Therapeutic Implications for Intrinsic Phenotype Classification of Metastatic Castration Resistant Prostate Cancer

Metastatic prostate cancers are recognized to exhibit subtypes categorized by underlying genomic alterations and phenotypes largely partitioned by androgen receptor signaling and neuroendocrine activity. In the present study we evaluated a phenotypic classification approach originally developed for subtyping breast carcinomas using the PAM50 gene signature. PAM50 subtypes associated with specific genotypes such as RB1 loss and phenotypes such as small cell/neuroendocrine carcinoma as well as tumor histology including cribriform morphology. In the context of clinical translation, PAM50 classification segregated tumors into groups with distinct druggable targets such as cell surface proteins amenable to antibody-drug-conjugates (ADCs). Classification into Luminal A, Luminal B and Basal tumors associated with time on androgen receptor signaling inhibitors, and responses to taxane chemotherapy. These findings support further clinical investigation of PAM50-based classification for prostate cancer patient stratification in therapeutic studies. RNA sequencing of prostate tumor patient-derived xenograft (PDX) models using Illumina TruSeq Library prep and sequenced on Illumina NovaSeq 6000 or HiSeq 2500.