Genotype-to-Phenotype Associations in the Aggressive Variant Prostate Cancer Molecular Profile (AVPC-m) Components

Simple Summary We treat prostate cancer like it is one disease, but it is clear that it behaves like different diseases in different patients, with some having excellent responses to hormonal therapies and prolonged survivals, and others having virulent, aggressive courses and short survivals. These differences reflect different tumor biologies and therapeutic sensitivities, but the absence of molecular markers that identify each of these subsets makes it difficult to develop treatments specific to each. We found that alterations in two or more of the tumor suppressors TP53, RB1 and PTEN characterize the more virulent prostate cancers, and that patients with this molecular profile (called the aggressive variant prostate cancer molecular profile) appear to benefit more from combination chemotherapies than those without. The alterations in these markers can be determined either by staining tumor tissues or by examining their DNA. In this study, we used 28 mouse models of the human disease to assess the performance of various assays in determining these alterations. We found that although both staining and DNA sequencing are complementary, staining (which is a broadly available technique) is likely sufficient to make these determinations. Our results will inform the use of this molecular signature in clinical research and clinical practice. The aggressive variant prostate cancer molecular profile (AVPC-m), composed of combined defects in TP53, RB1 and PTEN, characterizes a subset of prostate cancers linked to androgen indifference and platinum sensitivity. To contribute to the optimization of the AVPC-m assessment for inclusion in prospective clinical trials, we investigated the status of the AVPC-m components in 28 patient tumor-derived xenografts (PDXs) developed at MDACC. We subjected single formalin-fixed, paraffin-embedded (FFPE) blocks from each PDX to immunohistochemistry (IHC), targeted next-generation genomic sequencing (NGS) and Clariom-S Affymetrix human microarray expression profiling. Standard validated IHC assays and a 10% labeling index cutoff resulted in high reproducibility across three separate laboratories and three independent readers for all tumor suppressors, as well as strong correlations with loss-of-function transcriptional scores (LOF-TS). Adding intensity assessment to labeling indices strengthened the association between IHC results and LOF-TS for TP53 and RB1, but not for PTEN. For TP53, genomic alterations determined by NGS had slightly higher agreement scores with LOF-TS than aberrant IHC, while for RB1 and PTEN, NGS and IHC determinations resulted in similar agreement scores with LOF-TS. Nonetheless, our results indicate that the AVPC-m components can be assessed reproducibly by IHC using various widely available standardized assays.

Automated summary

Prostate cancer behaves differently in different patients, and understanding the molecular profiles of aggressive variants can inform targeted treatments. Alterations in the tumor suppressors TP53, RB1, and PTEN characterize the more virulent prostate cancers and predict their response to combination chemotherapies. Staining tumor tissues or examining their DNA can determine these molecular profiles.