The Molecular, Immunologic, and Clinicodemographic Landscape of MYC-Amplified Advanced Prostate Cancer

Abstract

Background: MYC is a commonly amplified, potentially targetable gene in prostate cancer (PCa). We sought to define the molecular, immunologic, and clinicodemographic landscape of MYC amplification (MYC_amp) in advanced PCa to establish a rationale for personalized treatment combinations.

Methods: Hybrid capture-based comprehensive genomic profiling (CGP) was performed on PCa tumor samples. MYC_amp = copy number ≥6 (CN). Patients treated between January 2011 and December 2020 were selected from a nationwide deidentified (280 clinics) EHR-derived clinicogenomic database (CGDB).

Results: Of 12,528 hormone-sensitive and castrate-resistant (CRPC) samples, MYC_amp was detected in 10.6% (median CN = 8). MYC_amp was more frequent in men with African versus European ancestry (12.9% vs. 10.2% P = .002), in metastatic vs. primary tissue (15.7% vs. 6.2% P < .001), and enriched in metastatic liver lesions (20.2%), but inversely associated with high microsatellite-instability (0.8% vs. 2.4%, P < .001). MYC CN≥15 was associated with PD-L1 expression (26.1% vs. 9.8%, P = .025). Amplification of AR, RAD21, LYN, CCND1, ZNF703, FGF3/4/19, and FGFR1 was enriched in MYC_amp vs. MYC_wt (all P < .001). In liquid samples with tumor fraction [TF]>0, MYC_amp was detected in 2.0% (28/1,402), and 4.5% (20/445) with TF>20%. In the CGDB, (67 MYC_amp and 658 MYC_wt), patients received similar treatments; most received hormone therapies (35.8% MYC_amp vs. 31.5% MYC_wt) or chemotherapy (37.3% MYC_amp vs. 27.7% MYC_wt) as first therapy after CGP report.

Conclusion: MYC_amp defines a biologically distinct subset of PCa patients and is characterized with multiple proxies of advanced disease. These data suggest that MYC_amp may be prognostic; independent cohorts are needed to validate these findings.

Keywords: Comprehensive genomic profiling; Disparity; Inequity; metastatic prostate cancer; prostate cancer.