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Supplement: Biomarkers as Indicators of Cancer Risk Reduction Following Dietary Manipulation: SESSION 5

PSA: A Biomarker for Disease. A Biomarker for Clinical Trials. How Useful Is It?^1,2

Department of Urology, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229

^* To whom correspondence should be addressed. E-mail: thompsoni{at}uthscsa.edu.

Prostate-specific antigen (PSA) was first described in 1971 but was thought inappropriate for screening in the early 1980s because of poor specificity and was used initially for monitoring treatment response. The initial upper limit was 20 µg/L, and early studies found that about 8% of men, the same fraction as the lifetime risk of death for prostate cancer in the early 1980s, had values above 4.0 µg/L. For this reason, initial screening series selected this value as the upper limit of normal. In the late 1990s, others found that values of 3.0 or even 2.5 µg/L had only a slight decrease in the positive predictive value. No formal validation of the marker was conducted. With the completion of the Prostate Cancer Prevention Trial, in which 9423 men randomized to placebo were recommended to undergo an end-of-study biopsy, regardless of PSA value, the opportunity came to evaluate the performance characteristics of the marker.

The evaluation of this group of patients found that PSA was not a dichotomous marker (positive if >4.0 and negative if <4.0) but was associated with a range of risk of prostate cancer with no lower limit at which there was no risk of cancer (1). The risk of cancer ranged from 6.6% for values 0.5 µg/L to 26.9% for values between 3.1 and 4.0 µg/L. Our subsequent analysis found that the receiver operating characteristic (ROC) curve for PSA had an area under the curve of 0.678 for cancer versus no cancer and 0.827 for Gleason 8 and greater disease compared with lower Gleason grades or no cancer (2). Because of the distribution of cancer and PSA in the population, the sensitivity and specificity of PSA for cancer detection for levels of 1.1, 2.6, and 4.0 µg/L are 83.4%/38.9%, 40.5%/81.1%, and 20.5%/93.8%, respectively.

There are multiple challenges in the use of PSA for clinical trials. One challenge is that interventions may change its performance. This has been suggested by Andriole in a long-term study of finasteride in which this agent improved the performance of PSA with ROC analysis (3). Other factors can affect PSA, including obesity. We have also demonstrated in a community-dwelling cohort, in a group of 2779 men without prostate cancer, that as body mass index increases, PSA falls with a 30% reduction in the highest quintile of PSA. There are also examples of studies in which a fall in PSA is demonstrated but important endpoints such as survival or morbidity-free survival are unaffected.

These data suggest that there are serious problems with the use of PSA as an endpoint for clinical trials for prostate cancer. There is no level of PSA for which cancer can be excluded, factors such as subject exposure and subtle changes in patient characteristics (e.g., weight gain) could affect the marker, and there is a lack of surrogacy between PSA changes and clinically meaningful measures of treatment efficacy. For these reasons, at this time, PSA cannot be used as a surrogate marker for interventions for prostate cancer.

	FOOTNOTES

 
¹ Published in a supplement to The Journal of Nutrition. Presented as part of the conference "The Use and Misuse of Biomarkers as Indicators of Cancer Risk Reduction Following Dietary Manipulation" held July 12–13, 2005 in Bethesda, MD. This conference was sponsored by the Center for Food Safety and Applied Nutrition (CFSAN), Food and Drug Administration (FDA), Department of Health and Human Services (DHHS); the Office of Dietary Supplements (ODS), National Institutes of Health, DHHS; and the Division of Cancer Prevention (DCP), National Cancer Institute, National Institutes of Health, DHHS. Guest Editors for the supplement publication were Harold E. Seifried, National Cancer Institute, NIH; and Claudine Kavanaugh, CFSAN, FDA. Guest editor disclosure: H.E. Seifried, no relationships to disclose; C. Kavanaugh, no relationships to disclose.

² Author disclosure: no relationships to disclose.

	LITERATURE CITED

TOP LITERATURE CITED

 

1. Thompson IM, Pauler DK, Goodman PJ, Tangen CM, Lucia MS, Parnes HL, Minasian LM, Ford LG, Lippman SM, et al. Prevalence of prostate cancer among men with a prostate-specific antigen level < or = 4.0 ng per milliliter. N Engl J Med. 2004;350:2239–46.[Abstract/Free Full Text]

2. Thompson IM, Ankerst DP, Chi C, Lucia MS, Goodman PJ, Crowley JJ, Parnes HL, Coltman CA Jr. Operating characteristics of prostate-specific antigen in men with an initial PSA level of 3.0 ng/ml or lower. JAMA. 2005;294:66–70.[Abstract/Free Full Text]

3. Andriole GL, Guess HA, Epstein JI, Wise H, Kadmon D, Crawford ED, Hudson P, Jackson CL, Romas NA, et al. Treatment with finasteride preserves usefulness of prostate-specific antigen in the detection of prostate cancer: results of a randomized, double-blind, placebo-controlled clinical trial. PLESS Study Group. Proscar Long-term Efficacy and Safety Study. Urology. 1998;52:195–202.[Medline]

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