BCL2 genotypes and prostate cancer survival.

PURPOSE: The antiapoptotic B­cell lymphoma 2 (BCL2) gene is a key player in cancer development and progression. A functional single-nucleotide polymorphism (c.-938C>A, rs2279115) in the inhibitory P2 BCL2 gene promoter has been associated with clinical outcomes in various types of cancer. Aim of the present study was to analyze the role of BCL2-938C>A genotypes in prostate cancer mortality. METHODS: The association between BCL2-938C>A (rs2279115) genotypes and prostate cancer outcome was studied within the prospective PROCAGENE study comprising 702 prostate cancer patients. RESULTS: During a median follow-up time of 92 months, 120 (17.1%) patients died. A univariate Cox regression model showed a significant association of the CC genotype with reduced cancer-specific survival (CSS; hazard ratio, HR, 2.13, 95% confidence interval, CI, 1.10-4.12; p = 0.024) and overall survival (OS; HR 2.34, 95% CI 1.58-3.47; p < 0.001). In a multivariate Cox regression model including age at diagnosis, risk group, and androgen deprivation therapy, the CC genotype remained a significant predictor of poor CSS (HR 2.05, 95% CI 1.05-3.99; p = 0.034) and OS (HR 2.25, 95% CI 1.51-3.36; p < 0.001). CONCLUSION: This study provides evidence that the homozygous BCL2-938 CC genotype is associated with OS and C in prostate cancer patients.

The elevated preoperative derived neutrophil-to-lymphocyte ratio predicts poor clinical outcome in breast cancer patients.

Existing preclinical and clinical data suggest that the presence of a systemic inflammatory response plays a critical role in the progression of several solid tumors. The derived neutrophil-to-lymphocyte ratio (dNLR) represents an easily determinable marker of systemic inflammation and has been proposed as a potential prognostic marker. The present study was performed to validate and further clarify the prognostic relevance of an elevated pre-treatment dNLR in a large cohort of European breast cancer patients. Data from 762 consecutive female breast cancer patients treated from 1999 to 2004 were evaluated. Disease-free survival (DFS) and overall survival (OS) were assessed using the Kaplan-Meier method. To evaluate the prognostic relevance, univariate and multivariate Cox regression models were performed for each endpoint. Applying receiver operating characteristics (ROC) analysis, the optimal cutoff level for the dNLR was 3. In univariate analysis, a dNLR ≥3 was associated with poor DFS (hazard ratio (HR) 1.87, 95 % confidence interval (CI) 1.28-2.73, p = 0.001) and OS (HR 1.67, 95 % CI 1.07-2.63, p = 0.025). Multivariate analysis revealed a significant association between the elevated dNLR and poor DFS (hazard ratio (HR) 1.70, 95 % CI 1.09-2.65, p = 0.018) but did not show a significant association between the dNLR and OS (HR 1.54, 95 % CI 0.91-2.59, p = 0.106). The present study shows that the pre-treatment dNLR is an independent prognostic factor that could be useful for future individual risk assessment in breast cancer patients.

Vitamin D and prostate cancer prognosis: a Mendelian randomization study.

PURPOSE: Decreased vitamin D levels have been associated with prostate cancer, but it is unclear whether this association is causal. A functional single-nucleotide polymorphism (SNP) in the group-specific component (GC) gene (T > G, rs2282679) has been associated with 25-hydroxy (25-OH) vitamin D and 1.25 dihydroxy (1.25-OH2) vitamin D levels. METHODS: To examine the hypothesized inverse relationship between vitamin D status and prostate cancer, we studied the association between this SNP and prostate cancer outcome in the prospective PROCAGENE study comprising 702 prostate cancer patients with a median follow-up of 82 months. RESULTS: GC rs2282679 genotypes were not associated with biochemical recurrence [hazard ratios (HR) 0.91, 95 % confidence interval (CI) 0.73-1.12; p = 0.36], development of metastases (HR 1.20, 95 % CI 0.88-1.63; p = 0.25) or overall survival (HR 1.10; 95 % CI 0.84-1.43; p = 0.50). CONCLUSIONS: A causal role of vitamin D status, as reflected by GC rs2282679 genotype, in disease progression and mortality in prostate cancer patients is unlikely.

Validation of the neutrophil-to-lymphocyte ratio as a prognostic factor in a cohort of European prostate cancer patients.

PURPOSE: Recent studies have expanded the concept that the systemic inflammatory response has an important role in the progression of several solid tumors. The neutrophil-to-lymphocyte ratio (NLR), an easily determinable marker of systemic inflammation, has been associated with clinical outcome in various cancer entities. In the present study, we validated the prognostic relevance of an elevated NLR in a cohort of European prostate cancer patients. METHODS: Data from 415 consecutive prostate cancer patients treated with 3D conformal radiotherapy at a single tertiary academic center from 1999 to 2007 were included in this retrospective study. Clinical progression-free survival (PFS), distant metastases-free survival (DMFS), and overall survival (OS) were assessed using the Kaplan-Meier method. To evaluate the prognostic relevance, univariate and multivariate Cox regression models were performed for each end point. RESULTS: Based on previously published studies, an NLR ≥ 5 was selected as cutoff value for external validation. Multivariate analysis identified an increased NLR as an independent prognostic factor for clinical PFS [hazard ratio (HR) 3.09, 95 % CI 1.64-5.82, p < 0.001], DMFS (HR 3.51, 95 % CI 1.80-6.85, p < 0.001), and OS (HR 2.16, 95 % CI 1.17-3.99, p = 0.013). CONCLUSION: The NLR seems to represent an independent prognostic marker and should be considered for future individual risk assessment in patients with prostate cancer.

The association of an elevated plasma fibrinogen level with cancer-specific and overall survival in prostate cancer patients.

PURPOSE: Fibrinogen plays an important role in the pathophysiology of tumour cell invasion and metastases. In recent studies, an elevated plasma fibrinogen level has been associated with poor prognosis in different types of cancer. The present study was performed to analyse the prognostic impact of an elevated fibrinogen level in prostate cancer patients. METHODS: We evaluated data from 268 prostate cancer patients who underwent 3D conformal radiotherapy between 1999 and 2006 at a single tertiary academic center. Cancer-specific survival (CSS), overall survival (OS), and clinical disease-free survival (DFS) were assessed using the Kaplan-Meier method. Univariable and multivariable Cox regression models were performed for each endpoint. RESULTS: Applying receiver operating characteristics (ROC) curve analysis, the optimal cut-off level for the plasma fibrinogen level was 530 mg dl(-1), respectively. Univariable (HR 3.638, 95 % CI 1.15-11.47, p = 0.027) and multivariable analyses (HR 3.964, 95 % CI 1.06-14.87, p = 0.041) revealed a significant correlation between increased plasma fibrinogen and CSS. Univariable analysis also showed a significant association between the elevated plasma fibrinogen level and decreased OS (HR 3.242, 95 % CI 1.53-6.89, p = 0.002), that remained significant in multivariable analysis (HR 3.215, 95 % CI 1.44-7.19, p = 0.004). No significant associations were found for clinical DFS. CONCLUSION: Although our data show a significant association between an elevated plasma fibrinogen level and poor prostate cancer prognosis, they have to be interpreted cautiously. Limitations of the present study are caused by its retrospective design, the limited accuracy obtained using ROC curve analysis, and potential confounding factors like cardiovascular disease and inflammatory diseases that have not been accounted for.

Association of vascular endothelial growth factor--a gene polymorphisms and haplotypes with breast cancer metastases.

BACKGROUND: Vascular endothelial growth factor (VEGF-A) is a key regulator of tumor-induced angiogenesis and essential for tumor growth and distant tumor spread. The aim of the present study was to evaluate the role of VEGF-A polymorphisms and haplotypes for metastatic progression in breast cancer patients. MATERIAL AND METHODS: We performed a prospective study including 801 breast cancer patients. Occurrence of metastases was examined in regular follow-up investigations. Seven VEGF-A polymorphisms were selected and determined by 5'-nuclease assays (TaqMan). The selection of VEGF-A variants was based upon their location (promoter or UTR) as well as a minor allele frequency of at least 0.10. Haplotypes and linkage disequilibrium were determined using the Haploview program. RESULTS: Within a median follow-up time of 84 months, 165 (21%) patients developed distant metastases. In univariate analysis, carriers of the CCCCC haplotype formed by five polymorphisms upstream the coding region were at decreased risk of distant metastases [hazard ratio (HR)=0.743; 95% CI 0.579-0.953; p=0.019]. Univariate analysis also revealed a decreased risk of distant metastases for postmenopausal patients carrying the -634G>C polymorphism (HR 0.704; 95% CI 0.514-0.965; p=0.029) and the CCCCC haplotype (HR=0.645; 95% CI 0.464-0.898; p=0.009). After adjustment for other co-variates, the HR for distant metastases was 0.651 (95% CI 0.447-0.948) for postmenopausal carriers of the -634G>C polymorphism (p=0.025; corrected p-value=0.262), and 0.586 (95% CI 0.393-0.873) for postmenopausal patients with the CCCCC haplotype (p=0.009, corrected p-value=0.189). CONCLUSION: The results from univariate and multivariate analyses suggest an influence of VEGF-A gene variants on the development of distant metastases in breast cancer patients. However, none of the observed associations reached statistical significance after correction for the effects of multiple testing. Additional prospective and sufficiently powered studies are essential before firm conclusions about the role of VEGF-A gene variants for distant progression in breast cancer can be drawn.

Relative telomere length and prostate cancer mortality.

PURPOSE: Telomeres are essential for the maintenance of chromosomal integrity and telomere length has been associated with cancer risk and development. Aim of the present study was to analyze the prognostic value of leukocyte relative telomere (RTL) length in long-term prostate cancer (PCa) mortality. METHODS: Blood samples of PCa patients were obtained before initiation of radiotherapy. RTL of peripheral blood leukocytes was determined by a quantitative polymerase chain reaction method in 533 patients with PCa. Main outcome was overall mortality. RESULTS: During a median follow-up time of 149 months, 188 (35.3%) patients died. In a univariate Cox regression analysis, RTL quartiles (longer RTL) were significantly associated with higher overall mortality (hazard ration (HR) = 1.20; 95% confidence interval (CI): 1.05-1.36; p = 0.006). In a multivariate Cox regression model including age at diagnosis, androgen deprivation therapy, and risk group (based on PSA level, GS, and T stage), RTL quartiles remained a significant predictor of higher overall mortality (HR = 1.22; 95% CI: 1.07-1.39; p = 0.003). CONCLUSIONS: Longer leukocyte RTL predicts higher overall mortality in patients with PCa.

An elevated preoperative plasma fibrinogen level is associated with poor disease-specific and overall survival in breast cancer patients.

INTRODUCTION: Plasma fibrinogen plays an important role in the pathophysiology of tumor cell invasion and metastases. High plasma fibrinogen levels have been associated with poor prognosis in different types of cancer. In the present study, we evaluated the prognostic significance of the preoperative plasma fibrinogen level in a large cohort of breast cancer patients. MATERIALS AND METHODS: Data from 520 consecutive breast cancer patients, treated between 1999 and 2004, were evaluated. Disease-specific survival (DSS), overall survival (OS), and distant metastasis-free survival (DMFS) were assessed using Kaplan-Meier curves. To evaluate the independent prognostic significance of fibrinogen, multivariable Cox regression models were applied. The influence of fibrinogen on the predictive accuracy was further determined by the Harrell's c-index. RESULTS: Univariable analysis revealed a significant association between an elevated plasma fibrinogen level and DSS (hazard ratio (HR) 1.70, 95% CI 1.07-2.76, p = 0.026) that remained significant in multivariable analysis (HR 1.71, 95% CI 1.02-2.85; p = 0.042). An increased fibrinogen level was also significantly associated with decreased OS in univariable (HR 1.71, 95% CI 1.11-2.64, p = 0.015) and multivariable analysis (HR 1.62, 95% CI 1.01-2.61; p = 0.048). In patients with ER/PR+, HER2- tumors, plasma fibrinogen was associated with DSS in univariable (HR 2.65, 95% CI 1.15-6.14, p = 0.023) and multivariable analysis (HR 3.63, 95% CI 1.37-9.64, p = 0.010). Furthermore, in those patients, the estimated c-index of the multivariable model for DSS was 0.755 without fibrinogen and 0.785 when fibrinogen was added. CONCLUSIONS: An elevated preoperative plasma fibrinogen level may represent an independent prognostic marker for survival in breast cancer patients.

Evaluation of the platelet-to-lymphocyte ratio as a prognostic indicator in a European cohort of patients with prostate cancer treated with radiotherapy.

OBJECTIVES: Recent evidence suggests that the presence of a systemic inflammatory response plays an important role in the progression of several solid tumors. The platelet-to-lymphocyte ratio (PLR) has been proposed as an easily assessable marker of systemic inflammation and has been shown to represent a prognostic marker in different cancer entities. To evaluate the prognostic value of the PLR in prostate cancer, we performed the present study. METHODS AND MATERIALS: Data from 374 consecutive patients with prostate cancer, treated with 3D conformal radiotherapy from 1999 to 2007, were analyzed. Distant metastases-free survival (MFS), cancer-specific survival (CSS), overall survival (OS), biochemical disease-free survival, and time to salvage systemic therapy were assessed using the Kaplan-Meier method. Cox proportional hazards analysis was performed to calculate hazard ratio (HR) and 95% CI. Multivariate Cox regression analysis was performed to adjust for other covariates. RESULTS: Using receiver operating characteristics analysis, the optimal cutoff level for the PLR was 190. Kaplan-Meier analyses revealed that PLR≥190 was a prognostic factor for decreased MFS (P = 0.004), CSS (P = 0.004), and OS (P = 0.024) whereas a significant association of an elevated PLR with biochemical disease-free survival (P = 0.740) and time to salvage systemic therapy (P = 0.063) was not detected. In multivariate analysis, an increased PLR remained a significant prognostic factor for poor MFS (HR = 2.24, 95% CI: 1.06-4.76, P = 0.036), CSS (HR = 3.99, 95% CI: 1.19-13.4, P = 0.025), and OS (HR = 1.87, 95% CI: 1.02-3.42, P = 0.044). CONCLUSIONS: Our findings indicate that the PLR may predict prognosis in patients with prostate cancer and may contribute to future individual risk assessment in them.

The elevated C-reactive protein level is associated with poor prognosis in prostate cancer patients treated with radiotherapy.

BACKGROUND: C-reactive protein (CRP) is a sensitive marker of inflammation that has been linked with prognosis in various solid tumours. In the present study, we analysed the prognostic relevance of elevated plasma CRP levels in prostate cancer patients treated with radiotherapy. METHODS: A total of 261 prostate cancer patients treated with 3D-conformal radiotherapy were evaluated retrospectively. Cancer specific survival (CSS), overall survival (OS) and clinical disease-free survival (DFS) were assessed using Kaplan-Meier analysis. To evaluate the independent prognostic significance of CRP plasma levels, multivariate Cox regression models were applied. RESULTS: The median follow-time was 80months. Applying receiver operating characteristics (ROC) analysis, the optimal cut-off level for the plasma CRP was 8.6mgl(-1). An elevated CRP level was associated with decreased CSS in univariate (hazard ratio (HR) 3.36, 95% confidence interval (CI) 1.42-7.91; p=0.006) and multivariate analysis (HR 4.31, 95% CI 1.22-15.1; p=0.023). Furthermore, a significant association with OS was detected in univariate (HR 2.69, 95% CI 1.57-4.59; p<0.001) and multivariate analyses (HR 3.24, 95% CI 1.84-5.71, p<0.001). Multivariate analysis also showed a significant association between plasma CRP and clinical DFS (HR 2.07, 95% CI 1.02-4.17; p=0.043). CONCLUSIONS: In the present study, an elevated plasma CRP (⩾8.6mgl(-1)) has been identified as a prognostic factor for poor CSS, OS and DFS in prostate cancer patients undergoing radiotherapy. The association between elevated CRP levels and poor prognosis was independent of other measures of prognosis such as tumour stage, Gleason grading and prostate specific antigen (PSA) level at diagnosis. If confirmed by additional studies, our findings may contribute to future individual risk assessment in prostate cancer patients.