Genome-Based Classification and Therapy of Prostate Cancer

Abstract

In the past decade, multi-national and multi-center efforts were launched to sequence prostate cancer genomes, transcriptomes, and epigenomes with the aim of discovering the molecular underpinnings of tumorigenesis, cancer progression, and therapy resistance. Multiple biological markers and pathways have been discovered to be tumor drivers, and a molecular classification of prostate cancer is emerging. Here, we highlight crucial findings of these genome-sequencing projects in localized and advanced disease. We recapitulate the utility and limitations of current clinical practices to diagnosis, prognosis, and therapy, and we provide examples of insights generated by the molecular profiling of tumors. Novel treatment concepts based on these molecular alterations are currently being addressed in clinical trials and will lead to an enhanced implementation of precision medicine strategies.

Keywords: copy number alterations; genomics; molecular markers; mutations; patient stratification; precision medicine; prostate cancer.

Figure 1

Characteristic molecular alterations in different stages of prostate cancer. Inactivation is markedly observed in castration-resistant (CR) * and neuroendocrine (NE) ** tumors. ^† Genetic alterations in the DNA damage repair pathways are increased in CR but are almost absent in NE tumors. AR = androgen receptor; LBD = ligand binding domain.

Figure 2

Management options with selected therapeutic agents for localized and advanced prostate cancer. Purple bars denote treatments with regulatory approval; green bars denote therapeutic agents in clinical trials. PCa = prostate cancer; CRPC = castrate-resistant PCa; mCRPC = metastatic CRPC; NEPC = neuroendocrine PCa; MRI = magnetic resonance imaging; US = ultrasound; PET/CT = positron emission tomography/computed tomography; BETi = BET inhibition; PARPi = PARP inhibition; EZH2i = EZH2 inhibition; PD-1i = PD-1 inhibition; and PRRT = peptide receptor radionuclide therapy.