Stromal androgen receptor regulates the composition of the microenvironment to influence prostate cancer outcome.

Androgen receptor (AR) signaling in stromal cells is important in prostate cancer, yet the mechanisms underpinning stromal AR contribution to disease development and progression remain unclear. Using patient-matched benign and malignant prostate samples, we show a significant association between low AR levels in cancer associated stroma and increased prostate cancer-related death at one, three and five years post-diganosis, and in tissue recombination models with primary prostate cancer cells that low stromal AR decreases castration-induced apoptosis. AR-regulation was found to be different in primary human fibroblasts isolated from adjacent to cancerous and non-cancerous prostate epithelia, and to represent altered activation of myofibroblast pathways involved in cell cycle, adhesion, migration, and the extracellular matrix (ECM). Without AR signaling, the fibroblast-derived ECM loses the capacity to promote attachment of both myofibroblasts and cancer cells, is less able to prevent cell-matrix disruption, and is less likely to impede cancer cell invasion. AR signaling in prostate cancer stroma appears therefore to alter patient outcome by maintaining an ECM microenvironment inhibitory to cancer cell invasion. This paper provides comprehensive insight into AR signaling in the non-epithelial prostate microenvironment, and a resource from which the prognostic and therapeutic implications of stromal AR levels can be further explored.

Comparative analysis of three risk assessment tools in Australian patients with prostate cancer.

UNLABELLED: What's known on the subject? and What does the study add? Prognostic tools, such as the Cancer of the Prostate Risk Assessment (CAPRA) score and the 1998 Kattan and 2006 Stephenson nomograms, predicting biochemical recurrence after radical prostatectomy are widely used for treatment decision making and counselling patients. However, tools derived in certain cohorts tend to perform less well when they are applied to populations that are dissimilar in terms of population or disease characteristics, health systems or treatment practices. Some of the loss in accuracy of a prognostic tool is a consequence of unknown factors and hence the performance of a tool when applied to a different population is unknown and largely unpredictable. This study validates these widely used tools in South Australian patients treated at three public hospitals. All three tools discriminated well according to risk of recurrence in these patients. However, when compared against observed rates of recurrence, it was found that predictions of recurrence varied widely between the three tools, suggesting that their use in counselling patients on such risk may not be appropriate. Interestingly, the oldest of the three tools (Kattan 1998) was the best predictor of absolute risk of recurrence. In the paper, this is linked to later adoption of updated Gleason grading, among other factors. SUMMARY: In many countries, prognostic tools, which draw on the experience of thousands of patients with cancer, are used to predict cancer outcomes, but accuracy varies. This paper compares the accuracy of three widely used tools predicting prostate cancer recurrence after surgery in Australian patients. The results show that all tools were good at predicting which patients were most likely to experience recurrence and which were least. However, prediction of absolute risk varied and the oldest tool was the most accurate. OBJECTIVE: • To compare performance of the CAPRA score and two commonly used risk assessment nomograms, the 1998 Kattan and the 2006 Stephenson, in an untested Australian cohort. PATIENTS AND METHODS: • We present data on 635 men from the South Australian Prostate Cancer Clinical Outcomes Database who underwent radical prostatectomy between January 1996 and May 2009 and had all required variables for predicting biochemical recurrence (BCR). • BCR was defined as prostate-specific antigen ≥ 0.2 ng/mL or secondary treatment for a rising prostate-specific antigen. • Accuracy was evaluated using Harrell's concordance index, plotting calibration curves, and constructing decision analysis curves. RESULTS: • Concordance indices were high for all three tools: 0.791, 0.787 and 0.744 for the 2006 Stephenson nomogram, CAPRA score and 1998 Kattan nomogram respectively. • At 3 years, calibration of the tools (agreement between predicted and observed BCR-free probability) was close to ideal for the 1998 Kattan nomogram, whereas the 2006 Stephenson model underestimated and the CAPRA model overestimated BCR-free probability. • The 1998 Kattan and 2005 CAPRA tools performed better than the 2006 Stephenson nomogram across a wide range of threshold probabilities using decision curve analysis. CONCLUSION: • All three tools discriminate between patients' risk effectively. • Absolute estimates of risk are likely to vary widely between tools, however, suggesting that models should be validated and, if necessary, recalibrated in the population to which they will be applied. • Recent development does not mean a nomogram is more accurate for use in a particular population.

Abnormal PSA tests--delays in referral.

BACKGROUND: The main benefit of prostate specific antigen (PSA) testing is to help detect prostate cancer at an early, curable stage. Delays between the first abnormal PSA test and biopsy can undermine that benefit, but have not yet been studied. We investigated delays before biopsy together with associated PSA increases as an indicator of disease progression. METHODS: We identified 241 patients with a primary care referral because of an elevated PSA result (>4 ng/mL) and no previous prostate biopsy. Prostate specific antigen results and intervals between PSA testing, specialist clinic referral, appointment and biopsy were stratified by age. RESULTS: Median times between first abnormal PSA, referral, consultation and biopsy were modest but associated with increases in PSA. Extended delays (>20 months) between first abnormal PSA and referral occurred in 25% of younger men. A PSA result less than 10 ng/mL was the best predictor of a delay to refer. DISCUSSION: Rising PSA and possible cancer progression during investigation for prostate cancer suggest that prompt care is advisable.