Looking for a Simplified Diagnostic Model to Identify Potentially Lethal Cases of Prostate Cancer at Initial Diagnosis: An ImGO Pilot Study

SIMPLE SUMMARY: Several genetic anomalies are recurrent in prostate cancer (PC) and allow this disease to be classified into distinct molecular subtypes; however, these anomalies have no predictive role and have limited relevance for clinical practice. Within this pilot study, metastatic castration-resistant PC (mCRPC) and metastatic castration-sensitive PC (mCSPC) were used for identifying and understanding lethal prostate tumor clones, from a genomic point of view. Some elements, such as a high Gleason Score and the presence of a cribriform pattern or intraductal carcinoma were evaluated as phenotypic markers of potentially lethal PC. Our results provide hypothesis-generating data, as the idea of evaluating mCSPC and mCRPC as a phenotypic/biologic model able to be translated in clinical practice. The confirmation of a high incidence of TP53 and BRCA2 mutations in larger trials may find a therapeutic implication through the choice of whether or not to use “more” therapy in respect to “selective” treatments approaches. ABSTRACT: The recurrent genetic anomalies used to classify prostate cancer (PC) into distinct molecular subtypes have limited relevance for clinical practice. In consideration of WHO 2016 histological classification, which includes the introduction of Gleason Score 4 for patients with cribriform component and the definition of intraductal carcinoma as a new entity, a retrospective pilot study was conducted to investigate, by histological review, if there were any variations of Gleason Score and the incidence of intraductal carcinoma and cribriform pattern, intended as “phenotypic” markers of potentially lethal PC, among metastatic castration-sensitive PC (mCSPC) and metastatic castration-resistant PC (mCRPC) samples. Potentially predictive factors were also assessed. Among 125 cases, a variation in the Gleason Score was reported in 26% of cases. A cribriform (36%) or intraductal (2%) pattern was reported in a higher percentage. Of them, a primary Gleason pattern 4 was reported in 80% of cases. All patients with intraductal carcinoma present a BRCA2 mutation, also found in 80% of cases with a cribriform pattern. This pilot study documented some hypothesis-generating data, as the evaluation of de novo mCSPC and mCRPC as phenotypic/biologic model to be translated in clinical practice. A cribriform pattern/intraductal carcinoma might be a marker of potentially lethal PC. The high incidence of TP53 and BRCA2 mutations in de novo mCSPC may also have a therapeutic implication.