BERKELEY, CA (UroToday.com) - Circulating tumor cells (CTC) in prostate cancer represent a new so-called biomarker.
Biomarkers have been widely developed for every cancer, at every stage, for several purposes such as increasing the ability to predict outcome, treatment efficacy, drug toxicity, etc. Biomarkers aim to provide the most accurate treatment/surveillance schedule for prostate cancer patients - giving the appropriate intense treatment for patients with poor prognosis, and the appropriate non-toxic treatment for patients with good prognosis.
The introduction of biomarkers remains very difficult in clinical practice since none are 100% sensitive nor 100% specific for the desired endpoint (outcome, treatment efficacy or drug toxicity), but the more we can rely on them, the more accurate we will be. For example, some patients with low-risk prostate cancer relapse and die from cancer. For these patients, evaluation of the prognosis with the clinical stage, serum PSA and Gleason Score is thus inefficient, meaning that new biomarkers are urgently needed. CTC and even disseminated tumor cells (DTC) detected in the bone marrow, both defined as real-time ‘liquid biopsy’ of the prostate tumor, could be relevant candidates for new biomarkers. Several studies already demonstrated a strong correlation between CTC/DTC and survival (Weckermann D et al., J Clin Oncol 2009). In consequence, in the future, treatment of low-risk patients could depend also on CTC/DTC evaluation. Thus, low-risk patients with a high level of CTC/DTC could be treated like those with intermediate- or high-risk prostate cancer. In this frame, we could imagine a clinical trial randomizing the use of hormonotherapy or not in low-risk patients with a high level of CTC/DTC at baseline and/or after treatment (surgery or radiotherapy).
Another application of biomarkers in prostate cancer was suggested by some authors who proposed the use of the serum PSA level as the primary endpoint, instead of survival, to predict efficacy of a new treatment in randomized trial (Petrylak et al., J Natl Cancer Inst 2006). The idea was to conclude on the superiority of the experimental treatment if the decline in serum PSA was more pronounced, before waiting for the occurrence of death or relapse. In this case, serum PSA is described as a “surrogate marker” of survival. The advantage of this strategy is to dramatically reduce the duration of clinical trials, in particular in localized prostate cancer. In this case, CTC could be a relevant candidate since it is strongly correlated with prognosis - sometimes more than serum PSA level. However, robust methodology is really needed because a correlate does not necessarily mean a surrogate. In the present review, we discuss known criteria (Prentice criteria and others) to establish surrogacy. Even if surrogacy is demonstrated in a retrospective manner, the putative surrogate marker has to be confirmed in a phase III prospective randomized trial. If, up to now, serum PSA level failed to confirm its surrogacy, Scher et al. (ASCO 2011 LBA4517) recently presented very interesting preliminary results of such a strategy to characterize CTC as a surrogate in a phase III trial in metastatic prostate cancer. As expected, it seemed that CTC could be a surrogate biomarker, with some caution regarding correlation with CTC and effect of treatment on survival (one of the Prentice criteria). Surprisingly, the LDH level also seemed to validate criteria of surrogacy, which is a very economical and convenient biomarker. Final data of this trial and surrogacy evaluation are eagerly awaited.
Finally, CTC holds a very promising fundamental potential. These migrating tumor cells can be characterized at the protein (i.e., immunocytochemistry, flow cytometry, EPSIPOT) and molecular (i.e., DNA, mutation analysis, mRNA, microRNA) levels. Such approaches are an intense field of research in the world (Pantel & Alix-Panabières, Trends Mol Med, 2010). Prognosis and surrogacy of CTC/DTC biomarkers may be improved by such additional analyses.
Like other new and expensive biomarkers, such as the mRNA signatures, CTC/DTC detection must be standardized and studied in phase III trials in order to confirm its strong prognostic power and surrogacy. A new biomarker needs to add prognosis information compared to other known prognostic factors, otherwise it will only increase the cost of the treatment. However, we (and many other authors) strongly believe that detection of CTC/DTC will increase the accuracy of the prognosis evaluation, regarding the obvious link between CTC/DTC, metastasis and death of prostate cancer patients.
Written by:
Jérôme Doyen (lead author) and Catherine Alix-Panabières 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.
Circulating tumor cells in prostate cancer: A potential surrogate marker of survival - Abstract
UroToday.com Prostate Cancer Section