Baseline PSA Testing for Men in Their 40s: Testing in Average-Risk Men Aged 40 to 50 Years Should Not Be Routinely Performed

Many urologists believe that all men, regardless of risk, should be offered a baseline prostate-specific antigen (PSA) test at age 40 years. I was once one of those urologists.[1] How did we come to this conclusion?

Using frozen sera samples from the Baltimore Longitudinal Study of Aging (BLSA), investigators found that low levels of PSA in young men (between 40 and 50 years of age) were directly associated with the development of prostate cancer (PCa) decades after performance of the baseline PSA test.[2] The relative risk of developing PCa among men aged 40 to 49.9 years with a PSA level above the median (0.6 ng/mL) was almost 4-fold higher after 2 to 3 decades than it was in men with a PSA level below the median value. These risk levels were similar for men aged 50 to 59.9 years who had PSA levels above and below the median for that age group (0.7 ng/mL). About the same time that these data were arrived at, a computer simulation was used to test different screening strategies with respect to the number of PCa deaths prevented, PSA tests, and prostate biopsies per 1,000 men.[3] The investigators reported that a strategy of PSA testing at ages 40 and 45, followed by biennial testing beginning at age 50, was estimated to reduce PCa mortality and number of PSA tests and biopsies performed per 1,000 men, compared with annual PSA testing beginning at age 50 years. PSA testing of men in their 40s was adopted as policy by the National Comprehensive Cancer Network[4] by consensus based on (1) reports that younger men are more likely than older men to have low-grade cancers with a favorable prognosis and improved biochemical control after surgery for PCa[5,6]; (2) the finding that younger men are less likely to have side effects from treatment[7]; and (3) further confirmation that baseline PSA levels in young men were associated not only with PCa but also with aggressive disease decades after a baseline test.[8,9] With this evidence, why would a baseline PSA test at age 40 years be inadvisable for the man at average risk?

A policy of screening for PCa involves an intervention in asymptomatic men. Thus, the bar is high for demonstrating that benefits will outweigh harms for any such intervention. For example, the US Food and Drug Administration decision not to approve 5-alpha-reductase inhibitors for PCa prevention in asymptomatic men was based on the possibility that harms could outweigh benefits if the drugs increased the rate of high-grade disease.[10] It is not sufficient to conclude that benefits will outweigh harms because a test is associated with future disease, or because younger men have less aggressive disease than older men. In fact, there is more evidence that harms (side effects associated with the treatment of PCa) will outweigh benefits (PCa mortality reduction) if men at age 40 to 50 years have a baseline PSA test.[11]

First, there is no such thing as a “baseline test.” Once a PSA test is performed, screening has begun and future tests will be performed-in all likelihood, annually or biennially-if for no other reason than to avoid the liability of a missed diagnosis. Second, the incidence of a lethal PCa phenotype among men younger than age 50 years is low.[12] Ninety-eight percent of PCa deaths occur after age 54 years, and 91% after age 70 years. The conclusion that routine testing of all average-risk men will reduce these deaths that occur mostly in men over age 70 years is a speculative leap of faith. Third, younger men are more likely than older men to harbor low-grade cancer with a longer lead time.[13] This would make it less likely that screening of men in their 40s would improve health outcomes compared with screening men in their 50s. In fact, it was estimated that, compared with initiating screening at age 50 years, screening beginning at age 40 years would result in the prevention of less than 1 PCa death per 1,000 men.[14] Fourth, men in their 40s who undergo screening and are found to have a diagnosis of PCa will live with any side effects of treatment longer than men in their 50s, based on remaining years of life. Lastly, while the “absence of evidence is not evidence of absence,” two randomized trials of screening did not evaluate screening among men in their 40s,[15,16] and therefore do not inform the decision to begin PSA testing early.

For all of the above reasons, the American Urological Association guideline panel recommended against routine PSA testing for average-risk asymptomatic men younger than 55 years of age.[11] For others at higher risk (eg, those with a family history or of African-American race), the panel recommended individualizing decisions-especially for those with a family history of early-onset PCa (before age 55 years) and/or PCa in multiple first-degree relatives or multiple generations. While some men in their 40s and early 50s will benefit from PSA testing, the evidence suggests that harms will likely outweigh benefits for most men at average risk. However, each time we perform a biopsy in a younger man who has high-grade cancer, or perform a radical prostatectomy on a younger man with high-grade cancer, this becomes “supporting evidence” to routinely test younger men based on the power of the anecdote. As the Nobel prize–winning author, Daniel Kahneman, states in his book Thinking, Fast and Slow,[17] “The amount of evidence and the quality do not count for much, because poor evidence can make a very good story.”

Financial Disclosure:The author has no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article.

References:

1. Carter HB. Rationale for earlier and less frequent prostate cancer screening. Urology. 2001;58:639-41.

2. Fang J, Metter EJ, Landis P, et al. Low levels of prostate-specific antigen predict long-term risk of prostate cancer: results from the Baltimore Longitudinal Study of Aging. Urology. 2001;58:411-6.

3. Ross KS, Carter HB, Pearson JD, Guess HA. Comparative efficiency of prostate-specific antigen screening strategies for prostate cancer detection. JAMA. 2000;284:1399-405.

4. Kawachi MH, Bahnson RR, Barry M, et al. NCCN clinical practice guidelines in oncology: prostate cancer early detection. J Natl Compr Canc Netw. 2010;8:240-62.

5. Carter HB, Epstein JI, Partin AW. Influence of age and prostate-specific antigen on the chance of curable prostate cancer among men with nonpalpable disease. Urology. 1999;53:126-30.

6. Khan MA, Han M, Partin AW, et al. Long-term cancer control of radical prostatectomy in men younger than 50 years of age: update 2003. Urology. 2003;62:86-91.

7. Eastham JA, Kattan MW, Rogers E, et al. Risk factors for urinary incontinence after radical prostatectomy. J Urol. 1996;156:1707-13.

8. Lilja H, Ulmert D, Bjork T, et al. Long-term prediction of prostate cancer up to 25 years before diagnosis of prostate cancer using prostate kallikreins measured at age 44 to 50 years. J Clin Oncol. 2007;25:431-6.

9. Ulmert D, Cronin AM, Bjork T, et al. Prostate-specific antigen at or before age 50 as a predictor of advanced prostate cancer diagnosed up to 25 years later: a case-control study. BMC Med. 2008;6:6.

10. Walsh PC. Re: FDA panel votes against drugs said to prevent prostate cancer. J Urol. 2011;185:1275-6.

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12. Howlader N, Noone AM, Krapcho M, et al, editors. SEER cancer statistics review, 1975-2010. National Cancer Institute. Updated June 14 2013. Available from: http://seer.cancer.gov/csr/1975_2010/. Accessed January 21, 2014.

13. Draisma G, Boer R, Otto SJ, et al. Lead times and overdetection due to prostate-specific antigen screening: estimates from the European Randomized Study of Screening for Prostate Cancer. J Natl Cancer Inst. 2003;95:868-78.

14. Howard K, Barratt A, Mann GJ, Patel MI. A model of prostate-specific antigen screening outcomes for low- to high-risk men: information to support informed choices. Arch Intern Med. 2009;169:1603-10.

15. Schroder FH, Hugosson J, Roobol MJ, et al. Prostate-cancer mortality at 11 years of follow-up. N Engl J Med. 2012;366:981-90.

16. Andriole GL, Crawford ED, Grubb RL 3rd, et al. Mortality results from a randomized prostate-cancer screening trial. N Engl J Med. 2009;360:1310-9.

17. Kahneman D. Thinking, fast and slow. New York: Farrar, Straus and Giroux; 2011.