Another step toward a rational, risk-stratified PSA testing methodology


A newly published article in the Journal of Clinical Oncology has suggested that PSA testing between 40 and 59 years of age may be able to predict for risk of clinically significant prostate cancer later in life.

The article by Preston et al. is based on data and blood samples from men participating in the Physician’s Health Study (PHS) that were used to test the research hypothesis. (See also this media release from the T. H. Chan School of Public Health at Harvard University.)

Basically, Preston et al. were able to obtain blood samples from 945 patients who participated in the PHS, inclusive of 234 prostate cancer patients and 711 age-matched controls. The physicians who participated in this study were enrolled in 1982 and followed for the next 30 years. Of the 234 patients for whom blood samples were available and who developed prostate cancer during the course of the study, 71 developed a lethal form of the disease (and were rematched to 213 controls).

Preston et al. have been able to show the following:

  • Average (median) PSA levels among the control participants (who did not develop prostate cancer) were
    • 0.68 ng/ml among the men of 40 to 49 years
    • 0.88 ng/ml among the men of 50 to 54 years
    • 0.96 ng/ml among the men of 55 to 59 years.
  • Risk for development of lethal prostate cancer was strongly associated with baseline PSA in midlife.
  • “A total of 82%, 71%, and 86% of lethal cases occurred in men with PSA above the median at ages 40 to 49, 50 to 54, and 55 to 59 years, respectively”, but what this means is that
    • Among men of 40 to 49 years of age who went on to have lethal prostate cancer, 82 percent had a PSA level greater than the median for their age group.
    • Among men of 50 to 54 years of age who went on to have lethal prostate cancer, 71 percent had a PSA level greater than the median for their age group.
    • Among men of 55 to 59 years of age who went on to have lethal prostate cancer, 86 percent had a PSA level greater than the median for their age group.
  • Men with a PSA level below the median (<1.0 ng/ml) at 60 years of age were unlikely to develop lethal prostate cancer in the future.

Preston et al. conclude that:

PSA levels in midlife strongly predict future lethal [prostate cancer] in a US cohort subject to opportunistic screening. Risk-stratified screening on the basis of midlife PSA should be considered in men age 45 to 59 years.

These data appear to correlate well with data previously published by the Swedish and American team led by Lilja and Vickers, which also demonstrated that a single PSA level taken among Swedish patients in their mid to late 40s could be used to project risk for a diagnosis of prostate cancer up to 25 years later.

Commenting on the implications of this study, the senior author, Dr. Lorelei Mucci, is quoted as stating that:

Our study does not imply prostate biopsy or definitive treatment is immediately required in younger men with higher PSA levels at baseline, as this could lead to over diagnosis.  Rather, these men should undergo more intensive PSA screening to enable earlier identification of cancer and potential cure while still possible.

What we have here appears to be confirmatory evidence that risk stratification is both reasonable and possible as a way to use PSA testing to identify, early on, the majority of men who are going to be at high risk for clinically prostate cancer over the next 20 years. Men at such elevated risk could therefore be followed with regular PSA testing to monitor their risk level and determine when a biopsy and other tests become essential.

Such a strategy would clearly also help to minimize risk for over-diagnosis and over-treatment of men at little to no serious risk for clinically significant prostate cancer.

The two questions that are not effectively answered by this study are: (a) whether a man might want to have at least three PSA tests in his lifetime (at say ages 45, 55, and 60) to provide the most effective evidence of no significant risk for prostate cancer; (b) whether men known to be at elevated risk because of race, genetic/family history, or other factors might want to have an additional, first PSA value taken (say) 5 years earlier, at about age 40, to optimize their chances of early detection. Few African Americans, for example, were enrolled in the PHS back in the early 1980s.

11 Responses

  1. So this implies that the old “safe” threshold of 4.0 is no longer valid and was in fact far too high, correct? What does this suggest that my two sons, ages 40 and 38, do re: PSA testing given that at age 69 I was diagnosed with Gleason 4 + 5 = 9 with positive margin at base, SVI, and EPE at age 71, positive iliac nodes? I must have had prostate cancer at age 60 or earlier which I then was told was BPH. I’m not aware of any other prostate cancer in my family.

  2. Dear Bob:

    (1) We have known for about 20 years now that the once supposedly “safe” threshold of 4.0 ng/ml was not, in fact, safe at all. The Prostate Cancer Prevention Trial proved that for us.

    (2) Your sons will have to make their own decisions about what they want to do, but if I was wearing their shoes I would get a baseline PSA test at 40 years of age and another one at 45. If those PSA values are down around 0.7 ng/ml or thereabouts, they may never have anything to worry about.

  3. “supposedly ‘safe’ threshold of 4.0 ng/ml was not, in fact, safe at all.”

    Now you are confusing me. AS at 4.0 is, I believe, common. Are you saying that blind ignorance at 4.0 ng/ml is not safe or non-treatment at 4.0 ng/ml is not safe?

  4. So 86% men age 55-59 with a PSA greater than 1.01 (the approximate median in that age group) will develop lethal prostate cancer?

  5. You misquote the authors in your third bullet point! They said that, “A total of 82%, 71%, and 86% of lethal cases occurred in men with PSA above the median at ages 40 to 49, 50 to 54, and 55 to 59 years, respectively.” You wrote something completely different.

  6. Does this mean that a PSA > 1.0 is bad news for anyone who is younger than 60 ?

  7. Sitemaster, thanks for your article, but your 3rd set of bullets, the passage beginning with “Lethal cases…” is worded in such a way as to have caused confusion in offline discussion about this article.

    The original author wrote:

    “A total of 82%, 71%, and 86% of lethal cases occurred in men with PSA above the median at ages 40 to 49, 50 to 54, and 55 to 59 years, respectively.”

    Another way to say this, using a term common “amongst” your British English, is this:

    “Amongst the small subset of all cases that were eventually lethal, it was found that the majority of men had PSA values above the median value for their respective age categories.” Or something like that.

    I offer this because some are reading the passage your wrote as implying that “Lethal cases of prostate cancer were observed later in 82 percent of men with a PSA value above the median for their age at 40 to 49 years of age,” and this was not the message of the original author.

    Thanks for your great work!

  8. Dear Mike:

    I am saying three different things at once. First, blind ignorance at any PSA level is not safe. Second, we have known for 20+ years that a PSA level of 4.0 ng/ml is not a PSA level at which one magically goes from being safe to not being safe (because one may not have been safe with a PSA much lower than that). Third, making management decisions on the basis of a single PSA level alone is rarely one of the world’s best ideas.

    A man with a PSA level of 9.0 ng/ml and a small amount of Gleason grade 3 + 3 = 6 prostate cancer may be able to stay on active surveillance for the rest of his life. A man with a PSA level of 3.5 ng/ml and a Gleason score 4 + 4 = 8 probably would be wise to consider treatment if he has a reasonable life expectancy of > 5 years.

  9. Dear John:

    No, a PSA > 1.0 is not necessarily bad news for anyone younger than 60 at all. But it does place them at higher risk than men of comparable age with a PSA level of < 1.0 ng/ml.

  10. Dear Testing123:

    To be strictly accurate I misinterpreted rather poorly phrased statement by the authors (which I shall correct in the next couple of minutes). I did not “misquote the authors” for the simple reason that I did not quote them at all. :O)

  11. Dear Mark:

    Please see the rephrased statement above.

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