2. UroToday Home
  3. Recent Abstracts
  4. Urologic Oncology
  5. Prostate Cancer

Predicting prostate biopsy outcome: Prostate health index (phi) and prostate cancer antigen 3 (PCA3) are useful biomarkers, "Beyond the Abstract," by Matteo Ferro, Dario Bruzzese, Sisto Perdonà, Claudia Mazzarella and Daniela Terracciano

BERKELEY, CA (UroToday.com) - Results of prostate biopsies are currently dichotomized in the presence and absence of cancer.

Biopsy outcomes that are neither benign nor malignant are diagnosed, in most of cases, as high-grade prostatic intraepithelial neoplasia (HGPIN) or atypical small acinar proliferation (ASAP). PSA serum level and DRE are the main tools to select subjects for prostate biopsy,[1] even with assay-dependent variations in PSA [2] and inter-observer variability of DRE.[3] Several studies address this issue and new biomarkers that may improve the detection of PCa have been proposed.[4,5] Among these, prostate health index (phi) and prostate cancer antigen 3 (PCA3) appear extremely promising.[6]

 To date, a head-to-head comparison between phi and PCA3 has yet to be reported. Such comparison could be very interesting in order to establish which is the best test as predictor of biopsy outcome and whether the combination of the two biomarkers improves PCa detection.

Our study was designed in an effort to assess accuracy of phi and PCA3 to predict benign, malignant, and HGPIN diagnosis in men undergoing first biopsy. We enrolled 250 male subjects undergoing first prostate biopsy. Among them, only those meeting eligibility criteria according to the study protocol were ultimately enrolled: age over 50 years, no prior prostate surgery and biopsy, no bacterial, acute, or chronic prostatitis, no use of 5-α reductase inhibitors in the previous six months, PSA values included between 2 and 20 ng/ml, negative digital rectal examination (DRE), availability of serum and urine samples, and corresponding clinical data. Primary aim of the study was to compare the identifying ability of PCa-negative, PCa-positive and HGPIN of Beckman Coulter phi [(p2PSA/fPSA) x √tPSA] and PCA3 score [(PCA3 mRNA/PSA mRNA) x 1000].

We found that %p2PSA, phi and PCA3 were significantly higher and %fPSA was significantly lower in cancer than in non-cancer. Furthermore, statistical analysis indicated that phi values, as %p2PSA and %fPSA, unlike PCA3 score, were significantly different in HGPIN conditions and cancer. PCA3 score was significantly higher in HGPIN than in PCa-negative group. ROC curve analysis showed that %p2PSA, phi and PCA3 outperformed fPSA, %fPSA and p2PSA. Of note, the AUCs of these biomarkers were not significantly different, indicating a comparable ability to discriminate benign from malignant conditions.

A relevant finding of this study was that men with HGPIN show comparable PCA3 scores as men with PCa, differently from phi. These data agree with previous reports showing that the discriminative performance of PCA3 score is lower between HGPIN and PCa.[7,8] Moreover, we found that PCA3 scores were significantly higher in HGPIN than in PCA-negative group. This finding probably reflects early molecular changes in a presumptive premalignant lesion.[9] In addition, HGPIN are strong risk factor for PCa in re-biopsy,[10,11] thus some of our patients diagnosed as HGPIN may actually have PCa. According to a previous report, this result supports the premise that low PCA3 score is a good indicator of benign lesion.[12] To our knowledge, this is the first report indicating the association between phi and HGPIN biopsy outcome. Interestingly, our results are consistent with a recent study showing that the intensity of [-2] pro-PSA staining at immunochemistry progressively increased in benign, HGPIN and neoplastic specimens.[13]

The choice of evaluating HGPIN was made as it represents the only other category of biopsy outcome that may realistically be considered as a pre-malignant condition, according to virtually all available evidence.[14,15]

Despite the strength of a prospective observational study including patients with available data of both phi and PCA3 and with centrally pathological evaluation, our study examined only a small number of cases. Therefore larger studies are needed to address several important questions such as

  1. the comparison of the single biomarker and the usefulness of the “combined” one,
  2. the identification of valuable cut-off values to be used in clinical practice, and
  3. the ability of phi and PCA3 alone or in combination to predict clinically significant PCa.

 

References

  1. Heidenreich A, Bellmunt J, Bolla M, et al. EAU guidelines on prostate cancer. Part 1: screening, diagnosis, and treatment of clinically localised disease. Eur Urol 2011; 59:61-71.
  2. Stephan C, Kramer J, Meyer HA, et al. Different prostate-specific antigen assays give different results on the same blood sample: an obstacle to recommending uniform limits for prostate biopsies. BJU Int 2007; 99:1427-1431.
  3. Gosselaar C, Kranse R, Roobol MJ, Roemeling S, Schroder FH. The interobserver variability of digital rectal examination in a large randomized trial for the screening of prostate cancer. Prostate 2008; 68:985-993.
  4. Evans CP. Identification of molecular targets in urologic oncology. World J Urol 2009; 27:3-8.
  5. Prior C, Guillen-Grima F, Robles JE, et al. Use of a combination of biomarkers in serum and urine to improve detection of prostate cancer. World J Urol; 28:681-686.
  6. Bessede T, Malavaud B. [The new biomarkers of prostate cancer]. Prog Urol 2011; 21 Suppl 2:S63-67.
  7. Haese A, de la Taille A, van Poppel H, et al. Clinical utility of the PCA3 urine assay in European men scheduled for repeat biopsy. Eur Urol 2008; 54:1081-1088.
  8. Morote J, Rigau M, Garcia M, et al. Behavior of the PCA3 gene in the urine of men with high grade prostatic intraepithelial neoplasia. World J Urol 2010; 28:677-680.
  9. Wang R, Chinnaiyan AM, Dunn RL, Wojno KJ, Wei JT. Rational approach to implementation of prostate cancer antigen 3 into clinical care. Cancer 2009; 115:3879-3886.
  10. Epstein JI, Herawi M. Prostate needle biopsies containing prostatic intraepithelial neoplasia or atypical foci suspicious for carcinoma: implications for patient care. J Urol 2006; 175:820-834.
  11. Schlesinger C, Bostwick DG, Iczkowski KA. High-grade prostatic intraepithelial neoplasia and atypical small acinar proliferation: predictive value for cancer in current practice. Am J Surg Pathol 2005; 29:1201-1207.
  12. Klecka J, Holubec L, Pesta M, et al. Differential display code 3 (DD3/PCA3) in prostate cancer diagnosis. Anticancer Res 2010; 30:665-670.
  13. Hull D, Ma J, Singh H, Hossain D, Qian J, Bostwick DG. Precursor of prostate-specific antigen expression in prostatic intraepithelial neoplasia and adenocarcinoma: a study of 90 cases. BJU Int 2009; 104:915-918.
  14. Montironi R, Mazzucchelli R, Lopez-Beltran A, Cheng L, Scarpelli M. Mechanisms of disease: high-grade prostatic intraepithelial neoplasia and other proposed preneoplastic lesions in the prostate. Nat Clin Pract Urol 2007; 4:321-332.
  15. Netto GJ, Epstein JI. Widespread high-grade prostatic intraepithelial neoplasia on prostatic needle biopsy: a significant likelihood of subsequently diagnosed adenocarcinoma. Am J Surg Pathol 2006; 30:1184-1188. 

Written by:

Matteo Ferro, Dario Bruzzese, Sisto Perdonà, Claudia Mazzarella and Daniela Terracciano 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. 

 

Predicting prostate biopsy outcome: Prostate health index (phi) and prostate cancer antigen 3 (PCA3) are useful biomarkers - Abstract

More Information about Beyond the Abstract

 

 


COMMENTS:

 

 

Dr. Ferro:

This is a very interesting article but notably absent are at least three references directly pertinent to this article:

Makarov DV, Isharwal S, Sokoll LJ, Marlow C, Epstein JI, Partin AW, Carter HB, and Veltri RW. proPSA Measurements in Serum and Tissue are Associated with Treatment Necessity Among Men Enrolled in Expectant Management for Prostate Cancer. Clin Cancer Res 2009; 15(23):7316–21.

Isharwal S, Makarov DV, Sokoll L, Landis P, Marlow C, Epstein JI, Partin AW, Carter HB, and Veltri RW: proPSA and diagnostic biopsy tissue DNA content combination improves accuracy to predict the need for prostate cancer treatment among men enrolled in a proactive surveillance program. Urology, 2011; 77(3):763.e1-6.

Tosoian JJ, Loeb S, Isharwal S, Landis P, Elliot DJ, Feng Z, Veltri R, Epstein JI, Partin AW, Trock B, H. Carter B and Sokoll LJ. [-2] proPSA is Associated with Biopsy Reclassification in Men on Active Surveillance for Prostate Cancer. Accepted for J Urology, March, 2012.

Thank you,
Robert W. Veltri