Intrinsic markers of tumour hypoxia and angiogenesis in localised prostate cancer with respect to the outcome of radical treatment
Roy Vergis1, Catherine Corbishley2, Andrew Norman1, Jaclyn Bartlett1, Sameer Jhavar1, Michael Borre4, Sara Heeboll4, Alan Horwich1, Robert Huddart1, Vincent Khoo3, Ros Eeles1, Colin Cooper1, Matthew Sydes5, David Dearnaley1, Chris Parker1
1Institute of Cancer Research, Sutton, UK, 2St George's Hospital, Tooting, UK, 3Royal Marsden NHS Foundation Trust, Sutton, UK, 4Aarhus University Hospital, Skejby, Denmark, 5MRC, London, UK
Background
The expression of intrinsic markers of tumour hypoxia and angiogenesis are important predictors of outcome in several cancer types, but have been little studied in prostate cancer. We tested the predictive value of intrinsic markers of hypoxia and angiogenesis in localised prostate cancer treated either with radiotherapy or with surgery.
Method
We applied a needle biopsy-tissue microarray technique to study diagnostic samples from men with prostate cancer treated in two randomized controlled trials of radiotherapy dose escalation. Multivariate analysis by Cox proportional hazards was done to assess the relationship between biochemical control and immunohistochemical staining of hypoxia inducible factor-1 alpha (HIF-1 alpha), vascular endothelial growth factor (VEGF) and osteopontin (OPN) expression. The analysis was repeated in a cohort treated by radical prostatectomy.
Results
201 radiotherapy patients, and 289 surgical patients, were included in the analysis of outcome. For patients treated with radiotherapy, staining for VEGF (p=0.008) and HIF-1 alpha (p=0.02) expression, but not OPN (p=0.978), were statistically significant predictors of time to biochemical failure on multivariate analysis, independent of clinical T stage, Gleason score, PSA and radiotherapy dose. For patients treated with surgery, VEGF (p<0.0001), HIF-1 alpha (p<0.0001) and OPN expression (p=0.0005) were each significantly associated with time to biochemical failure on multivariate analysis, independent of pathological T stage, margin status, Gleason score and PSA.
Conclusion
Increased expression of VEGF, HIF-1 alpha, and, for patients treated with surgery, OPN, identifies patients at high risk of biochemical failure who would be suitable for enrolment into trials of treatment intensification.
