Molecular, immunologic, and clinicodemographic landscape of MYC-amplified (MYCamp) advanced prostate cancer (PCa).
Authors: Mahal Brandon Arvin Virgil , Zhang Liangliang , Alshalalfa Mohamed , Graf Ryon , Tukachinsky Hanna , Huang Richard S.P. , McGregor Kimberly , Schrock Alexa Betzig , Venstrom Jeffrey Michael 
Published: June 2021

5041 Background: The MYC oncogene is one of the most commonly amplified genes in PCa, contributes to androgen independent growth, and is potentially targetable. We sought to define the molecular, immunologic, and clinicodemographic landscape of MYCamp in advanced PCa to better understand progression and establish rationale for personalized treatments and combinations. Methods: Hybrid capture-based comprehensive genomic profiling (CGP) was performed on tumor samples from predominantly advanced PCa samples. MYCamp was defined as copy number (CN) ≥6. PD-L1 IHC was performed using Dako 22C3. A subset of patients (pts) with advanced PCa were selected from the Flatiron Health- Foundation Medicine (FM) clinicogenomic database (CGDB), a nationwide de-identified EHR-derived clinical DB linked to FM CGP data for pts treated from 01/2011-12/2020. The de-identified data originated from approximately 280 US cancer clinics (̃800 sites of care). Results: The genomic profiles of 12,528 tissue samples from unique PCa pts (including hormone sensitive and castrate resistant) were evaluated. MYCamp was detected in 10.6%, with a median MYC CN of 8. Median age was 67 years (67 for MYCwt versus 68 for MYCamp). MYCamp occurred at a higher frequency in men with African (N = 190/1,473, 12.9%) versus European (N = 996/9,796, 10.2%) ancestry (P = 0.002), was more frequent in metastatic biopsy sites vs primary (15.7% vs 6.2%, P < 0.001), and was most common in liver mets (20.2%). MYCamp CN > 15 was enriched for PD-L1 positivity (26.1%) compared with MYCwt (9.8%) or MYCamp CN 6-15 (11.5%) (CN > 15 vs wt P = 0.025). In pts with MYCamp vs MYCwt PCa AR, RAD21, PTEN, CCND1, ZNF703, FGF19, FGFR1, and FGF3 each had significantly higher rates of CN changes (all p < 0.001); TP53 mutation was also more common with MYCamp (47.5% vs 39.7%, P < 0.001). MYCamp tumors were less likely to harbor microsatellite instability vs MYCwt (0.8% vs 2.4%, P < 0.001) and had higher tumor mutational burden (median 2.6 vs 1.7 mut/Mb, P < 0.001). In liquid samples with evidence of circulating tumor DNA (compositive tumor fraction [cTF] > 0) from PCa pts MYCamp was detected in 2.0% (28/1,402), and in 4.5% (20/445) with cTF > 20%. Among evaluable PCa pts in the CGDB, (67 MYCamp and 658 MYCwt) MYCamp did not significantly impact treatment decisions, with the majority receiving novel hormone therapies (35.8% MYCamp vs. 31.5% MYCwt) or chemotherapy containing regimens (37.3% MYCamp vs. 27.7% MYCwt) as first therapy after CGP report. Conclusions: Herein, we report the largest analysis to date of molecular, immunologic, and clinicodemographic features of MYCamp advanced PCa. These findings suggest that MYCamp defines a biologically distinct subset of PCa pts for whom personalized combination treatments utilizing targeted and/or immunotherapies may be effective. Independent cohorts are needed to validate these findings.