Authors Severi G, FitzGerald LM, Muller DC, Pedersen J, Longano A, Southey MC, Hopper JL, English DR, Giles GG, Mills J
Review Date July 2014
Citation Cancer Medicine 2014: Jun 7; doi: 10.1002/cam4.281 [Epub ahead of print]
With the widespread use of PSA testing, many diagnosed prostate cancers are localised (within the prostate gland) and may be slow growing and not lead to metastases or death from prostate cancer. However, it is difficult to determine which cancers are indolent and which may need aggressive treatment; current prognostic algorithms have limited predictive power. There is a good deal of research into additional tissue biomarkers that may improve prognostic models and help with treatment decisions; however, as yet none are validated for clinical use.
The aim of this Australian study was to assess whether a panel of biomarkers, associated with a range of disease outcomes in previous studies, could predict death from prostate cancer for men with localised disease, independently of Gleason score and clinical stage.
The authors used a case-only design with men diagnosed with histologically confirmed prostate cancer identified from three epidemiological studies run by Cancer Council Victoria. All studies involved passive follow up of the participants from the date of diagnosis via linkage to the Victorian Registry of Births, Deaths and Marriages and the National Death Index. For the purpose of this study ‘cases’ were defined as those with localised disease and a prostate cancer specific cause of death, as determined by expert review. For each case two men who had not died of prostate cancer, and had survived at least as long as the corresponding case, were randomly selected (using incidence density sampling and matched for Gleason score) as controls or ‘referents’. Diagnostic tissue was retrieved to assess expression of the biomarkers AZGP1, MUC1, NKX3.1, p53 and PTEN by semiquantitative immunohistochemistry (IHC). Poisson regression was used to estimate mortality rate ratios (MRRs) adjusted for age, Gleason score and stage, and to estimate survival probabilities.
Attempts were made to retrieve diagnostic archival tissues from 102 cases and 254 referents but material (mostly ‘cores’ obtained by TRUS needle biopsy) was found for only 83 cases and 232 referents. Median time from diagnosis to death from prostate cancer was 4.4 years (IQR 2.8-6.4 years).
Expression of two biomarkers was associated with increased prostate cancer mortality: MUC1 (MRR=2.51, 95% CI 1.14–5.54, P = 0.02) and p53 (MRR=3.08, 95% CI 1.41–6.95, P = 0.005). On the other hand, AZGP1 expression was associated with decreased mortality (MRR 0.44, 95% CI 0.20–0.96, P = 0.04). Analyzing all markers under a combined model indicated that the three markers were independent predictors of prostate cancer death and survival.
5-year survival probabilities differed across marker expression categories, ranging from 0.90 (95% CI 0.61–0.97) for tumors expressing only AZGP1 to 0.36 (95% CI 0.05–0.71) for tumors expressing MUC1 and p53 but not AZGP1. For men with Gleason score 6 and clinical stage T1c tumors, 5-year survival probability was higher than 0.98 for tumors expressing AZGP1 only or AZGP1 and MUC1, while it was 0.86 (95% CI 0.54–0.97) for tumors expressing MUC1 and p53 but not AZGP1.
The authors concluded that the assessment of the biomarkers AZGP1, MUC1, and p53 expression in diagnostic tissue by IHC has the potential to improve estimates of risk of dying from prostate cancer based only on Gleason score and clinical stage, for men with localised disease at diagnosis.
Points to Note
- Given the serious side effects of prostate cancer treatments, the ability to discriminate potentially fatal prostate cancers from those that are unlikely to cause cancer-specific death is important but has proved to be difficult: biomarkers may help to improve prognostic models.
- The study showed MUC1 and p53 expression to be associated with increased risk of prostate cancer death in men with localised disease, while AZGP1 expression was associated with a lower mortality risk.
- Although PTEN was not found to be useful in this study, the authors acknowledge that the confidence intervals were wide and the data not conclusive; other studies have shown loss of PTEN expression in clinically localised tumours to be associated with mortality in low risk patients but not high risk patients.
- Strengths of the study were: a relatively large number of men who died from prostate cancer; assessing several biomarkers simultaneously; focusing on localised prostate cancer; use of standard diagnostic tissue and standardised IHC techniques.
- Limitations of the study included: PSA level at diagnosis was not available; the only information on treatment was whether radical prostatectomy had been done; a validation set was not available to validate the biomarker panel.
- However, if validated, a panel of markers including AZGP1, MUC1 and p53 may be useful in clinical settings to help make informed decisions about treatment following a diagnosis of localised prostate cancer.