Genomic analysis of cfDNA samples from Black patients with metastatic castration-resistant prostate cancer to explore gene alterations associated with tumor progression and treatment resistance.

Abstract

e17060 Background: Prostate cancer is among the most commonly diagnosed cancers in the United States, accounting for 29% of new cancer diagnoses among men in 2024. While overall treatment outcomes in metastatic castration resistant prostate cancer (mCRPC) continue to improve, outcome disparities in black men continue to persist. To date, characterization of mutations conferring treatment resistance in black men with mCRPC remains limited, particularly studies utilizing minimally invasive plasma-derived cell-free DNA (cfDNA). As such, we sampled cfDNA from black mCRPC patients at various points in their treatment course to characterize genetic shifts and identify candidate genes associated with disease progression and treatment resistance. Methods: Ultra-Low-Pass Whole-Genome Sequencing (ULP-WGS), whole exome sequencing (WES), and prostate-cancer specific custom panel sequencing (CP) were performed on 118 cfDNA samples obtained from 60 black men with mCRPC before, during treatment, and following tumor progression. Genomic analyses were performed, and corresponding findings were compared to those of white men from previous studies. Results: In both WES and CP, progression samples were shown to harbor more copy number variation and mutational diversity than samples obtained before or during treatment. Between the two sequencing platforms, high concordance was observed in coding mutations in established oncogenes such as FOXA1, SPOP, AR and PTEN. Progression samples were enriched in AR, TP53, and KMT2D mutations. Notably, 55% of progression samples demonstrated AR enhancer amplification, but not all of these samples harbored AR gene body amplification. Unsupervised clustering of chromatin accessibility profiles of 377 transcription factor binding sites (TFBSs) revealed four distinct subclusters of patients. Cluster 4 was enriched for mCRPC, had higher tumor fraction and PSA values compared to other clusters, and was defined by higher levels of prostate-related TFBSs such as AR, NKX3-1, and FOXA1. One HSPC sample had low tumor fraction but was grouped into Cluster 4 suggesting that chromatin accessibility can capture tumor aggressiveness better than somatic profiles in a subset of samples. Conclusions: This study characterized genomic shifts in black mCRPC patients, a population understudied in cancer genomics research, throughout their treatment course. We identified genomic alterations potentially associated with tumor progression and treatment resistance, including enrichment of AR, TP53, and KMT2D mutations. Additionally, AR enhancer amplification in progression samples suggests that epigenomic factors influence disease progression in patients with AR-driven mCRPC.