The persistent inability to differentiate between indolent and aggressive PC has been one of the major limitations of PSA PC screening. To our knowledge, evaluating combinations of laboratory biomarkers, used concomitantly with an elevated PSA, has not been researched as a PSA augmentation strategy. Therefore, the key focus of this study was to determine if the laboratory biomarkers under evaluation were related to more advanced/aggressive PC stages. Our study found that HGB (OR=1.42 95% CI 1.27-1.59), RBC count (OR=2.52 95% CI 1.67-3.78), PSA (OR=1.04 95% CI 1.03-1.05), serum creatinine (OR=1.55 95% CI 1.12-2.15), and ‘Black” ethnicity (OR=1.88 95% CI 1.25-2.85) were significantly related to the PC group (method 1 PC stages I-IV). RBC count (p < 0.0001), HGB (p < 0.0001) and creatinine (p < 0.05) demonstrated increased PC risk with a 1 unit negative change in their value; while age (p < 0.005), PSA value (p < 0.005), and MCV level (p < 0.0001) demonstrated increased PC risk with 1 unit positive increase in their respected values (consistent with what one would expect). Analysis method 2 (PC stage I in comparison group) demonstrated HGB (OR 1.47 95% CI 1.31, 1.61), RBC count (OR 2.15 95% CI 1.43, 3.23), serum creatinine (OR 1.83 95% CI 1.18, 2.85), PSA (OR 1.033 95% CI 1.02, 1.05), MCV (OR 1.05 95% CI 1.02, 1.08), and age (OR 1.018 95% CI 1.01, 1.04) were significantly related to PC stages II-IV. ROC curves were compared to address whether the addition of these significant lab biomarkers would improve PC prediction when compared to PSA alone. The AUC increased from: Primary Analysis PSA alone 0.59, (95% CI 0.55, 0.61) to PBCDR best fit model 0.68, (95% CI 0.65, 0.71); Secondary Analysis PSA alone 0.63, (95% CI 0.58, 0.66), to PBCDR best fit model 0.72, (95% CI 0.68, 0.75). The differences between the models are statistically significant. In addition to the ROC curve, the validity (sensitivity/specificity) and positive/negative predictive values were determined. For the PSA only model, one can only determine the positive predictive value, given patients with a PSA less than 4 ng/dL are not routinely forwarded for prostate biopsy. The PPV of PSA alone (> = 4 ng/dL) decreased from 44.7% (method 1) to 20.6% (method 2). This indicates PSA is less effective as a tool for identifying the more clinically relevant PC (stages II-IV). Conversely, the PPV of the PBCDR method 2 (cut point 1) model was 55.3%, with a NPV of 81.9%, and specificity of 96.2%. These values demonstrate the PBCDR yielded significantly higher validity and predictive scores than that of PSA alone. In alignment with our hypothesis that there exists a gradient of change between the significant lab biomarkers and increasing levels of PC; HGB, RBC, PSA and Albumin demonstrated a significant gradient.
One important potential benefit of the PBCDR model is a reduction in prostate biopsies. In our study population, the PPV of PSA alone (in identifying stage II-IV PC) was 20.6% (284/1378). The PBCDR model (Method 2, cut-point 1), yielded a positive predictive value of 55.3% (52/94), a specificity of 96.2%, and sensitivity of 18.3%. If this particular PBCDR model was employed (as opposed to PSA alone), the number of unnecessary biopsies (those that did not identify PC stage II-IV) would have been reduced from 1,092 to 92. Moreover, with a specificity of 96.2%, the PBCDR model would correctly identify greater than 9 out of every 10 men who do not have PC. In 1998, the JH VA performed 1,610 biopsies. If one were to apply the PBCDR (comparing PC stage II-IV vs. stage I PC, PIN, BPH, and prostatitis) to the 1,378 subjects within this study, 52 of the 92 total biopsies (PPV= 55.3%) would have been positive for PC versus the PSA alone (PPV 44.7%). In addition, if the PBCDR would have been employed, approximately 1,052 negative biopsies would not have been performed. This would have resulted in a substantial decrease in cost for the VA, as well as reduced anxiety for the patient, and a reduced risk of biopsy morbidity (given the biopsies would have never been performed).
Our study was consistent with previous published reports in many ways. The proportion of PC that was localized to the prostate is consistent with the screening stage shift phenomenon (increased amounts of pre-clinical disease are detected), with Stage I comprising 53.9% of all PC cases; Stage II 35.7%; Stage III 7.8%; and Stage IV 2.59% (data not shown).
Secondly, all laboratory biomarkers demonstrated ‘movement’ in the direction away from the ‘normal’ value that is consistent with previous literature and is biologically plausible.15 For instance, the mean PSA value increased from 7.67 (prostatitis) to 44.03 (stage IV PC). Multiple published studies have reported that a low hemoglobin value is an independent risk factor for poor survival outcomes in patients with hormone refractory PC . In addition; the correlation between PC and hematologic disorders has been long recognized for its clinical significance, with anemia a frequent clinical manifestation of advancing PC [9, 11]. In this study, the laboratory parameters HGB, RBC count, and MCV (all indicators of hematologic state) demonstrated values below their normal reference range in patients with clinically relevant PC (stage II-IV). When comparing the subjects with histologically confirmed prostatitis to patients with histologically confirmed stage III PC, the difference becomes evident. HGB decreased from 14.27 to 12.59 (p < 0.05), RBC count decreased from 4.67 to 4.58 (p < 0.05). Lastly, there was an 83% increase in the risk of PC for African American (AA) men when compared to Caucasian men, which is consistent with AA ethnicity as being a major PC risk factor .
Our study has limitations. Men followed by the VA may be subjected to a less or more stringent screening with respect to PC than are other men in the general U.S. population and therefore may not be representative to non-VA healthcare system patient populations. In addition, certain laboratory biomarkers had incomplete data which lead to the exclusion for analysis and interpretation. Although clinicians often obtain a complete blood count (CBC), basic metabolic panel (BMP), and urinalysis (UA) at the time of PSA screening, certain assays (e.g. PT/aPTT, and Folate) are not routinely included in these panels. Both PT and aPTT are used to evaluate the coagulation system, with increasing levels of both being an independent predictor of disseminated intravascular coagulation (a systemic condition seen occasionally with metastatic PC) . A high plasma levels of Folate has been previously reported as both protective and as a risk factor for PC development . Given the plausible links to PC, they warrant further investigation.
Although each prostate biopsy was evaluated by two or more trained pathologists, the possibility that misclassification of disease status (i.e. patients who have PC were classified as ‘no PC’) does exist. Given that the outcome variable (PC yes or no) is determined by the results of a prostate biopsy, and that the biopsies themselves are a sampling of the entire prostate, there is a chance that the biopsy did not contain cancerous cells, yet the prostate itself does. However it is unlikely that an individual would be categorized as having PC if the carcinoma was not present on histological sample. It is more likely that a patient with PC is misclassified as not having PC, which would drive the results towards the Null hypothesis.
Other variables were not available for analysis. Information on PC family history was lacking in patient notes; and family history on any medical condition was available in less than 50% of the study participants. In addition, tobacco, alcohol use, and socio-economic status were unavailable for analysis.
A case–control design was utilized in this study. This type of design was employed as PC cases and suitable comparison subjects were identified and compared with respect to their lab values and prior exposures. While this design provided greater statistical efficiency, the potential for uncontrolled confounding and selection bias exists. Although the PBCDR tool can be used with all ages and PSA values, the lack of prostate biopsies in patients with PSA values below 4.0 ng/dl limits evaluating the effectiveness of the PBCDR in this important group.
Despite these limitations, our study has important strengths. This study was completed on a robust sample population (1,378 subjects, of which 616 had PC), and this high proportion of cases increases overall study power and statistical efficiency. This increased study power afforded us the opportunity to stratify on key parameters, such as PC stage and ethnicity. The results are biologically plausible and consistent with existing knowledge. It is accepted that there is a relationship between PC and systemic diseases that occur in the presence of both local and metastatic spread of PC . Moreover, it has been demonstrated that the specified laboratory biomarkers evaluated in this study are highly correlated with the systemic diseases related to PC spread .
Men with PC have been described as falling into one of four groups, and screening can only really benefit one. The first group consists of men with normally progressing disease that is identified clinically; the second group includes men with PC that advances very rapidly. For the above two groups, screening is of little benefit. The third group contains men with screen-detected PC that would have never advanced to clinically relevant disease; therefore they are exposed to unnecessary procedures and treatments. Lastly, group four contains asymptomatic men who have PC identified through screening and receive beneficial outcomes that otherwise would have been deprived if not for the screening . One difficulty in PC screening is identifying group 4 relative to group 3. The results of this study suggest that the PBCDR might improve our ability to detect PC while also decreasing the number of prostate biopsies. Moreover, the PBCDR seems to be more accurate with PC stages II-IV, providing a novel, simple to implement, inexpensive tool that has the potential to separate more severe PC from indolent PC. This has important implications, especially if PSA is used as a cost effective PC screening program. The overlap of PSA values in men with PC and non-cancerous prostate conditions has been well documented. A thorough physical exam with DRE is the mainstay of PC detection, and a patient’s life expectancy and co-morbidities should be considered when developing a unique treatment course of action. However this study provides a glimpse of the potential benefit that these additional lab parameters can provide.
In conclusion, our study results suggest that evaluating certain biomarkers in conjunction with PSA may improve PC prediction prior to biopsy. Moreover, the biomarkers may be more helpful in detecting clinically relevant PC. Follow-up studies should begin with replicating this study on different U.S. VA patient populations, involving multiple practices, capturing PC family history, and evaluating other biomarkers (such as PSA values lower than 4.0 ng/dl, PT/aPTT and folate) that may assist in improving PC screening efficiency.