NADiA® ProsVue™ PSA slope is an independent prognostic marker for identifying men at reduced risk of clinical recurrence of prostate cancer after radical prostatectomy, "Beyond the Abstract," by Judd W. Moul, MD

BERKELEY, CA (UroToday.com) - Prostate cancer remains the most prevalent male malignancy in the United States. Over the last 25-year era of PSA screening, the age at diagnosis has decreased with a concomitant increase in the number of younger men diagnosed with early-stage or clinically localized disease.[1, 2] However, we have seen a backlash against early prostate cancer detection programs in the past 2 years. As a direct result, the number of radical prostatectomies (RPs) has declined by 20-25% from greater adoption of active surveillance combined with a reduced number of cases diagnosed as fewer men are being screened by their primary care physicians.[3] As a result of these societal changes, there is a shift towards offering RP more selectively to men with higher-risk disease and signs that the stage migration related to PSA screening is starting to reverse.[4] The net result of these trends is that a higher proportion of men could be at risk for prostate cancer recurrence heralded by a rising serum PSA level post-RP. Aside from these changes, urologists now have access to newer pre-operative molecular biomarkers that detect abnormalities in gene expression using paraffin-embedded prostate tissue from prostate biopsies or specimen obtained by RP. More men and their surgeons are interested in personalized medicine that requires accurate post-RP risk assessment.

Post-RP risk stratification approaches use common adverse pathologic findings (APFs) such as Gleason score, positive surgical margins, extracapsular extension, seminal vesicle invasion and lymph node involvement. Multivariate models (nomograms) incorporating these factors predict the likelihood of BCR but are not suitably generalizable for identifying individual men at high or low risk of clinical recurrence.[5] We developed the NADiA® ProsVue™ assay to personalize post-RP risk assessment in conjunction with traditional AFPs. ProsVue is an in vitro diagnostic assay that determines the least-squares linear slope of 3 NADiA serum PSA (sPSA) results collected between 1.5 and 20 months post-RP. The limit of quantification of the NADiA PSA assay is more than 10-fold lower than commercial PSA methods, and its intra-assay precision is < 9.0%.[6] These features provided a unique opportunity to evaluate PSA kinetics at previously undetectable serum concentrations. Pilot studies led to a hypothesis that a ProsVue result ≤ 2.0 pg/mL/month predicts a reduced risk of developing a clinically recurrent event (CRE) post-RP.

The NADiA ProsVue 510(k) clinical study protocol was prospectively designed and incorporated archived serum samples from 4 institutions. A cohort random sampling of eligible men identified 64 cases and 240 controls. We showed that a ProsVue result ≤ 2.0 pg/mL/month was the most powerful independent predictor of a reduced risk of CRE over a median 11-year followup post-RP. Multivariate Cox regression adjusted for pre-RP sPSA (continuous expression), pathologic Gleason score (binary expression), and pathologic stage (binary expression) showed a HR of 9.8 (95% CI 5.4–17.8) in men with ProsVue results > 2.0 pg/mL/month vs. men with results ≤ 2.0. ProsVue was the strongest independent predictor of clinical progression-free survival (p < 0.0001), and Gleason score was the only other significant predictor (HR 5.4, 95% CI, 2.1–13.8, p = 0.0004).[7] Results of the multivariate analysis appear in the table below.

Covariates in Cox model

CRE (% total)

Multivariate Cox analysis

HR

(95% CI)

P

ProsVue (pg/mL/month)

≤2.0

18/245 (  7.3)

1.0

 

 

>2.0

46/59 (78.0)

9.8

(5.4–17.8)

<0.0001

Pre-RP PSA (continuous)

64/204 (21.1)

1.0

(1.0–1.0)

0.6470

Pathologic
Gleason score

<7

5/140 (  3.6)

1.0

 

 

≥7

59/164 (36.0)

5.4

(2.1–13.8)

0.0004

Final
pathologic stage

pT2a-c

13/170 (  7.6)

1.0

 

 

pT3, pT4

51/134 (38.1)

1.7

(0.9–3.4)

0.1050

Although Cox regression is the superior method for estimating power of a variable to predict a subsequent event, researchers are sometimes interested in using Receiver-Operating Characteristic (ROC) curves to demonstrate the association of a variable with an outcome, irrespective of the time to an event or follow-up. The ProsVue 510(k) study demonstrated excellent predictive power for prostate cancer recurrence, but only minimal ROC analysis was performed to satisfy particulars of FDA review. Therefore, we generated a first model (Full Model) containing all of the covariates in the multivariate Cox regression model used in the study, a second model excluding ProsVue, and a third model with ProsVue expressed as a binary variable alone. We compared the areas under the curves (AUCs) for all 3 models using the method of DeLong[8] and repeated the same steps with ProsVue expressed as a continuous variable. The results of this comparison are summarized in the tables below.

Binary expression of ProsVue

AUC (95% CI)

SE

Clinical recurrences

Full Model

0.924 (0.887–0.962)

0.019

have higher values

Full Model excluding ProsVue

0.830 (0.774–0.885)

0.028

have higher values

ProsVue Only

0.832 (0.775–0.890)

0.029

have higher values

 

 

 

 

Contrast between AUCs

Difference (95% CI)

SE

Z

P value

Full Model vs. ProsVue excluded

0.09 (0.05–0.14)

0.022

4.40

<0.0001

Full Model vs. ProsVue alone

0.09 (0.05–0.14)

0.023

3.97

<0.0001

ProsVue excluded vs. ProsVue alone

0.00 (-0.08–0.08)

0.040

-0.07

0.9453

Continuous expression of ProsVue

AUC (95% CI)

SE

Clinical recurrences

Full Model

0.935 (0.900–0.970)

0.018

have higher values

Full Model excluding ProsVue

0.830 (0.774–0.885)

0.028

have higher values

ProsVue Only

0.906 (0.858–0.955)

0.025

have higher values

 

 

 

 

Contrast between AUCs

Difference (95% CI)

SE

Z

P value

Full Model vs. ProsVue excluded

0.11 (0.06–0.15)

0.024

4.47

<0.0001

Full Model vs. ProsVue alone

0.03 (-0.05–0.07)

0.022

1.34

0.1790

ProsVue excluded vs. ProsVue alone

-0.08 (-0.15–0.00)

0.037

-2.07

0.0381

When ProsVue is expressed as a binary variable, excluding it from the Full Model significantly reduced AUC. By itself, ProsVue is as powerful as the other 3 variables in the Full Model (excluding ProsVue). When ProsVue is expressed as a continuous variable, excluding it from the Full Model also significantly reduced AUC. ProsVue drives the Full Model because there is no difference between the AUC of the Full Model and the AUC of ProsVue alone.

Our manuscript was the first study of a prognostic assay for identifying men at risk of clinical prostate cancer recurrence with >10 years median follow-up. ProsVue was the most powerful indicator of reduced risk of clinical recurrence and added prognostic value to established risk factors. ProsVue testing could possibly reduce healthcare costs by reducing the intensity of follow-up in men identified at a reduced risk for recurrence. Further studies define the role of the assay in risk models and nomograms. A prospective study is underway to determine if a ProsVue result ≤ 2.0 pg/mL/month influences referrals for secondary post-RP treatment in men at pathologic risk of recurrence.

The era of personalized medicine is upon us. Urologists now have a new arsenal of molecular biomarkers, including the NADiA ProsVue assay.  

References:

  1. Jemal A, Tiwari RC, Murray T, et al. Cancer statistics, 2004. CA Cancer J Clin 2004:54:8-29.
  2. Moul JW, Wu H, Sun L, et al. Epidemiology of radical prostatectomy for localized prostate cancer in the era of prostate-specific antigen: An overview of the Department of Defense Center for Prostate Disease Research national database. Surgery 2002;132:213-219.
  3. Cohn JA, Wang CE, Lakeman JC, et al. Primary care physician PSA screening practices before and after the final U.S. Preventive Services Task Force recommendation. Urol Oncol 2013 August 1, pii: S1078-1439(13)00199-3. doi: 10.1016/j.urolonc.2013.04.013. [Epub ahead of print]
  4. Silberstein JL, Vickers AJ, Power NE, et al. Reverse stage shift at a tertiary care center: Escalating risk in men undergoing radical prostatectomy. Cancer 2011;117:4855-4860.
  5. Shariat SF, Kattan MW, Vickers AJ, et al.: Critical review of prostate cancer predictive tools. Future Oncology 2009;5:1555-1584.
  6. McDermed JE, Sanders R, Fait S, et al.: Nucleic acid detection immunoassay for prostate specific antigen based on immuno-PCR methodology. Clin Chem 2012;58:732-740.
  7. Moul JW, Lilja H, Semmes OJ, et al. NADiA ProsVue Prostate-Specific Antigen slope is an independent prognostic marker for identifying men at reduced risk of clinical recurrence of prostate cancer after radical prostatectomy. Urology 2012; 80:1319-1327.
  8. DeLong ER, DeLong DM, Clarke-Pearson DL. Comparing the areas under two or more correlated receiver operating characteristic curves: a nonparametric approach. Biometrics 1988;44:837-845. 

Written by:
Judd W. Moul, MD as part of Beyond the Abstract on UroToday.com. This initiative offers a method of publishing for the professional urology community. Authors are given an opportunity to expand on the circumstances, limitations etc... of their research by referencing the published abstract.

Division of Urologic Surgery and Duke Cancer Institute, Duke University Medical Center, Durham, NC USA

NADiA ProsVue prostate-specific antigen slope is an independent prognostic marker for identifying men at reduced risk of clinical recurrence of prostate cancer after radical prostatectomy - Abstract

More Information about Beyond the Abstract