Population screening to identify preclinical disease is considered a central factor in the decades-long decrease in mortality seen in certain cancers. However, hope in the face of deadly disease can sometimes blind us to the scientific evidence. According to the recent U.S. Preventive Services Task Force recommendation,1 such might be the case with routine prostate-specific antigen (PSA) screening, the most widely used method in efforts to detect early prostate cancer. To add clarity to this ongoing debate, The ASCO Post recently spoke with Richard J. Ablin, PhD, DSc (Hon), Professor of Pathology at the University of Arizona College of Medicine, The Arizona Cancer Center, and the BIO5 Institute, Tucson, and the discoverer of PSA.
Discovering PSA
What were the salient events leading up to your discovery of PSA?
In 1968, after completing a postdoctoral fellowship in the Bacteriology and Immunology (currently Microbiology) Department at the University of Buffalo Medical School, I joined two urologists at the Millard Fillmore Hospital in Buffalo, who had developed cryosurgery (or cryoablation) for the treatment of prostate cancer. Several of the patients treated cryosurgically had advanced metastatic disease (T4, M1), for example, to the lungs and cervical vertebrae. Remarkably, postoperative radiologic evidence revealed that their distant metastases had regressed or disappeared. Naturally, people wanted to know why freezing of the primary prostatic cancer was destroying distant metastasis.
In concert with cryosurgical studies in laboratory animals that developed an immune response to antigens (proteins) of the frozen tissue, I hypothesized that in patients with prostate cancer who had a remission of their metastases, the frozen-tissue destruction might have liberated a prostate cancer–specific antigen (or antigens) that was in turn responsible for the cryoimmunotherapeutic effect. Therefore, I initiated a series of immunologic studies of normal, benign, and malignant human prostatic tissues to ascertain whether a tumor-specific antigen was at work. I couldn’t find one—we are still looking—but I did discover a prostate tissue/organ–specific antigen, ergo, PSA, which was present in normal, benign, and malignant tissue.
Following these striking immune responses to freezing (for which I coined the term “cryoimmunotherapy”) and the identification of PSA, I took a cursory look at the possible clinical relevance of the tissue-specificity of PSA. For this purpose and by way of example, I electrophoretically analyzed serum specimens from patients with prostate cancer prior to and following treatment. I observed an elevated area based on the electrophoretic mobility of PSA in the pretreatment specimens, which was markedly reduced or absent related to the treatment. In patients who had a clinical recurrence of disease, the previously reduced or absent area was increased.
This empirically suggested that PSA could possibly be used, following further studies, for prognosis. I dropped this line of inquiry, which perhaps in hindsight was not the best choice, as I wanted to continue my investigations for a possible prostate cancer–specific antigen.
‘Four Cruxes’
In several prominent editorials you argue uneaquivocally that population screening for prostate cancer is bad public health policy. Please explain why.
Because PSA cannot diagnose prostate cancer. To that end, I’ve shaped my reasoning into what I call the “four cruxes.” First, PSA, the protein I identified in 1970, is prostate-specific, not cancer-specific. It is present in the normal, the benign, and the malignant prostate and can be elevated by numerous benign factors.
Second, there is no dichotomy in the level of PSA as a diagnostic tool for prostate cancer. In other words, a man can have a PSA of 0.5 ng/mL and have prostate cancer, while another man can have a PSA of 11 ng/mL and not have cancer.
Third, the PSA test cannot distinguish an indolent cancer from an aggressive cancer. Prostate cancer is akin to a “turtle” and a “rabbit” in an open box. The turtle is the indolent, nonaggressive cancer; it wanders around inside the box and goes nowhere. The rabbit is the aggressive cancer; it hops around and might even jump out of the box at anytime and metastasize. We can’t tell the difference between the turtle and the rabbit.
And fourth, prostate cancer is an age-related cancer. If a group of asymptomatic men between the ages of 60 to 69 years undergo a prostatic biopsy, more than 65% of them would have prostate cancer. Therefore, a PSA-prompted biopsy may or may not, related to the individual’s age, find cancer. However, unable to determine among these men which are the turtles and which are the rabbits, results in a huge amount of unnecessary procedures and possibly associated morbidities. Again, the central problem is that we can’t differentiate between indolent and aggressive cancers of the prostate. It’s like flipping a coin.
Mass Screening Origins
How did your discovery make the leap from a couple of papers to a mass screening juggernaut?
Nine years after my identification of PSA in 1970, some other researchers rediscovered my work and subsequently developed what we know as the PSA test. FDA approved the PSA test in 1986, as a prognostic assay to monitor patients with prostate cancer following treatment, ie, as a “harbinger” for the recurrence of disease. Even though it was not approved for screening asymptomatic men, the impetus of a noninvasive test—albeit not cancer-specific—in concert with the uncertainties of a digital rectal exam (DRE) prompted the urologic community to begin using PSA as a screening tool.
Then in 1987, Thomas Stamey, MD, and colleagues wrote a New England Journal of Medicine paper extolling the benefits of PSA screening,2 setting off a medical tsunami. For instance, from 1986 to 1991, there was an 82% increase in the diagnosis of prostate cancer. From 1989 to 1992, radical prostatectomies almost tripled, soaring from 78 men per 100,000 to 206 per 100,000, in a few years. In the same period, radical prostatectomies for men over 75 years of age doubled, going from 44 men per 100,000 to 89 per 100,000. We now have 30 million American men per year undergoing routine PSA screening, leading to mountains of unnecessary biopsies and treatments.
Truth be told, 15 years after his influential publication Dr. Stamey recanted his original position, indicating it was predominantly benign prostatic hypertrophy (BPH) that was associated with an increased PSA. In reference to conducting radical prostatectomies, he commented, “We originally thought we were doing the right thing.”
FDA’s Role
When did FDA approval change from prognostic to diagnostic?
In 1994, FDA compounded the problem by approving PSA testing in conjunction with DRE as a diagnostic method for prostate cancer, in spite of having knowledge of three of the four “cruxes” I mentioned earlier. The FDA also never considered the risks vs benefits equation in PSA screening. Consequently, more than 1 million American men have been overdiagnosed and overtreated.
For example, in 1985, prior to PSA testing, the risk of a man developing prostate cancer during his lifetime was about 8.5 %; mortality was 2.5 %. Fast-forward to the latest data in 2005—the 8.5% incidence ballooned to 18%, but the mortality only increased to 3%. So we doubled the incidence of this disease, but the mortality rate has had a minute uptick.
I’m not suggesting that prostate cancer should be ignored; it’s a deadly disease that kills about 30 thousand American men a year. The problem is that this test is being hyped in the media as a tool to detect cancer, which it isn’t. Prostate cancer–surviving celebrities tour the country chanting, “get screened, get treated, and get cured.” Unfortunately, it’s not that neat a package.
Risk Stratification
What about PSA as a risk-stratification tool?
It’s an excellent approach if it’s handled correctly. However, given the inherent flaws of the test, you would need to do population screening to identify men with “elevated” PSA levels who could possibly be stratified into various risk categories. But, with the heterogeneous nature of prostate cancer and no dichotomy in the level of PSA, what is an “elevated” level? Once you establish baseline PSA levels, you could follow them in intervals of 6 months to a year. This is particularly applicable to men with a family history of prostate cancer.
However, for that approach to work, the medical community would need to reshape its biopsy-treatment profit-driven model and recognize that the test is also detecting abnormalities such as prostatitis and BPH. Then, using serial PSA follow-ups in concert with other diagnostic tests could possibly produce health benefits.
Declining Mortality
What about the argument of decreasing mortality?
A decrease in mortality—and particularly prostate cancer–specific mortality—is a good thing, but don’t jump to the conclusion that it’s the result of PSA testing. In looking, for example, at the impact of PSA screening in Seattle and Connecticut over 15 years, where the intensity of screening and treatment was higher in Seattle, the prostate cancer–specific mortality was virtually identical. There are more examples like that.
Improvement in surgical techniques and treatment modalities along with healthier patients with increased life expectancies have had an impact on survival; it’s just harder to quantify those factors. In fact, recent data show a decrease in mortality in most cancers, save for a few.
Closing Thoughts
Any last words on PSA?
Ancient alchemists attempted to turn common metals into gold and silver—thus far, it has not been possible. PSA was developed as a prognostic marker to follow a man with prostate cancer and perhaps help tailor his future treatments, not as a diagnostic tool in asymptomatic men. The manner in which the PSA test has been employed for screening doesn’t work, and to use it that way on such a mass scale is nothing short of criminal—lest we forget the dictum Primum non nocere: “First, do no harm.” ■
Disclosure: Dr. Albin reported no potential conflicts of interest.
Reference
1. U.S. Preventive Services Task Force: Screening for prostate cancer: Current recommendation. May 2012. Available at www.uspreventiveservicestaskforce.org/prostatecancerscreening.htm. Accessed June 18, 2012.
2. Stamey TA, Yang N, Hay AR, et al: Prostate-specific antigen as a serum marker for adenocarcinoma of the prostate. N Engl J Med 317:909-916, 1987.
