Prostate cancer biology from clinical prognostic low- to intermediate-risk groups: looking up at the multiple patterns tracking the way forward

This opinion focuses on the management of low- and intermediate-risk prostate cancer (PCa) groups, emphasizing the need for additional prognostic factors beyond existing risk categories. Molecular biology and multiparametric magnetic resonance imaging (mpMRI) applications are still facing challenges or limitations, whereas nomograms, particularly those predicting pelvic lymph node invasion and therefore associating with aggressive biology, could potentially have a prognostic impact on disease progression. We also discuss the impact of the prostate microenvironment, endocrine dependency, and variations in testosterone levels on cancer biology, introducing new concepts such as endogenous testosterone density. In the aging male population, PCa has become a worldwide epidemic issue of considerable magnitude. The European Association of Urology (EAU) and the National Comprehensive Cancer Network (NCCN), the two most important associations dealing with the subject, are yearly forced to update guidelines for addressing appropriate management recommendations to avoid overtreatments that may severely impair the quality of life of patients with relative regrets.1–4 These issues may arise particularly for the low-risk and intermediate-risk PCa groups, as defined by EAU and NCCN, which are not equivalent, generating controversy when dealing with this topic involving heterogeneous sets of patients. Likewise, management options may vary from monitoring strategies up to active treatments including radical prostatectomy and radiation therapy (RT).1,2 Radical prostatectomy is most frequently performed by the robot-assisted approach (robot-assisted radical prostatectomy [RARP]) eventually associated with extended pelvic lymph node dissection (ePLND).1,2 Nevertheless, especially when life is expectantly long, the 10-year risk of dying for PCa could be a serious drawback also for low- and favorable intermediate-risk classes varying from 1.2% to 4.2% in the former and from 2.3% to 4.7% in the latter for treated and untreated patients, respectively.5 So far, further prognostic factors are required to stratify patients beyond the actual subcategories collecting the low- and intermediate-risk PCa groups. Specifically, low-risk PCa group could be divided into very low-risk and low-risk subgroups, while intermediate-risk PCa group includes favorable and unfavorable subgroups.1,2 Although molecular biology on germline variants will help resolve the issue in the future, it still stands far away from daily practice. MpMRI is widely applied in clinical practice, but it still holds limitations including the nonreproducibility when dealing with multicenter studies.1,2,6 Multilevel nomograms are probably required to improve the accuracy of validated prognostic factors (such as early biochemical recurrence, unfavorable tumor grades, and prostate-specific antigen [PSA] doubling time) after primary active treatments including surgery and radiotherapy.7 From this perspective, nomograms predicting pelvic lymph node invasion (PLNI) could have a prognostic potential impact on disease progression for associating with aggressive biology and thus can help for further stratification of patients in the low and intermediate categories. Nevertheless, the topic stands unresolved.7,8 Likewise, this way has been explored for Briganti's 2012 nomogram in an original investigation.9 This investigation shows that Briganti's 2012 nomogram is associated with PCa progression independently by other factors. Briganti's 2012 nomogram probably performs at a multidimensional level, with single variables integrating and interacting with each other, defining aggressive cancer phenotypes, which will progress along disease natural history. Otherwise, an impaired prostate microenvironment may also impact on induction and progression of cancer biology, especially from the low- to intermediate-risk groups. Notably, PCa stands as an endocrine-dependent tumor; accordingly, how variations of endogenous testosterone levels may impact on prostate microenvironment is a topic that has also been explored in this special issue. Testosterone biology is related to body mass index (BMI) and endogenous testosterone density, which is the ratio between endogenous testosterone and prostate volume. Those are subjects unfolding new concepts of the tumor biology, which is still based on total testosterone measurements along the natural history of the disease. This happens just as much as to localized stages as to systemic disease, collecting phases of sensibility as well as resistance to treatments of androgen blockade.10,11 As prospected, multiple patterns involving PCa biology from the low- to intermediate-risk groups are actually ongoing and the subject is continuously in progress. The way forward is to look up at these multiple patterns, interacting and integrating to each other and unfolding new pathways, which will be explored while unfolding the topics collected in the current issue. COMPETING INTERESTS The author declares no competing interests.