Predicting High-Dose-Rate Brachytherapy Boost Benefit Using Hypoxia and Angiogenesis Gene Expression in Localised Prostate Cancer.

[BACKGROUND] High-dose-rate brachytherapy boost (HDR-BTb) combined with external beam radiotherapy (EBRT) improves biochemical relapse-free survival (bRFS) in localised prostate cancer (PCa) yet ∼21% of patients relapse despite dose escalation. Hypoxia and angiogenesis biomarkers have been linked to treatment outcomes through immunohistochemistry (IHC) but genomic validation at the transcriptomic level remains lacking. This study hypothesised that hypoxia- and angiogenesis-related gene expression profiles could predict clinical benefit from HDR-BTb escalation, refining patient selection.

[METHODS] Whole transcriptome analysis using Clariom S microarrays was conducted within a phase III single-centre randomised controlled trial comparing EBRT alone versus EBRT+HDR-BTb. Primary and secondary endpoints were bRFS, metastasis-free survival (MFS), and overall survival (OS). Expression of CD34, SLC2A1, HIF1A, and SPP1 was evaluated alongside established 28- and 32-gene hypoxia signatures. Composite interaction terms combining high/low gene expression assessed joint biomarker effects. Statistical analyses included log-rank tests and Cox proportional hazards models performed using R (R Core Team, 2024). Differentially expressed genes (DEGs) and pathway enrichment analyses were obtained in EBRT and HDR-BTb patients with or without relapse.

[RESULTS] Eighty-one men (EBRT+HDR-BTb = 39; EBRT = 42) were analysed (median follow-up: 131 months). High HIF1A and CD34 expression were prognostic for worse MFS (P = .01) and bRFS (P = .04), respectively. SPP1 and the 32-gene signature were associated with worse OS (P = .02). Predictive analysis showed HDR-BTb benefit in patients with low HIF1A (P = .004), low SLC2A1 (p = 0.04), low 32-gene scores (p = 0.047), and high CD34 (p = 0.02). A significant SLC2A1-CD34 interaction predicted HDR-BTb benefit (P = .017). In relapsed HDR-BTb patients, nine DEGs were identified and enriched for muscle and immune-related pathways, distinct from the 62 DEGs seen in the EBRT cohort, with no overlap.

[CONCLUSION] Gene expression had limited prognostic value, and relapse DEGs differed by treatment. Low SLC2A1, high CD34, and their interaction predicted HDR-BTb benefit. These findings support biomarker-led stratification using hypoxia-related signatures in PCa.