The Role of PCA 3 as a Prognostic Factor in Patients with Castration-resistant Prostate Cancer (CRPC) Treated with Docetaxel

Discussion

Early efforts to identify the influence of medical intervention on PCA 3 scores have produced equivocal results. In their pilot study, van Gils et al. investigated the effect of dutasteride on the PCA3 score to find a variable and unpredictable response, albeit in a small, mixed cohort of patients with benign prostatic hyperplasia and localized prostate cancer (13). The only other study to date that investigated the prospective role of PCA 3 as a prognostic marker for advanced disease and treatment response was The Triptocare study. It consists of a prospective, open-label, multicentre, single-arm phase III study of triptorelin 22.5 mg in men with locally advanced and/or metastatic disease who were previously naive to ADT and results were recently published (14). The study assessed PCA 3 and TMPRSSG-ERG scores at baseline and after 1, 2 and 6 months of treatment with triptorelin. In a population of 322 patients, 39 (12.1%) had non-assessable PCA3 at baseline. The frequency of non-assessable PCA 3 increased with time on androgen deprivation, namely 109 patients at 1 month (33.9%), 215 patients (68.7%) at 3 months and 232 patients (77.9%) at 6 months of treatment. Of great interest is the finding of the proportion of hormone-naive individuals who never expressed PCA 3 at baseline (n=39, 12.1%). This sub-group was not further investigated, however, as it was not part of the initial objective. As the majority of these patients had a Gleason score of equal or greater than 8, the paucity of PCA 3 detection could be attributed to higher grade and/or more advanced disease. In their assessment of PCA 3 expression in radical prostatectomy specimens, Robert et al. have demonstrated lower PCA 3 scores in high-grade cancers (15). Furthermore, high Gleason score at baseline was the only factor significantly correlating to non-assessability of PCA 3 at 6 months in the Triptocare study (14). On the other hand, the investigators also point-out that in the remainder of the study group, lower PCA 3 scores expression correlated significantly with higher baseline PSA values (>200 ng/ml). This is somewhat contradictory, as it was shown in the early research by Partin et al. that patients with advanced disease and higher grade and volume tumors are more likely to produce less PSA per gram tissue as a consequence of decreased differentiation (16).

The disruption of prostatic architecture in higher-grade tumors has also been postulated as an explanation for low PCA 3 scores. The loss of glandular pattern in higher Gleason score cancer leads to obliteration of the ducts and lumen, thus making it difficult to disseminate prostatic cells in the urine in order to achieve a measurable result (17). Histopathological changes in hormonally treated prostate cancer cells are mainly characterized by cellular shrinkage with little cytoplasm that translates to glandular shrinkage and an overall reduction in size. DRE in these patients often reveals a small, hard prostate. However, this hypothesis is contradicted by the fact that, although PCA 3 score was not assessable, prostate cells were identified in the urine of all patients in our study suggesting a molecular rather than a mechanical mechanism.

According to our findings, another possible mechanism would be an ablative effect of androgen deprivation to PCA 3 expression, something also shown in the Triptocare study. Continuation of ADT in CRPC patients throughout the chemotherapeutic period constitutes common practice and probably relates better to our results than any effect of docetaxel treatment. In our study, PCA 3 was non assessable both at baseline and at 12 months follow-up after the completion of chemotherapy. Based on the above findings, further research is required to answer the questions of the true nature of PCA 3 mRNA in prostate cancer molecular pathogenesis pathways and its expression during the various stages of progression. The Triptocare investigators point out, in addition, that hormone-naive patients with metastases produced significantly lower PCA 3 scores than men without metastases(14) In our study of exclusively metastatic patients, non-assessable PCA 3 score was the rule, which substantiates further the hypothesis of declining PCA 3 expression with ADT and advancing disease.

In both studies, PCA 3 score failed to prove as a marker for disease prognostication and treatment response. Nevertheless, paucity of PCA 3 expression with ADT has never been demonstrated previously and this discovery may have yet to reveal its full potential. In retrospect, the evident gradual decrease in PCA 3 score detection with ongoing ADT and the eventual complete non-assessability demonstrated in our cohort appear to be sequential events. The EFFECT trial is another prospective open label, single arm, multicentre trial that is currently ongoing and investigates the effect of leuprorelin acetate at 6 months on PSA, PCA 3 and TMPRSS2-ERG-mRNA amongst other markers. In our cohort, 8 patients received goserelin acetate, 5 patients leuprorelin acetate, 3 patients triptorelin previously and continued throughout chemotherapy. The trial aims to recruit 50 patients and compare testosterone and PSA with the newer biomarkers to provide more evidence and much needed answers in the field of advanced prostatic malignancy (18).