Abstract B064: Race-related genetic variation and response to secondary hormonal therapy in metastatic castration-resistant prostate cancer

Prostate cancer (PCa) is the most prevalent cancer and third leading cause of cancer death among men in the United States. PCa incidence, aggressiveness and mortality are significantly higher among African Americans (AAs) compared with men of other racial groups. Despite the worse prognosis associated with African ancestry, several recent studies have shown that PCa patients of African ancestry have a better response to certain PCa therapeutic regimens than those of European ancestry. The overall objective of our study is to identify ancestry-related genetic variation that associates with outcomes on abiraterone/prednisone therapy in metastatic castration-resistant prostate cancer (mCRPC). Our central hypothesis is that differences in ancestry-related single nucleotide polymorphisms (SNPs), gene expression and/or metabolites will associate with prostate-specific antigen (PSA) response and time to progression on secondary hormonal therapy in mCRPC patients. Toward our objective, we collected whole blood, archival tumor tissue and serum from 50 self-identified AA and 50 self-identified white patients enrolled in the Abi Race study, a Phase II study of abiraterone/prednisone in AA and white men with mCRPC. To perform ancestral and genome-wide genotyping, we isolated DNA from the whole blood samples collected at baseline and interrogated DNA using the Infinium Multi-Ethnic Global BeadChip (Illumina). Preliminary analysis identified 622 SNPs that associated with PSA progression-free survival on abiraterone or variation in minor allele frequency by ancestry. To perform gene expression profiling, we isolated RNA from archival formalin-fixed, paraffin-embedded PCa tissue and interrogated RNA using a NanoString Custom CodeSet (NanoString Technologies). Preliminary analysis revealed significant race-related differential expression of 30 prostate cancer-related genes. To perform metabolomic profiling, we used fasting serum samples collected at baseline and during treatment and the Biocrates p400 HR Kit (Biocrates Life Sciences AG). From this analysis, we have prioritized four ancestry-related metabolites associated with time to confirmed PSA progression for further study. Future analyses will focus on defining the functional significance of the aforementioned ancestry-related genetic variation using preclinical cancer models and validation of the aforementioned ancestry-related genetic variation in an independent cohort. These findings will further understanding of a