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[82]
borne out in longer-term studies . Moreover, these endpoints represent points of clinical intervention,
which can result in significant, life-long morbidities secondary to salvage therapy and chemical castration.
Thus, given the curative potential of local therapy and the significant adverse effects of long-term salvage
therapy after treatment failure, it is imperative that techniques be developed to better classify risks of treat-
ment relapse in the localized setting. To that end, the potential utility of intrinsic tumour genomics as pre-
dictive or prognostic biomarkers has been explored by several groups.

CNA burden is an established independent prognostic factor for biochemical relapse [58,59] , although recent
evidence suggests that multi-omic profiling may more accurately classify aggressive disease than assessment
[83]
of individual analytes alone . To that end, a novel clinico-genomic signature, based on a CNA (MYC gain),
two aberrantly methylated genomic loci (TCERG1L and ACTL6B), an SNV (ATM), an inter-chromosomal
translocation (chr7:61Mbp), and clinical T stage, dramatically outperformed CNA burden for predicting rap-
[10]
id biochemical relapse in intermediate-risk disease . Moreover, the performance of this signature is further
[9]
enhanced by inclusion of tumour subclonality as a prognostic factor . These signatures compare favourably
[58]
to existing, FDA-approved classifiers based on mRNA abundance , and can be called based on tissue avail-
able in routinely-available, pre-treatment needle core biopsies [9,10,49,58,60] .
Thus, while prospective validation of these biomarkers is required, it appears highly likely that genomic clas-
sifiers will vastly outperform clinical prognostic factors and have the potential to revolutionize treatment
stratification for localized prostate cancer. Most prostate cancers are multi-focal [49,77] , and there is substantial
genomic heterogeneity associated with separate disease foci [49,77,79,84] , including in genes with established
[49]
prognostic value (e.g., MYC gain) . Nevertheless, genomic signatures derived from the largest (index) lesion
[10]
can predict disease aggression with accuracy of at least 85% , far exceeding the performance of established
clinical prognostic factors. As such, whatever the influence of spatial heterogeneity on prognosis, it is largely
accounted for within a single disease focus, although there are clearly cases where this relationship does not
[76]
hold . Thus, the question arises whether enhancements to prognostic signatures based on intrinsic genom-
ics of single loci will further improve biomarker performance- due to inclusion of novel analytes, deeper
profiling of rare variants, or both. It is likely that for a subset of prostate cancers, clinical aggression cannot
[76]
be accurately predicted from the index lesion , and thus profiling of additional foci will be required for ac-
curate triage. One possible solution to this problem is a movement toward the so-called liquid biopsy, which
would reflect the aggregate of all cancer-associated aberrations and thus would, in theory, overcome genomic
heterogeneity. Indeed, extra-prostatic extension can be accurately identified based on proteomic analysis of
[85]
post-digital rectal examination urine , supporting the viability of this approach.

Ultimately, clinical trials are required to validate the ability of these tools to improve treatment outcomes
for localized prostate cancer. One potential model is to provide a “signature score” for all patients; patients
whose signature score portends a favourable clinical outcome would receive standard of care therapy, while
those with adverse signature scores would be randomized to receive either standard of care or intensified
therapy [Figure 2]. While the specific intensification strategies to be employed are beyond the scope of this
review, they may involve additional therapies that are already approved for treatment of localized prostate
cancer. For example, a man with intermediate risk disease who would ordinarily be treated with IGRT alone
might instead receive radiotherapy plus neoadjuvant androgen deprivation.

CONCLUSION
The rapid improvement of second-generation sequencing technologies - and the concomitant reduction in
sequencing prices - have dramatically improved our understanding of the molecular underpinnings of pros-
tate cancer. Indeed, in the next 2-3 years, it is anticipated that discovery of somatic driver mutations in local-
ized prostate cancer will saturate at the 0.5%-1% recurrence level. Unfortunately, very little of the currently-