The Quandary of DNA-Based Treatment Assessment in De Novo Metastatic Prostate Cancer in the Era of Precision Oncology

Abstract

Guidelines for genetic testing have been established for multiple tumor types, frequently indicating the most confident molecularly targeted treatment options. However, considering the often-complex presentation of individual cancer patients, in addition to the combinatorial complexity and inherent uncertainties of molecular findings, deriving optimal treatment strategies frequently becomes very challenging. Here, we report a comprehensive analysis of a 68-year-old male with metastatic prostate cancer, encompassing pathology and MRI findings, transcriptomic results, and key genomics findings from whole-exome sequencing, both somatic aberrations and germline variants. We identify multiple somatic aberrations that are known to be enriched in prostate cancer, including a deletion of PTEN and a fusion transcript involving BRCA2. The gene expression patterns in the tumor biopsy were also strikingly similar to prostate tumor samples from TCGA. Furthermore, we detected multiple lines of evidence for homologous recombination repair deficiency (HRD), including a dominant contribution by mutational signature SBS3, which is specifically attributed to HRD. On the basis of the genomic and transcriptomic findings, and in light of the clinical case presentation, we discussed the personalized treatment options that exist for this patient and the various challenges that one faces in the process of translating high-throughput sequencing data towards treatment regimens.