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.

Figure 1

Curative and non-curative states in prostate cancer. Localized prostate cancers (CaPs) can be divided into low-, intermediate- and high-risk (including locally advanced) groups using T-category, pre-treatment prostate-specific antigen (PSA) level and the pathologic Gleason score. These groups have increasing probability of CaP-specific mortality. Low-risk tumours can be aggressively followed using active surveillance. By contrast, intermediate-risk tumours are treated with surgery, external beam radiotherapy (EBRT) or brachytherapy. In cases where a local recurrence occurs after surgery, patients can be treated with post-operative EBRT and convert a local failure into a cure. In high-risk CaP, there is an increased probability for occult systemic metastases, therefore systemic androgen deprivation [androgen-deprivation therapy (ADT)] is used in combination with EBRT. Palliative systemic therapy is the mainstay for patients with castrate-resistant disease in the micrometastatic or macrometastatic stages to increase progression-free survival by months. These therapies include additional ADT (including the use of newer agents, such as abiraterone and enzalutamide), chemotherapy, immunotherapy, systemic radionucleotides (RA233) and use of bespoke molecular-targeted agents. It is argued that an understanding of the genomic and microenvironmental factors that lead to occult metastases could drive intensification protocols using systemic agents in the localized CaP setting to improve the cure rates with radiotherapy and surgery. LHRH, luteinizing hormone-releasing hormone; Post-op, post-operative; RA223, radium-223.

Figure 2.

Combining genomics and hypoxia assays to drive personalized prostate cancer medicine. Genomic signatures (DNA, RNA, epigenetic or miRNA-based) could be combined with hypoxia assays (using imaging such as positron emission tomography–fluoroazomycin arabinoside or intrinsic/extrinsic markers in situ) to triage patients with low probability of systemic metastases to local treatment alone and patients with high probability of metastases to local treatment plus systemic treatment (e.g. combined modality therapy). Systemic treatments could include those shown in Figure 1 that are currently used for metastatic disease, hypoxia-specific cytotoxins or novel agents designed to target abnormal signalling or DNA repair pathways based on susceptibility biomarkers. ADT, androgen-deprivation therapy; EBRT, external beam radiotherapy; PARP1, poly(ADP-ribose) polymerase; TIC, tumour initiating cell.