Assessing Prostate Cancer Risk: Results from the Prostate Cancer Prevention Trial

Ian M. Thompson ) 0 Donna Pauler Ankerst 0 Chen Chi 0 Phyllis J. Goodman 0 Catherine M. Tangen 0 M. Scott Lucia 0 Ziding Feng 0 Howard L. Parnes 0 Charles A. Coltman 0 Jr. 0 0 Affiliations of authors: Department of Urology, University of Texas Health Science Center , San Antonio, TX (IMT); The Fred Hutchinson Cancer Research Center , Seattle, WA (DPA, CC, PJG, CMT , ZF); University of Colorado, Denver, CO (MSL); Division of Cancer Prevention, National Cancer Institute , Bethesda , MD (HLP); Southwest Oncology Group, San Antonio, TX (CAC). University of Texas HSC at San Antonio , 7703 Floyd Curl Dr., San Antonio, TX 78229 ( - Background: Prostate-specific antigen (PSA) testing is the primary method used to diagnose prostate cancer in the United States. Methods to integrate other risk factors associated with prostate cancer into individualized risk prediction are needed. We used prostate biopsy data from men who participated in the Prostate Cancer Prevention Trial (PCPT) to develop a predictive model of prostate cancer. Methods: We included 5519 men from the placebo group of the PCPT who underwent prostate biopsy, had at least one PSA measurement and a digital rectal examination (DRE) performed during the year before the biopsy, and had at least two PSA measurements performed during the 3 years before the prostate biopsy. Logistic regression was used to model the risk of prostate cancer and high-grade disease associated with age at biopsy, race, family history of prostate cancer, PSA level, PSA velocity, DRE result, and previous prostate biopsy. Risk equations were created from the estimated logistic regression models. All statistical tests were two-sided. Results: A total of 1211 (21.9%) men were diagnosed with prostate cancer by prostate biopsy. Variables that predicted prostate cancer included higher PSA level, positive family history of prostate cancer, and abnormal DRE result, whereas a previous negative prostate biopsy was associated with reduced risk. Neither age at biopsy nor PSA velocity contributed independent prognostic information. Higher PSA level, abnormal DRE result, older age at biopsy, and African American race were predictive for high-grade disease (Gleason score 7) whereas a previous negative prostate biopsy reduced this risk. Conclusions: This predictive model allows an individualized assessment of prostate cancer risk and risk of high-grade disease for men who undergo a prostate biopsy. [J Natl Cancer Inst 2006;98:52934] Since the advent of prostate-specific antigen (PSA) screening in the late 1980s, approximately 50% of U.S. men have had a PSA test performed regularly (1). Early large-scale prostate cancer screening studies used 4.0 ng/mL PSA as a threshold value to prompt a recommendation for prostate biopsy (2,3). Subsequent studies suggested that the risk of prostate cancer, as determined at prostate biopsy, among men who have PSA levels between 2.5 ng/mL and 4.0 ng/mL is similar to that among men with PSA levels greater than 4.0 ng/mL (4,5). Nevertheless, PSA level has, in general, been treated as a dichotomous biomarker. That is, a PSA level greater than 4.0 ng/mL has been considered abnormal and a prostate biopsy has been recommended, whereas a PSA level at or below 4.0 ng/mL has been considered normal, with no action necessary. The completion of the Prostate Cancer Prevention Trial (PCPT), a phase III randomized, double-blind, placebo-controlled trial of finasteride for the prevention of carcinoma of the prostate (6), provided the first opportunity to examine the risk of prostate cancer among men who had a broad range of PSA values, including many below 4.0 ng/mL. By examining the end-of-study biopsy samples from men who had a normal PSA level, we recognized that prostate cancer could be found at all levels of PSA and that, in this group of men with normal PSA levels, 15% had prostate cancer (1). PSA level is only one of several determinants of prostate cancer risk. Family history of prostate cancer, age, race, and digital rectal examination (DRE) findings also play a role in the assessment of prostate cancer risk (2,3). However, possible interactions between these and other variables that are associated with the risk of prostate cancer are not known. Here we used prostate biopsy data from 5519 participants in the PCPT to examine whether interactions among these variables can be used to predict prostate cancer risk in an individual patient. SUBJECTS AND METHODS The PCPT randomly assigned 18 882 men who were 55 years old or older and had a normal DRE and a PSA level less than or equal to 3 ng/mL to either finasteride or placebo for 7 years (4). A PSA test and DRE were performed annually. Study participants assigned to placebo were recommended to undergo a prostate biopsy if any DRE result was abnormal or if their PSA value exceeded 4.0 ng/mL. At the end of the 7 years on study, all men who had not been diagnosed with prostate cancer were asked to undergo an end-of-study prostate biopsy. The PCPT was approved by the institutional review boards at all study sites, and all participants provided written informed consent. This analysis included all participants in the placebo group who underwent a prostate biopsy after any of the six annual visits or at the seventh year visit, when an end-of-study biopsy was recommended. Inclusion criteria for this analysis were a PSA test and DRE within 1 year of the biopsy as well as an additional PSA measurement during the 3 years before the biopsy to compute PSA velocity. For participants with multiple biopsies, the most recent study biopsy was used to assess the effect of a prior negative biopsy on prostate cancer risk; qualitatively similar risk estimates were obtained when the first study biopsy was used instead of the most recent study biopsy. For purposes of prostate cancer risk modeling, a family history of prostate cancer was coded as 0 (no) or 1 (yes); race as 0 (not African American) or 1 (African American); most recent DRE result at time of biopsy as 0 (negative or normal) or 1 (positive or suspicious for cancer); and previous biopsy history as 0 (no previous biopsy) or 1 (one or more previous biopsies, all negative for prostate cancer). The value for age was the participants age at prostate biopsy. To improve the goodness-of-fit of the models to the observed data, all models used PSA values that were transformed using the natural logarithm [log(PSA)]. All previous PSA measurements obtained within 3 years of a participants prostate biopsy were used to compute his PSA velocity, which was defined as the slope of log(PSA) per year as obtained by linear regression. There are many ways to define a change in the level of PSA over 3 years of follow-up, and there is no consensus on the optimal definition. Table 1 lists the 19 alternative definitions of PSA velocity that we evaluated in addition to the definition used in the analysis. We chose the first definition because it considers all PSA values o (...truncated)