Ancestral characterization of the genomic landscape, comprehensive genomic profiling utilization, and treatment patterns may inform disparities in advanced prostate cancer: A large-scale analysis.
Authors: Sivakumar Smruthy , Lee Jessica Kim , Moore Jay A. , Hopkins Julia , Newberg Justin , Schrock Alexa Betzig , Vince Randy , Franco Idalid Ivy , Seldon Crystal Selesteen , MILLS JENNIFER , Venstrom Jeffrey Michael , Mahal Brandon Arvin Virgil 
Published: June 2021

5003

Background: Prostate cancer (PCa) incidence, mortality, and outcomes vary widely across race/ethnicity. The underlying drivers of these differences are multifactorial, including systemic barriers that lead to wide variation in access to care including genomic and precision medicine. Men of African ancestry (AFR) are particularly underrepresented in genomic and precision medicine studies. Therefore, we sought to comprehensively assess patterns of gene alterations, comprehensive genomic profiling (CGP) utilization, and treatment patterns in a large, diverse advanced PCa cohort. Methods: 11,741 PCa patients with CGP, as part of routine clinical care (Foundation Medicine Inc., FMI) were evaluated for their genomic landscape. Predominant ancestry was inferred using a SNP-based approach (Connelly et al, AACR 2018). Independently, the US-based de-identified Flatiron Health (FH)-FMI clinico-genomic database (CGDB) of 897 evaluable PCa patients was also queried. Clinical characteristics and treatment selections were described for patients who received metastatic or castrate-resistant diagnosis between 1/2011 and 6/2020. Results: The FMI cohort included 1,422 (12%) men of AFR and 9,244 (79%) men of European ancestry (EUR). Median age was lower in AFR compared with EUR men (64 vs. 67, p < 0.001). TP53 and PTEN alterations and TMPRSS2-ERG rearrangements occurred less frequently in AFR than EUR men (35% vs. 43%, 21% vs. 33%, 15% vs. 33% respectively, p < 0.05). In contrast, alterations in SPOP (11.9% vs. 7.3%), CDK12 (10.0% vs. 5.2%), CCND1 (6.0% vs. 3.8%), KMT2D (7.7% vs. 5.1%), HGF (4.1% vs. 2.5%), and MYC (13.4% vs. 10.6%) were enriched in the AFR cohort (p < 0.05). Alteration frequency in BRCA1/2, AR, DNA damage response pathway genes, and actionable genes with therapy implications, were similar across ancestry. Of note, BRAF alterations were slightly enriched in AFR (5.0% vs. 3.2%, p < 0.05). In the CGDB cohort (79 AFR, 762 EUR), AFR men received a median of 2 lines of therapy prior to CGP, compared to 1 line for EUR men. Notably, the proportion of patients receiving immunotherapy and PARPi was similar across ancestry, however AFR men were less likely to receive clinical study drug compared with EUR men (11% vs 30%, p < 0.001), even among men with actionable alterations (1% vs 6%, p < 0.001). Conclusions: To our knowledge, this study encompasses the largest cohort, particularly of AFR men in a genomic study, that defines CGP utilization, the genomic landscape and therapeutic implications of CGP in PCa across ancestry. Overall, there were largely similar rates of actionable gene alterations across ancestry. Notably, AFR men were less likely to receive CGP earlier in their treatment course, and less likely to be treated on clinical trials, which could impact the genomic landscape, outcomes, and ultimately disparities.