortality. 

 

Long-term Prostate-specific Antigen Velocity in Improved Classification of Prostate Cancer Risk and Mortality

Ørsted DD, Bojesen SE, Kamstrup PR, Nordestgaard BG.
Eur Urol. 2013;64:384-393. 

Ørsted and colleagues reported on whether long-term PSAV improves classification of prostate cancer risk and mortality. Among 7455 men in the Copenhagen City Heart Study, they identified 503 men (121 with prostate cancer; 382 matched control subjects) aged 30 to 80 years with repeated PSA measurements taken over 20 years. The goals of the study were to examine individual changes in PSA over a long time interval, and determine whether these changes were associated with prostate cancer risk and mortality beyond what is predicted by total PSA. Their findings were then applied to the general male population aged 40 to 80 years living in Denmark from 1997 through 2006 (n = 1,351,441). 

Virtually all study participants were white Danish men, and the median age at baseline was similar for men with prostate cancer and those without it (age 68 and 69 years, respectively). The absolute and relative long-term PSAV increased continuously as a function of time from > 20 years earlier up until prostate cancer diagnosis in cases compared with matched control subjects (P = .002 and P = .001, respectively). 

On multivariable analysis, PSAV > 0.35 ng/mL/year was associated with a 5.3-fold increased risk of prostate cancer and a 3.4-fold increased risk of disease-specific death after controlling for PSA. Similarly, when expressed as a percent change, a long-term PSAV > 10% was associated with a 2.7-fold increased risk of diagnosis, but a nonsignificant 2.2-fold increased risk of prostate cancer death in the model with PSA. 

The authors did not find a statistically significant increase in area under the curve (AUC) using kinetic measurements in addition to PSA, although the use of receiving operating characteristic (ROC) analysis for this purpose has been criticized.8 Thus, the authors proceeded to report net reclassification analysis to determine whether PSAV reclassified the risk of prostate cancer diagnosis and mortality. This analysis revealed that adding long-term PSAV to models already including baseline PSA values and age resulted in statistically significant net reclassification, although the emphasis on continuous net reclassification analysis in this study has been questioned.9 Instead, using an arbitrary threshold of 5% risk of 10-year mortality, PSAV did not significantly reclassify events, but led to significant reclassification of nonevents.

Overall, the study has several strengths and limitations. The study population was representative of the general population of men, well-characterized, with long (28 years) and complete (100%) follow-up. Limitations included a homogeneous cohort that mainly included white participants of Danish descent who had only two or three PSA values over such a long period. In most studies with PSA measurements taken ≥ 4 years apart,10,11 PSA kinetics measurements were less predictive than in studies where PSA kinetics were calculated from PSA measurements drawn 1 to 2 years apart,12,13 as the metric was originally described. Furthermore, some men may have been diagnosed with prostate cancer or died after their first examination, which may have excluded men with the most aggressive cancers.

Nevertheless, these data suggest that long-term PSA changes may be useful in identifying men with a low probability of prostate cancer mortality, and, as a result, may ultimately reduce unnecessary prostate biopsies. However, we need to determine the optimal interval between PSA measurements and method of kinetics calculation for clinical use. Furthermore, whether prostate cancer is curable at the point when PSAV indicates intervention is of key importance. The majority of study participants with PSAV > 0.35 ng/mL/year and/or > 10% per year had PSA levels < 10 ng/mL, suggesting probable detection within the window of curability.

Changes in Serum Prostate-specific Antigen Levels and the Identification of Prostate Cancer in a Large Managed Care Population

Wallner LP, Frencher SK, Hsu JW, et al.
BJU Int. 2013;111:1245-1252.

Wallner and colleagues, from Kaiser Permanente in Southern California, determined whether the rate of change in total serum PSA levels accurately detects prostate cancer and whether it adds any predictive value to a single measurement of serum PSA alone. The authors performed a retrospective cohort analysis of 219,388 community-dwelling men, aged ≥ 45 years, enrolled in the Kaiser Permanente Southern California health plan from 1998 to 2007. All men had no history of prostate cancer at baseline and underwent at least three PSA measurements. The authors evaluated the annual percent change in total serum PSA levels, and determined the accuracy of PSA changes for overall prostate cancer detection as well as detection of Gleason ≥ 7 disease compared with a single PSA measurement. 

A total of 10,035 men developed prostate cancer during the study period. These men were slightly older, more likely to be African American, and had shorter follow-up times when compared with men who did not develop prostate cancer (all P < .001). Men in this study received approximately five PSA tests during the study period and the mean number of PSA tests was marginally higher among men who developed prostate cancer (5.32 tests) compared with men who did not (5.28 tests; P = .002).

In the overall study population, the mean change in PSA levels was 2.9% per year and the rate of change in PSA increased modestly with age (P < .001). Overall, men who developed prostate cancer experienced a more rapid percent change in PSA per year than men who did not (P < .001). Moreover, the authors reported that annual percent changes in PSA accurately predicted the presence of prostate cancer (AUC = 0.963) and aggressive disease (AUC = 0.955), representing greater predictive accuracy for aggressive disease than a single measurement of PSA alone (AUC = 0.727). Furthermore, the combination of PSA and PSA velocity did not improve the accuracy of prostate cancer detection beyond that of PSA velocity alone.

There are several strengths of this study including its large sample size, with considerable follow-up, and a large retention rate (> 80%). Previous studies evaluating PSAV have relied on the absolute changes in PSA over time, whereas the current study evaluated the annual percent change in PSA, which the authors suggest may be a more accurate measure of PSAV. It would be interesting to assess how this metric compares with PSAV risk count, which has previously been shown to improve the identification of clinically significant disease.13  

A major limitation of the study by Wallner and colleagues is that not all men in the study underwent a prostate biopsy during follow-up, which introduces a verification bias. The study did not control for the surgical and medical management of benign prostatic hyperplasia and its effects on PSA levels. Three PSA assays were used throughout the study period which may result in pseudoacceleration or pseudodeceleration.14 Furthermore, the study registry did not capture prostate cancer diagnoses that occurred after membership termination. Finally, concern has been expressed about inconsistency between the data presented in the figures and text, which requires additional clarification.15

Discussion

Contrary to what has been previously suggested,15 no randomized trial has evaluated the outcomes of a screening program based on PSA kinetics. Each of the many observational studies and secondary analyses of PSAV has important drawbacks. However, the absence of evidence is not evidence of absence.16 If confirmed, the studies of Ørsted and colleagues6 and Wallner and associates7 will add to the growing body of literature supporting the value for PSA kinetics in improving detection beyond that of a single baseline PSA measurement. In particular, these studies suggest that PSAV may be useful when screening for aggressive disease, with the goal of ultimately reducing unnecessary prostate biopsies and overdiagnosis. Additional prospective evaluation is necessary to confirm that PSAV may identify men at a time point when their disease is curable and may benefit from curative intervention.   

References
  1. Eggener SE, Yossepowitch O, Roehl KA, et al. Relationship of prostate-specific antigen velocity to histologic findings in a prostate cancer screening program. Urology. 2008;71:1016-1019.
  2. Loeb S, Roehl KA, Helfand BT, et al. Can prostate specific antigen velocity thresholds decrease insignificant prostate cancer detection? J Urol. 2010;183:112-116.
  3. Loeb S, Metter EJ, Kan D, et al. Prostate-specific antigen velocity (PSAV) risk count improves the specificity of screening for clinically significant prostate cancer. BJU Int. 2012;109:508-513; discussion 513-514.
  4. Vickers AJ, Wolters T, Savage CJ, et al. Prostate-specific antigen velocity for early detection of prostate cancer: result from a large, representative, population-based cohort. Eur Urol. 2009;56:753-760.
  5. Vickers AJ, Till C, Tangen CM, et al. An empirical evaluation of guidelines on prostate-specific antigen velocity in prostate cancer detection. J Natl Cancer Inst. 2011;103:462-469.
  6. Ørsted DD, Bojesen SE, Kamstrup PR, Nordestgaard BG. Long-term prostate-specific antigen velocity in improved classification of prostate cancer risk and mortality. Eur Urol. 2013;64:384-393.
  7. Wallner LP, Frencher SK, Hsu JW, et al. Changes in serum prostate-specific antigen levels and the identification of prostate cancer in a large managed care population. BJU Int. 2013;111:1245-1252.
  8. Pencina MJ, D’Agostino RB Sr, D’Agostino RB Jr, Vasan RS. Evaluating the added predictive ability of a new marker: from area under the ROC curve to reclassification and beyond. Stat Med. 2008;27:157-172; discussion 207-212.
  9. Vickers AJ, Pencina M. Prostate-specific antigen velocity: new methods, same results, still no evidence of clinical utility. Eur Urol. 2013;64:394-396.
  10. Ulmert D, Serio AM, O’Brien MF, et al. Long-term prediction of prostate cancer: prostate-specific antigen (PSA) velocity is predictive but does not improve the predictive accuracy of a single PSA measurement 15 years or more before cancer diagnosis in a large, representative, unscreened population. J Clin Oncol. 2008;26:835-841.
  11. Wolters T, Roobol MJ, Bangma CH, Schroder FH. Is prostate-specific antigen velocity selective for clinically significant prostate cancer in screening? European Randomized Study of Screening for Prostate Cancer (Rotterdam). Eur Urol. 2009;55:385-392.
  12. Carter HB, Ferrucci L, Kettermann A, et al. Detection of life-threatening prostate cancer with prostate-specific antigen velocity during a window of curability. J Natl Cancer Inst. 2006;98:1521-1527.
  13. Loeb S, Metter EJ, Kan D, et al. Prostate-specific antigen velocity (PSAV) risk count improves the specificity of screening for clinically significant prostate cancer. BJU In. 2012;109:508-513; discussion 513-514.
  14. Loeb S, Chan DW, Sokoll L, et al. Prostate specific antigen assay standardization bias could affect clinical decision making. J Urol. 2008;180:1959-1962; discussion 1962-1963.
  15. Vickers AJ. Prostate cancer: Why is PSA velocity such a sticky concept? Nat Rev Urol. 2013;10:189-190.
  16. Perrin P. PSA velocity and prostate cancer detection: the absence of evidence is not the evidence of absence. Eur Urol. 2006;49:418-419.

 

Patient Perceptions and Shared Decisions About PSA Screening 

Reviewed by Daniel Wollin, MD, Stacy Loeb, MD
Department of Urology, New York University and the Manhattan Veterans Affairs Hospital, New York, NY 
[Rev Urol.2013;15(4):206-207 doi:10.3909/riu0600]

© 2014 MedReviews®, LLC  

 

The past few years have witnessed a rapidly changing panorama regarding recommendations for prostate cancer screening. At one extreme, the United States Preventive Services Task Force (USPSTF) issued a grade D recommendation against prostate-specific antigen (PSA) screening.1 Meanwhile, most other groups recommend shared decision making about screening, including a discussion between patients and physicians about the associated controversies and taking into consideration patient preferences.2 For example, the American Urological Association (AUA) recently issued new guidelines supporting shared decision making about PSA testing for average-risk men aged 55 to 69 years, while opposing PSA testing as part of health fairs and other community settings in which shared decision making is not part of routine practice.3 Two recent studies have attempted to quantify the effect of these changing recommendations on patient perceptions and patient-physician discussions regarding PSA screening.

National Evidence on the Use of Shared Decision Making in Prostate-Specific Antigen Screening

Han PK, Kobrin S, Breen N, et al.
Ann Fam Med. 2013;11:306-314.

Proper shared decision making between a patient and physician involves several components, including a discussion of the advantages, disadvantages, and scientific uncertainties. The goal of this study was to assess the extent to which shared decision making is actually used for PSA screening decisions and its implications.

Of 4217 men aged 50 to 74 years from the nationally representative sample of the 2010 National Health Interview Survey, 3427 men responded to a questionnaire about the nature of the prescreening conversation with their physician. Whether the physician was an internist, urologist, or other health professional was not addressed. In total, 55.8% of men reported at least one previous PSA test, whereas 44.2% of the study population reported never being screened. 

Overall, only 8.0% of the participants described conversations that included all three required components of shared decision making (advantages, disadvantages, and uncertainties). Conversely, 64.3% reported no discussion whatsoever. Higher screening intensity (4 to 5 PSA tests/5 years) was associated with partial shared decision making (1 or 2 of the required elements), along with increased age, higher education, and physician recommendation.  

Importantly, the vast majority of nonscreened men—88% (95% confidence interval, 86.2-90.1)—reported no discussion of PSA screening whatsoever. That is, the authors observed a significantly greater degree of uninformed nonuptake compared with uninformed uptake.

There are several limitations to this study, most significantly the reliance on self-reporting of screening-related conversations, which can be inaccurate.4 For example, patients who underreport PSA screening may also underreport shared decision making, potentially inflating the degree of uninformed nonuptake.However, a lack of screening in the absence of discussion is a feasible and troubling possibility, particularly given that primary care physicians may no longer feel obliged to discuss PSA with patients given the USPSTF grade D recommendation. Overall, this study revealed the pervasiveness of incomplete dialogues regarding the risks, benefits, and uncertainties of PSA screening in contemporary patient-physician encounters.

Prostate-specific Antigen Testing: Men’s Responses to 2012 Recommendation Against Screening

Squiers LB, Bann CM, Dolina SE, et al.
Am J Prev Med. 2013;45:182-189.

This study attempted to evaluate the awareness and attitudes of men in the United States toward the October 2011 USPSTF draft recommendation against PSA screening (which was officially announced in May 2012). One month after the draft was released (November–December 2011), online surveys were distributed to 1800 men aged 40 to 74 years asking about their degree of agreement with the new recommendation. Overall, 67.7% responded, of which 1089 had no history of prostate cancer and were thus eligible for participation. 

In this sample, 44% of patients had a PSA test within the past 2 years, and 39% reported never receiving a PSA test. Most men (70%) reported no discussion or did not recall a discussion about the benefits and harms of PSA screening with their provider. 

At the time of the survey, > 75% of participants had not heard about the new draft recommendation. Once shown the new recommendation, participants were asked if they would follow it and avoid PSA screening in the future. Overall, only 13% stated they would avoid further screening, whereas 54% planned to ignore the recommendation, and 33% had not decided. Logistic regression identified the following features as those significantly associated with intending to not follow the recommendation: black race/ethnicity, higher income, worried about developing prostate cancer, and having had a PSA checked within 2 years.

The greatest limitation of this study is its timing—the survey was conducted less than 1 month after the distribution of a draft recommendation and a majority of the participants had little to no exposure to the source material prior to the study. Given the significant amount of media coverage and policy discussion since this draft and several subsequent guidelines, the average male patient may now have greater exposure to the controversy. 

In summary, it is important to note that both these studies were performed prior to the official release of the updated USPSTF and AUA guidelines (2012 and 2013, respectively). Nevertheless, they highlight the fact that many contemporary patients were not well educated by their physicians regarding the potential benefits, harms, and uncertainties of PSA screening. Given that most organizations now recommend shared decision making, a unilateral decision by physicians to blindly screen or not to discuss screening as an option is concerning. Although time consuming, it is important that patients are given full information about the risks, benefits, and uncertainties of screening to actively participate in an informed decision-making process.   

References
  1. Moyer VA, for the USPSTF. Screening for prostate cancer: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med. 2012;157:120-134.
  2. Basch E, Oliver TK, Vickers A, et al. Screening for prostate cancer with prostate-specific antigen testing: American Society of Clinical Oncology Provisional Clinical Opinion. J Clin Oncol. 2012;30:3020-3025.
  3. Carter HB, Albertsen PC, Barry MJ, et al. Early detection of prostate cancer: AUA Guideline. J Urol. 2013;190:419-426.
  4. Rauscher GH, Johnson TP, Choi YI, Walk JA. Accuracy of self-reported cancer-screening histories: a meta-analysis. Cancer Epidemiol Biomarkers Prev. 2008;17:748-757.

 

Genetic Tests for Prostate Cancer

Reviewed by Adam Kern, MD, Alan W. Partin, MD, PhD
The Brady Urological Institute, Johns Hopkins Hospital,
Baltimore, MD
[Rev Urol.2013;15(4):208-209 doi:10.3909/riu0597]

© 2014 MedReviews®, LLC

 

Recent attention has focused on risk stratification for men for the early detection of prostate cancer insofar as triaging which men should undergo initial prostate-specific antigen (PSA) testing. However, risk stratification of men with biopsy-proven prostate cancer also remains an emerging field. Several nomograms exist to predict surgical pathology or the subsequent risk of posttreatment biochemical recurrence, including the Cancer of the Prostate Risk Assessment Postsurgical score (CAPRA-S), Memorial Sloan-Kettering Pre-Treatment Nomogram, and the Partin and Han tables. The rapidly declining cost of genetic analysis using off-the-shelf technology has ushered in a new generation of commercially available genetic assays that further delineate pre- and post-treatment prostate cancer risk for men with biopsy-proven disease. Here we review evidence validating three new genetic assays for prostate cancer that are recently US Food and Drug Administration (FDA) approved or pending approval.

Validation of a Cell-cycle Progression Gene Panel to Improve Risk Stratification in a Contemporary Prostatectomy Cohort

Cooperberg MR, Simko JP, Cowan JE, et al. 
J Clin Oncol. 2013;31:1428-1434.

Cooperberg and colleagues validated a previously described genetic risk score based on quantification of cell cycle progression (CCP), in a cohort of patients’ status post-radical prostatectomy (RP). CCP is calculated as a function of gene expression of 31 CCP marker genes relative to 15 housekeeping control genes. This assay is now FDA approved and marketed under the trade name Prolaris by Myriad Genetics (Salt Lake City, UT). Recurrence was defined as two PSA levels ≥ 0.2 ng/mL or any salvage treatment. The CCP score was assessed for prognostic value beyond that of standard postoperative risk assessment using the CAPRA-S.

In a cohort of 413 men, 82 (19.9%) experienced a recurrence. Adjusting for CAPRA-S, the hazard ratio (HR) for each unit increase in CCP score was 1.7 (95% confidence interval, 1.3-2.4). The authors also found that the combined CAPRA-S + CCP score consistently predicted outcomes across the range of clinical risk—including men with low-risk disease—and had superior performance to either individual score alone. Interestingly, at its extreme, CCP score remained highly predictive of clinical outcome regardless of CAPRA clinical risk group. No man with a low CCP score < −1 experienced a biochemical recurrence (BCR) during a 5-year period. Conversely, men with CCP score > 1.5% experienced BCR across all CAPRA risk subsets, including men with CAPRA-defined low-risk disease. The authors concluded that the independent CCP score serves as a predictor of posttreatment prostate cancer recurrence, and that models incorporating both CCP and CAPRA-S offer enhanced prognostic capability.

Development and Validation of the Biopsy-based Genomic Prostate Score as a Predictor of High Grade or Extracapsular Prostate Cancer to Improve Patient Selection for Active Surveillance

Cooperberg MR, Simko J, Falzarano S et al. 
American Urological Association Annual Meeting 2013, San Diego, CA. Abstract 2131.

In this study also by Cooperberg and colleagues, a biopsy-based genomic prostate score (GPS) scheme was analyzed to assess its utility in predicting high-risk extracapsular prostate cancer in order to improve patient selection for active surveillance (AS) based on biopsy result. GPS is calculated based on reverse transcription polymerase chain reaction quantification of a panel of 17 prostate cancer-associated genes in the biopsy specimen. Genomic Health Inc. (Redwood City, CA) is currently developing the GPS assay under the trade name Oncotype DX®, which is pending FDA approval. 

The authors validated the 17-gene GPS panel using both RP specimens and needle biopsy specimens. During initial investigation, a panel of 732 candidate genes was narrowed to 288 genes potentially predictive of clinical recurrence, based on final RP pathology results. A subset of 81 of these 288 genes was carried forward into analysis using prostate biopsy cores from low/intermediate pretreatment risk patients. Multivariate analysis combining both populations parsed out 17 genes from multiple biologic pathways that were highly associated with high-grade and/or pT3 disease, forming the basis for GPS.

The results of this initial validation study are encouraging. The 17-gene GPS may be used in the pretreatment paradigm to predict high-risk disease based on biopsy tissue alone, and may prove particularly useful in identifying suitable candidates for AS.

Validation of a Genomic Classifier That Predicts Metastasis Following Radical Prostatectomy in an At-risk Patient Population

Karnes RJ, Bergstralh EJ, Davicioni E, et al. 
J Urol. 2013;190:2047-2053.

This study aimed to develop a method to directly predict actual risk of prostate cancer metastasis based on tissue analysis of RP specimens. Men diagnosed with high-risk prostate cancer based on pretreatment clinical nomograms have heterogeneous outcomes, with imperfect correlation between ultimate tumor metastatic aggressiveness and observed clinical pathology after RP. Karnes and colleagues performed a validation study of a genomic classifier (GC) panel of 22 genes analyzed in a case-cohort study of 1010 post-RP specimens. The GC system is being developed by GenomeDx Biosciences (Vancouver, BC) under the trade name Decipher™. All patients were preoperatively assessed to be high risk based on either PSA > 20 ng/mL, Gleason ≥ 8, pT3b, or Gleason, PSA, seminal vesicle, and margin status (GPSM) score ≥ 10. GC scores were calculated for a subset of 219 patients and receiver-operating characteristics were calculated for GC assay performance.

GC had an area under the curve of 0.79 for predicting 5-year metastasis post-RP, outperforming comparative clinical-only models of disease metastasis. Importantly, among patients with Gleason 7 tumors, 41% had GC ≥ 0.4 and 44% of these men identified as high-risk on GC ultimately developed clinical metastasis. Conversely, 36% of patients with clinical high-risk disease (Gleason ≥ 8) based on pretreatment parameters had low GC scores, and the majority of these men had favorable long-term clinical outcomes, with 77% being metastasis free and 85% of them alive at 5 years post-treatment.

From these thought-provoking data, Karnes and colleagues concluded that GC assessment may identify men normally classified as “intermediate risk” who actually have a relatively high risk of prostate cancer metastasis. Even more importantly, GC may identify men labeled as pathologic “high-risk” based on standard parameters who actually have a low probability of developing metastases. Current guidelines recommend post-RP adjuvant treatment for men with high-risk features on post-RP pathology. Identification of this latter population of men using GC technology is particularly critical, potentially offering an avenue to spare them from adjuvant therapy and its associated side effects when there is little chance adjuvant treatment will offer a superior benefit over clinical observation.

These three studies highlight several exciting recent advances in the genetic diagnosis of prostate cancer. Commercially available tissue assays are, or will soon be, available that may help with risk stratification based on either pretreatment biopsy core sampling or post-RP specimen analysis. These technologies may be particularly useful in the identification of men unlikely to benefit from adjuvant therapy following extirpative treatment for prostate cancer. The current state-of-the-art is rapidly accelerating for the diagnosis of men with biopsy-proven prostate cancer.