Prostate cancer is a highly heterogeneous disease with different patients exhibiting a widely varying natural history. Cancers that escape primary treatment to recur at the site of the prostate or to metastasise throughout the body, inevitably prove to be lethal regardless of further treatment.
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This treatment ineffectiveness can be attributed in part to the diverse mutational landscapes found in prostate cancers in different patients and also to the growing realisation that there are different clonal populations of prostate cancer within the same patient, each possessing a different series of carcinogenic mutations potentially with different driving factors and differing responses to treatment. For this reason a greater understanding of the driving mutations of an individual’s disease may allow the design of a tailored treatment regimen specifically designed using targeted therapeutics to capitalise on one cancer’s weaknesses.
There are currently a number of programs focusing on increasing the understanding of the mutations that drive cancer. These programs are busily analysing genomic, transcriptomic and epigenetic variation through a range of sequencing technologies and providing valuable data that is becoming more and more widely available for analysis. One recent study of the clinical genomics of advanced prostate cancer, as part of the Stand Up To Cancer program, showed the high degree of genetic variance in prostate cancer but also declared that 50% of patients had an actionable mutation that could be targeted therapeutically.1 Furthermore databases are currently being built to facilitate the study of cancer genomics with data generated by a large number of research groups around the world. One such program, The Cancer Genome Atlas (TCGA), began in 2006 to bring together and standardise DNA, RNA, protein, and epigenetic molecular profiles for all cancer types.2 By the end of 2015, the TCGA Research Network plans to have analysed the genomic, epigenomic, and gene expression profiles of more than 10,000 specimens from more than 25 different tumour types with the aim of identifying novel cancer-specific molecular alterations, molecular alterations that could potentially be antagonised by targeted therapeutics.
This changing research landscape means now more than ever the ability to analyse individual cancers at the genomic levels in time to have a real clinical outcome is becoming closer and closer and one day may dominate the field of oncology. Tempering this enthusiasm however is the knowledge that whilst tumor specimens can now be analysed with unprecedented detail and accuracy the presence of an actionable mutation in a sample population genome does not necessarily signify it is a driver of that tumors growth, ability to metastasize or resist treatment. Separating the’ wheat from the chaff’ in genomics data will remain one of the great challenges in the field for some time to come. Our review looks deeply into the mutational nature of prostate cancer and analyses past efforts to capitalise on targeted molecular therapies in prostate cancer treatment, to highlight both the promise and pitfalls for the future of the field of mutation-directed prostate cancer treatment.
1. Robinson, D. et al. Integrative clinical genomics of advanced prostate cancer. Cell 161, 1215-28 (2015).
2. Cancer Genome Atlas Research, N. et al. The Cancer Genome Atlas Pan-Cancer analysis project. Nat Genet 45, 1113-20 (2013).
Hovens CM, Stuchbery R, Corcoran NM
Department of Surgery, The University of Melbourne, 5th Floor Clinical Sciences Building, Royal Melbourne Hospital, Grattan Street, Parkville, Victoria, Australia.