Abstract B064: Race-related genetic variation and response to secondary hormonal therapy in metastatic castration-resistant prostate cancer
Authors: Allen Tyler A , Lipton Gary , Sibley Alexander B , Healy Patrick , Patierno Brendon M , Lacroix Bonnie , Patierno Steven R , Owzar Kouros , Hyslop Terry , George Daniel J , Freedman Jennifer A 
Published: September 2020

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 ancestry-related biological factors that influence response to secondary hormonal therapy in mCRPC and could have direct implications for the timing and selection of AA patients for secondary hormonal therapy and those needing additional therapy. As secondary hormonal therapy use expands to earlier disease settings, these findings could support the need for further studies in AA men in these disease settings. Ultimately, such strategies have the potential to mitigate PCa disparity.

Citation Format: Tyler A Allen, Gary Lipton, Alexander B Sibley, Patrick Healy, Brendon M Patierno, Bonnie Lacroix, Steven R Patierno, Kouros Owzar, Terry Hyslop, Daniel J George, Jennifer A Freedman. Race-related genetic variation and response to secondary hormonal therapy in metastatic castration-resistant prostate cancer [abstract]. In: Proceedings of the Twelfth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2019 Sep 20-23; San Francisco, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl_2):Abstract nr B064.