Background: BC and CRC are heterogeneous diseases with several distinct disease subtypes. A 50-gene qPCR assay (PAM50) identifies 5 intrinsic biological subtypes: luminal A, luminal B, HER2-enriched, basal-like, and normal-like in breast cancer. Consensus molecular subtype in CRC (CMS) identifies 4 subtypes: CMS1-4. PC can be classified by specific genomic rearrangements, such as the TMPRSS2-ERG fusion occur or whether specific mutations such as SPOP and FOXA1 or germline BRCA is present, yet 25% of PC remains difficult to classify based on molecular drivers. We used comprehensive genomic and transcriptomic data to determine the association of somatic and germline mutations in molecular PC subtypes using the CMS and 50-gene breast cancer classifiers. Methods: Retrospective analysis on Whole exome (WES) DNA tumor and paired germline and matched deep whole transcriptomic sequencing (RNA-Seq) (∼200x106reads per tumor) data from NantHealth was performed. BC Intrinsic Subtypes and CMS sorting based on RNAseq assay was used to classify PC into 5 BC subtypes and CMS 1-4. Results: 90 PC patients were classifiable using RNAseq and WES DNA. BC subtype distribution was 64.4% Luminal A, 31.1% Luminal B, 2.2% HER2-enriched, 2.2% normal-like, and 0 classified as Basal-like. The CMS subtype distribution was 83.3% CMS4, 15.6% CM1, 1.1% CMS3, and 0 CMS2. Overlap comparison revealed that almost all LumA are CMS4 (56/58, 96.6%) and CMS1 are LumB (11/14, 78.6%). Analysis of germline DDR mutations in LumB compared to LumA showed LumB has significantly more DDR mutants than LumA (OR 2.68, p = 0.035 one-sided Fishers exact test). Conclusions: PC molecularly profiled using 50-gene and CMS classification we found LumA subtype as the predominant subgroup characterized by low TMB and high CMS4. LumB was characterized as higher TMB and greater CMS1 suggesting potential immunotherapy eligibility in this subtype. The presence of potentially pathogenic germline variants in DDR genes is associated with subsequent somatic increase in TMB, however, somatic expression subtyping (by BC or CRC types) is a stronger indicator of TMB than germline pPV in DDR genes.

Citation Format: Jacob J Adashek, Sumanta K Pal, Saihitha Veerapaneni, Elias Obeid, Christopher W Szeto, Sandeep K Reddy, Roberto Nussenzveig, Neeraj Agarwal. 50 gene breast cancer (BC) RNA subtype classifier and colorectal cancer (CRC) CMS subtype classifier applied to 90 prostate cancer (PC) patients reveals distinct subtype differences [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr B093. doi:10.1158/1535-7163.TARG-19-B093