An arranged marriage for precision medicine: hypoxia and genomic assays in localized prostate cancer radiotherapy

Abstract

Prostate cancer (CaP) is the most commonly diagnosed malignancy in males in the Western world with one in six males diagnosed in their lifetime. Current clinical prognostication groupings use pathologic Gleason score, pre-treatment prostatic-specific antigen and Union for International Cancer Control-TNM staging to place patients with localized CaP into low-, intermediate-and high-risk categories. These categories represent an increasing risk of biochemical failure and CaP-specific mortality rates, they also reflect the need for increasing treatment intensity and justification for increased side effects. In this article, we point out that 30-50% of patients will still fail image-guided radiotherapy or surgery despite the judicious use of clinical risk categories owing to interpatient heterogeneity in treatment response. To improve treatment individualization, better predictors of prognosis and radiotherapy treatment response are needed to triage patients to bespoke and intensified CaP treatment protocols. These should include the use of pre-treatment genomic tests based on DNA or RNA indices and/or assays that reflect cancer metabolism, such as hypoxia assays, to define patient-specific CaP progression and aggression. More importantly, it is argued that these novel prognostic assays could be even more useful if combined together to drive forward precision cancer medicine for localized CaP.

The usability of a 15-gene hypoxia classifier as a universal hypoxia profile in various cancer cell types

“…There has been an increasing interest in evaluating the hypoxic status in various tissue sites, as for example in prostate cancer [24,25]. A previous study aiming at evaluating the 15-gene hypoxia classifier in patients with loco-regional gastroesophageal cancer did not give a clear answer of the applicability [26].…”

The changing paradigm of tumour response to irradiation

“…Recent studies in primary tumours have, however, identified genomic instability as a driver of disease aggressiveness and treatment failure in both surgical and radiation treatment of prostate cancer. [137][138][139] Furthermore, it appears that patient-specific measurements of tumour hypoxia and genomic instability provide complementary information about clinical outcome, with hypoxia being more or less important in some genomic subgroups than in others, 138 emphasizing the role of the tumour microenvironment.…”

Hypoxia in prostate cancer

“…Oxygen concentration below 10 mm Hg increases the expression of HIF-1 factor and activates many other molecular pathways which ensure the maintenance of basic cellular functions. This complex and dynamic response has massive implications such as increased angiogenesis, transition from aerobic to anaerobic metabolism, the inhibition of apoptosis and activation of growth factors as well as irreversible changes in cell genome [12][13][14].…”