Vis, A.N.

Molecular grade (FGFR3/MIB-1) and EORTC risk scores are predictive in primary non-muscle-invasive bladder cancer (Article)

2010-09-01T00:00:00Z

Background: The European Organization for Research and Treatment of Cancer (EORTC) risk scores are not validated in an independent patient population. Molecular grade (mG) based on fibroblast growth factor receptor 3 (FGFR3) gene mutation status and MIB-1 expression was proposed as an alternative to pathologic grade in bladder cancer (BCa) [1]. Objective: To validate the EORTC risk score and to determine its relation to mG in a series with long-term follow-up as well as to determine reproducibility of pathologic grade and mG. Design, setting, and participants: In this multicenter study, we included 230 patients with primary non-muscle-invasive BCa (NMIBC). Measurements: Four uropathologists reviewed the slides. FGFR3 mutation status was examined by two assays. MIB-1 was assessed by immunohistochemistry. The EORTC risk scores for recurrence and progression were determined. Multivariable analyses were used to find prognostic factors. Results and limitations: Median follow-up was 8.62 yr (interquartile range: 6.6-11.8). FGFR3 mutations were significantly related to favorable disease parameters, whereas altered MIB-1 was frequently seen with pT1, high grade, and high EORTC risk scores. EORTC risk scores were significant in multivariable analyses for recurrence and progression. In multivariable analyses for progression and disease-specific survival, the mG had independent significance. The addition of mG to the multivariable model for progression increased the predictive accuracy from 74.9% to 81.7% (p < 0.001; Mantel-Haenszel test). The mG (89%) was more reproducible than the pathologic grade (41-74%). Conclusions: We validated the EORTC risk scores for primary NMIBC in a clinical and biomarker setting. Next to EORTC risk score, mG proved highly reproducible and predictive. Our long-term results justify an independent prospective analysis of mG and EORTC risk scores.

Key targets of hormonal treatment of prostate cancer. Part 2: The androgen receptor and 5α-reductase (Article)

2009-11-01T00:00:00Z

Objective The inhibition of 5α-reductase (5AR) blocks the synthesis of the most powerful intracellular androgen, dihydrotestosterone (DHT). The prostate has two 5AR isoenzymes (5AR1 and 5AR2) that change in expression and cellular location during the development of prostate cancer and tumour progression. The objective of this review is to provide an understanding of the pharmacological properties and the potential clinical benefits of 5AR inhibition. METHODS We searched Pubmed for data obtained from pharmacological, preclinical and clinical studies. Results 5AR1 expression increases with increasing aggressiveness and extension of malignant prostatic disease. Conversely, 5AR2 expression decreases from benign prostatic tissue to localized prostate cancer. The efficacy of 5AR2 monotherapy with finasteride alone or in combination with an androgen receptor antagonist on more final outcome measures seems to be limited. Combining an androgen receptor antagonist with a 5AR inhibitor in patients with asymptomatic, locally advanced or recurrent prostate cancer might be a reasonable first therapeutic hormonal approach. As plasma testosterone levels are maintained, beneficial effects on quality of life, potency and sexual function are expected. From studies on the dual 5AR inhibitor dutasteride, the drug produces a biochemical response in some men who progressed under androgen-deprivation therapy, and is generally well tolerated. Conclusions Achieving more potent suppression of intracellular DHT synthesis by 5AR inhibition is expected to provide clinical benefit to patients. Previous studies have shown that 5AR inhibition, by dutasteride in particular, halts/delays the progression of disease, and might even cause regression of disease in patients with advanced prostate cancer.

Key targets of hormonal treatment of prostate cancer. Part 1: The androgen receptor and steroidogenic pathways (Article)

2009-08-01T00:00:00Z

Objective: Knowledge of the molecular and cellular changes that occur during the transition of hormone-naïve to castration-resistant prostate cancer (CRPC) is increasing rapidly. This might provide a window of opportunity for (future) drug development, and for treating patients with these potential devastating states of disease. The objective of this review is to provide an understanding of the mechanisms that prostate cancer cells use to bypass androgen-deprived conditions. Methods: We searched PubMed for experimental and clinical studies that describe the molecular changes that lead to CRPC. Results: CRPC remains dependent on a functional androgen receptor (AR), AR-mediated processes, and on the availability of intraprostatic intracellular androgens. CRPCs might acquire different (molecular) mechanisms that enable them to use intracellular androgens more efficiently (AR amplification, AR protein overexpression, AR hypersensitivity), use alternative splice variants of the AR protein to mediate androgen-independent AR functioning, and have altered coactivator and co-repressor gene and protein expression. Furthermore, CRPCs might have the ability to synthesise androgens de novo from available precursors through a renewed and upregulated synthesis of steroid-hormone converting enzymes. Blocking of enzymes key to de novo androgen synthesis could be an alternative means to treat patients with advanced and/or metastatic disease. Conclusion: In CRPC, prostate cancer cells still rely on intracellular androgens and on an active AR for growth and survival. CRPCs have gained mechanisms that enable them to use steroids from the circulation more efficiently through altered gene expression, and through a renewed and up-regulated synthesis of steroid hormone-converting enzymes. Additionally, CRPCs might synthesise AR isoforms that enable AR mediated processes independent from available androgens. copyright

Editorial comment (Article)

2008-02-01T00:00:00Z

Overall Survival in the Intervention Arm of a Randomized Controlled Screening Trial for Prostate Cancer Compared with a Clinically Diagnosed Cohort (Article)

2008-01-01T00:00:00Z

Objectives: This population-based study provides comparisons of prostate cancer characteristics at diagnosis of two cohorts of men from two well-defined geographical areas exposed to different intensities of prostate cancer screening. Overall survival in both cohorts was compared with that in the general population. Methods: A cohort of 822 men randomized to the intervention arm of a prostate cancer screening trial and subsequently diagnosed with prostate cancer was compared with a nonrandomized cohort of 947 men who were clinically diagnosed with prostate cancer in a geographically neighboring region. In both cohorts, cases were diagnosed with prostate cancer between January 1989 and December 1997. A partitioning of overall survival by variables associated with cancer onset such as age at diagnosis, stage at diagnosis, and grade at diagnosis was performed. Results: Age at diagnosis, tumor extent at diagnosis, and grade at diagnosis were significantly different between the screened and clinically diagnosed cohort. The 5- and 10-yr survival rates were higher in the screened cohort than in the clinically diagnosed cohort (88.8% vs. 52.4%, and 68.4% vs. 29.6%, respectively). Significant differences in survival were evident for all age, stage, and grade subgroups, except for metastatic disease at diagnosis. Conclusions: Differences in overall survival favoring the screened population were observed for all baseline characteristics (age, stage, and grade of disease), and these variables may all explain differences in overall survival because screening achieves early diagnosis as well as a stage and grade shift. As observed survival rates in the screened population mirrored those within the general population, the contribution of lead time and overdiagnosis to final patient outcome is considered to be large as well.

Cancer Detection and Cancer Characteristics in the European Randomized Study of Screening for Prostate Cancer (ERSPC) - Section Rotterdam. A Comparison of Two Rounds of Screening (Article)

2007-07-01T00:00:00Z

Objectives: To evaluate the features, rates, and characteristics of prostate cancer detected during two subsequent screening rounds. Methods: Data were retrieved from the database of European Randomized Study of Screening for Prostate Cancer (ERSPC), section Rotterdam. Men, ages 55-74 yr were screened with a 4-yr interval. Different biopsy indications were used in the first and second screens in the PSA range <4.0 ng/ml. Clinical features and a total of 1548 sextant biopsies were recorded for Gleason score and tumour extent, and 550 radical prostatectomy specimens were evaluated for Gleason score, pathologic T category, and tumour volume. Results: Clinical stage, Gleason score, involvement of biopsy by tumour, and PSA levels were more favourable in patients of the second round compared with those of the first round. The number of men chosen for watchful waiting increased from 98 (10%) to 123 (22%) in the second round (p < 0.0001). In patients undergoing radical prostatectomy, median tumour volume in the first and second screening round was 0.65 and 0.45 ml (p = 0.001). Minimal cancer (cancer <0.5 ml, organ-confined, no Gleason pattern 4 or 5) was found in 122 (31.6%) in the first and 60 (42.6%) in the second screening round (p = 0.03). The 5-yr PSA progression-free survival after radical prostatectomy was 87%. Conclusions: Despite the 4-yr interval an important shift of all prognostic factors occurred in favour of round 2. In those men who underwent radical prostatectomy, 42.6% fulfilled the criteria of minimal cancer. These data suggest that overdiagnosis increases with repeat screening.

Should We Replace the Gleason Score with the Amount of High-Grade Prostate Cancer? (Article)

2007-04-01T00:00:00Z

Objectives: The stage and grade shift of currently diagnosed prostate cancer has led to a diminished prognostic power of the Gleason score system. We investigated the predictive value of the amount of high-grade cancer (Gleason growth patterns 4/5) in the biopsy for prostate-specific antigen (PSA) and clinical relapse after radical prostatectomy. Methods: PSA-tested participants (N = 281) of the European Randomized Study of Screening for Prostate Cancer (ERSPC) who underwent radical prostatectomy were analyzed. Besides clinical features, and serum-PSA, histopathologic features as determined in the diagnostic biopsy and matching radical prostatectomy specimen were related to patient outcome. Results: At a median follow-up of 7 yr, 39 (13.9%), 24 (8.5%), and 12 (4.3%) patients had PSA ≥0.1 ng/ml, PSA ≥1.0 ng/ml, and clinical relapse after radical prostatectomy, respectively. Using Cox proportional hazards, PSA level (p = 0.002), length of tumour (p = 0.040), and length of high-grade cancer (p = 0.006) in the biopsy, but not Gleason score, were independent prognostic factors for biochemical relapse (PSA ≥0.1 ng/ml) when assessed as continuous variables. In radical prostatectomies, the proportion of high-grade cancer (p < 0.001) was most predictive of relapse (PSA ≥0.1 ng/ml). For PSA ≥1.0 ng/ml and clinical relapse, the amount of high-grade cancer, both in the biopsy specimen (p = 0.016 and p = 0.004, respectively) and radical prostatectomy specimen (p = 0.002 and p = 0.005, respectively), but not Gleason score, was an independent predictor. Conclusions: In biopsy and radical prostatectomy specimens of surgically treated prostate cancer, the amount of high-grade cancer is superior to the Gleason grading system in predicting patient outcome. We propose that, in addition to the Gleason score, the amount of Gleason growth patterns 4/5 in the biopsy (whether absolute length or proportion) should be mentioned in the pathology report.

FGFR3 and P53 characterize alternative genetic pathways in the pathogenesis of urothelial cell carcinoma (Article)

2004-01-01T00:00:00Z

Fibroblast growth factor receptor 3 (FGFR3) and P53 mutations are frequently observed in bladder cancer. We here describe the distribution of FGFR3 mutations and P53 overexpression in 260 primary urothelial cell carcinomas. FGFR3 mutations were observed in 59% and P53 overexpression in 25%. Interestingly, FGFR3 and P53 alterations were mutually exclusive, because they coincided in only 5.7% of tumors. Consequently, we propose that they characterize two alternative genetic pathways in urothelial cell carcinoma pathogenesis. The genetic alterations were reflected in the pathology and the clinical outcome, i.e., FGFR3 mutations were found in low-stage/-grade tumors and were associated with a favorable disease course, whereas P53 alterations were tied to adverse disease parameters.

Population based screening for prostatic cancer : tumor features and clinical decision making (Doctoral Thesis)

2002-03-06T00:00:00Z

The aggregate morbidity and mortality attributed to prostate cancer are certainly sufficient to justify a search for rational, effective and efficient screening strategies. Unfortunately, the outcome of randomized controlled trials (RCTs) that investigate the efficacy of prostate cancer screening is still awaited. Before this final analysis takes place at the end of this decade, and before screening for prostate cancer can be applied as a nation-\vide health care measure, efforts should be made to optimize the validity of the screening tests, assess the quality of life in those screened, and evaluate (reduce) the costs associated with large scale screening programs. In other words, efforts should be made to make the screening regimen more effective, selective and efficient. The current thesis provides further insight into the pathology of screen-detected prostate cancer, and into its role in the clinical management of patients with this potentially lethal disease. Despite our knowledge that a definite answer on the question which cancers we wish to detect in screening programs to decrease the mortality of the disease can only be answered after the completion of RCTs, potential measures to make the screening regimen more selective and efficient are presented. Most data were obtained from the screening arm of the European randomized study of screening for prostate cancer (ERSPC), a large multicenter RCT that investigates the impact of screening on prostate cancer mortality and quality of life.

Does PSA screening reduce prostate cancer mortality? (Article)

2002-01-01T00:00:00Z

Molecular cytogenetic analysis of prostatic adenocarcinomas from screening studies : early cancers may contain aggressive genetic features (Article)

2001-01-01T00:00:00Z

No objective parameters have been found so far that can predict the biological behavior of early stages of prostatic cancer, which are encountered frequently nowadays due to surveillance and screening programs. We have applied comparative genomic hybridization to routinely processed, paraffin-embedded radical prostatectomy specimens derived from patients who participated in the European Randomized Study of Screening for Prostate Cancer. We defined a panel consisting of 36 early cancer specimens: 13 small (total tumor volume (Tv) < 0.5 ml) carcinomas and 23 intermediate (Tv between 0.5-1.0 ml) tumors. These samples were compared with a set of 16 locally advanced, large (Tv > 2.0 ml) tumor samples, not derived from the European Randomized Study of Screening for Prostate Cancer. Chromosome arms that frequently (ie, > or = 15%) showed loss in the small tumors included 13q (31%), 6q (23%), and Y (15%), whereas frequent (ie, > or = 15%) gain was seen of 20q (15%). In the intermediate cancers, loss was detected of 8p (35%), 16q (30%), 5q (26%), Y (22%), 6q, and 18q (both 17%). No consistent gains were found in this group. In the large tumors, loss was seen of 13q (69%), 8p (50%), 5q, 6q (both 31%), and Y (15%). Gains were observed of 8q (37%), 3q (25%), 7p, 7q, 9q, and Xq (all 19%). Comparison of these early, localized tumors with large adenocarcinomas showed a significant increase in the number of aberrant chromosomes per case (Rs = 0.36, P = 0.009). The same was true for the number of lost or gained chromosomes per case (Rs = 0.27, P: = 0.05; Rs = 0.48, respectively; P < 0.001). Interestingly, chromosomal alterations that were found in previous studies to be potential biomarkers for tumor aggressiveness, ie, gain of 7pq and/or 8q, were already distinguished in the small and intermediate cancers. In conclusion, our data show that chromosomal losses, more specifically of 6q and 13q, are early events in prostatic tumorigenesis, whereas chromosomal gains, especially of 8q, appear to be late events in prostatic tumor development. Finally, early localized tumors, as detected by screening programs, harbor cancers with aggressive genetic characteristics.

Pathologic features of prostate cancer found at population-based screening with a four-year interval (Article)

2001-01-01T00:00:00Z

BACKGROUND: The currently recommended frequency for prostate-specific antigen (PSA) screening tests for prostate cancer is 1 year, but the optimal screening interval is not known. Our goal was to determine if a longer interval would compromise the detection of curable prostate cancer. METHODS: A cohort of 4491 men aged 55-75 years, all participants in the Rotterdam section of the European Randomized Study of (population-based) Screening for Prostate Cancer, were invited to participate in an initial PSA screening. Men who received that screening were invited for a second screen 4 years later. Pathology findings from needle biopsy cores were compared for men in both rounds. Statistical tests were two-sided. RESULTS: A total of 4133 men were screened in the first round (the prevalence screen), and 2385 were screened in the second round. The median amount of cancer in needle biopsy sets was 7.0 mm (95% confidence interval [CI] = 5.4 mm to 8.6 mm) in the first round and 4.1 mm (95% CI = 2.6 mm to 5.6 mm) in the second round (P =.001). Thirty-six percent of the adenocarcinomas detected in the first round but only 16% of those detected in the second round had a Gleason score of 7 or higher (mean difference = 20% [95% CI = 10% to 30%]; P<.001). Whereas 25% of the adenocarcinomas detected in the first round had adverse prognostic features, only 6% of those detected in the second round did (mean difference = 19% [95% CI = 11% to 26%]; P<.001). Baseline PSA values were predictive for the amount of tumor in biopsies in men with cancer in the first round but not for that in the second round. CONCLUSION: Most large prostate cancers with high serum PSA levels were effectively detected in a prevalence screen. In this population, a screening interval of 4 years appears to be short enough to constrain the development of large tumors, although it is inconclusive whether this will result in a survival benefit.