Cell-Free DNA Genomic Profiling and Its Clinical Implementation in Advanced Prostate Cancer

Simple Summary Prostate cancer (PCa) accounts for the second-highest mortality rate in cancer-associated deaths. Liquid biopsy has great potential to tailor treatment choices in advanced PCa. In this study, we evaluated the utility and diagnostic potential of a custom-designed NGS cfDNA panel based on the AmpliSeq HD Technology in advanced PCa. cfDNA somatic mutations were detected in the majority (71%) of examined advanced PCa patients. The most frequently mutated genes in the PCa cohort of 68 patients (40 metastatic castration-resistant and 28 metastatic hormone-naive PCa) were: TP53, FOXA1, SPOP, PTEN, AR, CTNNB1, RB1, and PIK3CA. AR amplifications were detected in 31% of mCRPC patients. This approach appears to be a straightforward and cost-effective method for detecting clinically relevant somatic mutations in cfDNA to aid in clinical decision-making.Abstract Most men with prostate cancer (PCa), despite potentially curable localized disease at initial diagnosis, progress to metastatic disease. Despite numerous treatment options, choosing the optimal treatment for individual patients remains challenging. Biomarkers guiding treatment sequences in an advanced setting are lacking. To estimate the diagnostic potential of liquid biopsies in guiding personalized treatment of PCa, we evaluated the utility of a custom-targeted next-generation sequencing (NGS) panel based on the AmpliSeq HD Technology. Ultra-deep sequencing on plasma circulating free DNA (cfDNA) samples of 40 metastatic castration-resistant PCa (mCRPC) and 28 metastatic hormone-naive PCa (mCSPC) was performed. CfDNA somatic mutations were detected in 48/68 (71%) patients. Of those 68 patients, 42 had matched tumor and cfDNA samples. In 21/42 (50%) patients, mutations from the primary tumor tissue were detected in the plasma cfDNA. In 7/42 (17%) patients, mutations found in the primary tumor were not detected in the cfDNA. Mutations from primary tumors were detected in all tested mCRPC patients (17/17), but only in 4/11 with mCSPC. AR amplifications were detected in 12/39 (31%) mCRPC patients. These results indicate that our targeted NGS approach has high sensitivity and specificity for detecting clinically relevant mutations in PCa.