Advancing precision medicine for prostate cancer through genomics

Abstract

Prostate cancer is the most common type of cancer in men and the second leading cause of cancer death in men in the United States. The recent surge of high-throughput sequencing of cancer genomes has supported an expanding molecular classification of prostate cancer. Translation of these basic science studies into clinically valuable biomarkers for diagnosis and prognosis and biomarkers that are predictive for therapy is critical to the development of precision medicine in prostate cancer. We review potential applications aimed at improving screening specificity in prostate cancer and differentiating aggressive versus indolent prostate cancers. Furthermore, we review predictive biomarker candidates involving ETS gene rearrangements, PTEN inactivation, and androgen receptor signaling. These and other putative biomarkers may signify aberrant oncogene pathway activation and provide a rationale for matching patients with molecularly targeted therapies in clinical trials. Lastly, we advocate innovations for clinical trial design to incorporate tumor biopsy and molecular characterization to develop biomarkers and understand mechanisms of resistance.

Fig 1.

Pathway-guided treatment in prostate cancer. This diagram highlights pathways for targeting in prostate cancer, including the phosphatidylinositide 3-kinase (PI3K) pathway, ETS rearrangements, and androgen signaling. Green indicates putative treatment hypotheses for relevant pathways. Each of these pathways can be driven by genomic aberrations, such as point mutations, copy number alterations, and rearrangements. The diagram also highlights less common driving mutations involving RAS, RAF, and AKT oncogenes. Furthermore, there is potential for cooperation between pathways because these are not necessarily mutually exclusive. Genes highlighted in gold have known genomic alterations. AR, androgen receptor; mTOR, mammalian target of rapamycin, PARP, poly (ADP-ribose) polymerase; RTK, receptor tyrosine kinase.

Fig 2.

Translating genomics for prostate cancer trials. This diagram outlines a path to genomics-driven trials in prostate cancer. Patients with advanced prostate cancer would undergo a fresh tumor biopsy for assessment of their current disease and molecular stratification to trials, including random assignment within those groups. Because of the prevalence of phosphatidylinositide 3-kinase (PI3K) pathway activation, ETS rearrangements, and androgen signaling, genomic enrichment of patients for these common disease subsets may follow traditional trial structures including combination treatments. However, for rare or private molecular disease subsets, these patients may be better suited to studies based on molecular aberrations and that include multiple histologies. For all studies, repeat biopsy for genomic assessment will be valuable for evaluating mechanisms of resistance, including tumor subclone selection. AR, androgen receptor; PARP, poly (ADP-ribose) polymerase.