Z. H. Yang

Prognostic value of PTEN loss in men with conservatively managed localised prostate cancer

Background:The natural history of prostate cancer is highly variable and difficult to predict. We report on the prognostic value of phosphatase and tensin homologue (PTEN) loss in a cohort of 675 men with conservatively managed prostate cancer diagnosed by transurethral resection of the prostate.Methods:The PTEN status was assayed by immunohistochemistry (PTEN IHC) and fluorescent in situ hybridisation (PTEN FISH). The primary end point was death from prostate cancer.Results:The PTEN IHC loss was observed in 18% cases. This was significantly associated with prostate cancer death in univariate analysis (hazard ratio (HR)=3.51; 95% CI 2.60–4.73; P=3.1 × 10−14). It was highly predictive of prostate cancer death in the 50% of patients with a low risk score based on Gleason score, PSA, Ki-67 and extent of disease (HR=7.4; 95% CI 2.2–24.6; P=0.012) ), but had no prognostic value in the higher risk patients. The PTEN FISH loss was only weakly associated with PTEN IHC loss (κ=0.5). Both PTEN FISH loss and amplification were univariately predictive of death from prostate cancer, but this was not maintained in the multivariate analyses.Conclusion:In low-risk patients, PTEN IHC loss adds prognostic value to Gleason score, PSA, Ki-67 and extent of disease.

Prognostic value of Ki-67 for prostate cancer death in a conservatively managed cohort

Background:Standard clinical parameters cannot accurately differentiate indolent from aggressive prostate cancer. Our previous work showed that immunohistochemical (IHC) Ki-67 improved prediction of prostate cancer death in a cohort of conservatively treated clinically localised prostate cancers diagnosed by transurethral resection of the prostate (TURP). Here, we present results in a more clinically relevant needle biopsy cohort.Methods:Biopsy specimens were microarrayed. The percentage of Ki-67 positively stained malignant cells per core was measured and the maximum score per individual used in analysis of time to death from prostate cancer using a Cox proportional hazards model.Results:In univariate analysis (n=293), the hazard ratio (HR) (95% confidence intervals) for dichotomous Ki-67 (⩽10%, >10%) was 3.42 (1.76, 6.62) χ2 (1 df)=9.8, P=0.002. In multivariate analysis, Ki-67 added significant predictive information to that provided by Gleason score and prostate-specific antigen (HR=2.78 (1.42, 5.46), χ2 (1 df)=7.0, P=0.008).Conclusion:The IHC Ki-67 scoring on prostate needle biopsies is practicable and yielded significant prognostic information. It was less informative than in the previous TURP cohort where tumour samples were larger and more comprehensive, but in more contemporary cohorts with larger numbers of biopsies per patient, Ki-67 may prove a more powerful biomarker.

Validation of an RNA cell cycle progression score for predicting death from prostate cancer in a conservatively managed needle biopsy cohort

Background:The natural history of prostate cancer is highly variable and difficult to predict accurately. Better markers are needed to guide management and avoid unnecessary treatment. In this study, we validate the prognostic value of a cell cycle progression score (CCP score) independently and in a prespecified linear combination with standard clinical variables, that is, a clinical-cell-cycle-risk (CCR) score.Methods:Paraffin sections from 761 men with clinically localized prostate cancer diagnosed by needle biopsy and managed conservatively in the United Kingdom, mostly between 2000 and 2003. The primary end point was prostate cancer death. Clinical variables consisted of centrally reviewed Gleason score, baseline PSA level, age, clinical stage, and extent of disease; these were combined into a single predefined risk assessment (CAPRA) score. Full data were available for 585 men who formed a fully independent validation cohort.Results:In univariate analysis, the CCP score hazard ratio was 2.08 (95% CI (1.76, 2.46), P<10−13) for one unit change of the score. In multivariate analysis including CAPRA, the CCP score hazard ratio was 1.76 (95% CI (1.44, 2.14), P<10−6). The predefined CCR score was highly predictive, hazard ratio 2.17 (95% CI (1.83, 2.57), χ2=89.0, P<10−20) and captured virtually all available prognostic information.Conclusions:The CCP score provides significant pretreatment prognostic information that cannot be provided by clinical variables and is useful for determining which patients can be safely managed conservatively, avoiding radical treatment.

Mir143 expression inversely correlates with nuclear ERK5 immunoreactivity in clinical prostate cancer.

Background:Aberrant mitogen/extracellular signal-regulated kinase 5 (MEK5)–extracellular signal-regulated protein kinase 5 (ERK5)-mediated signalling has been implicated in a number of tumour types including prostate cancer (CaP). The mechanism for ERK5 activation in CaP remains to be fully elucidated. Studies have recently implicated the role of microRNA (miRNA) mir143 expression in the regulation of ERK5 expression.Methods:We utilised a tissue microarray (TMA) of 530 CaP cores from 168 individual patients and stained for both mir143 and ERK5. These TMAs were scored by a combination of observer and automated methods.Results:We observed a strong inverse relation between ERK5 and mir143, which manifested itself most strongly in the subgroup of 417 cores with non-zero mir143 and ERK5 immunoreactivity, or with only one of mir143 or ERK5 being zero (cc=0.2558 and P<0.0001). Mir143 neither correlate with Gleason scores or prostate-specific antigen levels, nor was it a predictor of disease-specific survival on univariate analysis.Conclusion:Although the mechanism for ERK5 activation in CaP remains to be fully elucidated, we have further validated the potential role of mir143 in regulating ERK5 levels in the clinical context. In addition, we demonstrate that the automated counting method for nuclear ERK5 is a clinically useful alterative to observer counting method in patient stratification in the context of ERK5 targeting therapy.

Focal amplification of the androgen receptor gene in hormone-naive human prostate cancer

Background:Androgen receptor (AR)-gene amplification, found in 20–30% of castration-resistant prostate cancer (CRPCa) is proposed to develop as a consequence of hormone-deprivation therapy and be a prime cause of treatment failure. Here we investigate AR-gene amplification in cancers before hormone deprivation therapy.Methods:A tissue microarray (TMA) series of 596 hormone-naive prostate cancers (HNPCas) was screened for chromosome X and AR-gene locus-specific copy number alterations using four-colour fluorescence in situ hybridisation.Results:Both high level gain in chromosome X (⩾4 fold; n=4, 0.7%) and locus-specific amplification of the AR-gene (n=6, 1%) were detected at low frequencies in HNPCa TMAs. Fluorescence in situ hybridisation mapping whole sections taken from the original HNPCa specimen blocks demonstrated that AR-gene amplifications exist in small foci of cells (⩽600 nm, ⩽1% of tumour volume). Patients with AR gene-locus-specific copy number gains had poorer prostate cancer-specific survival.Conclusion:Small clonal foci of cancer containing high level gain of the androgen receptor (AR)-gene develop before hormone deprivation therapy. Their small size makes detection by TMA inefficient and suggests a higher prevalence than that reported herein. It is hypothesised that a large proportion of AR-amplified CRPCa could pre-date hormone deprivation therapy and that these patients would potentially benefit from early total androgen ablation.

Concurrence of Multiple Human Papillomavirus Infections in a Large US Population-based Cohort

We examined the concurrence of multiple human papillomavirus (HPV) infections in 47,617 women who underwent cervical screening in New Mexico between December 2007 and April 2009 using the LINEAR ARRAY HPV Genotyping Test (Roche Diagnostics, Indianapolis, Indiana), which detects 37 different types of HPV. Our primary goal was to examine the distributions of multiple HPV types with a special interest in negative interactions, which could signal the possibility of type replacement associated with a common niche if some HPV types were prevented by vaccination. Multiple infections were found to be more common than expected under independence, but this could largely be accounted for by a woman-specific latent heterogeneity parameter which was found to be dependent on age and cytological grade. While multiple infections were more common in young women and in those with abnormal cytology, greater heterogeneity was seen in older women and in those with normal cytology, possibly reflecting greater variability in exposure due to current or past HPV exposure or due to heterogeneity in related HPV reactivation or in immune responses to HPV infection or persistence. A negative interaction was found between HPV 16 and several other HPV types for women with abnormal cytology but not for those with normal cytology, suggesting that type replacement in women vaccinated against HPV 16 is unlikely to be an issue for the general population.