Abstract 3507: Race-related genetic variation and response to secondary hormonal therapy in metastatic castration-resistant prostate cancer

Abstract

Abstract Prostate cancer (PCa) is the second most common cancer diagnosed in men globally, after lung cancer. PCa incidence, aggressiveness and mortality are significantly higher among African Americans (AAs) compared with men of other racial/ethnic 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 polymorphic CAG trinucleotide repeats located in the androgen receptor (AR) gene 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 at baseline and archival tumor tissue 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). We identified nine candidate SNPs in genes having previously reported relevance to cancer and/or PCa that were associated with longer time to confirmed PSA progression (TTP) in blacks and shorter TTP in whites. 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 PCa-related genes. To accomplish AR CAG repeat length profiling, we performed PCR using primers flanking the CAG repeat region and utilized a DNA Bioanalyzer to measure the relative nucleotide length. AR CAG repeat lengths varied from 8 to 40 and we are currently investigating the association between length and patient outcomes on abiraterone/prednisone therapy. 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 Allen, Gary Lipton, Alexander B. Sibley, Patrick Healy, Brendon Patierno, Bonnie Lacroix, Steven 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 Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3507.