Sabine Krenn-Pilko

The elevated preoperative platelet-to-lymphocyte ratio predicts poor prognosis in breast cancer patients

Background:The elevation of the platelet-to-lymphocyte ratio (PLR), an easily applicable blood test based on platelet and lymphocyte counts has been associated with poor prognosis in patients with different types of cancer. The present study was aimed to investigate the prognostic significance of the preoperative PLR in a large cohort of breast cancer patients.Methods:Data from 793 consecutive non-metastatic breast cancer patients, treated between 1999 and 2004, were evaluated retrospectively. The optimal cutoff values for the PLR were calculated using receiver operating curve analysis. Cancer-specific survival (CSS), overall survival (OS) as well as distant metastasis-free survival (DMFS) were assessed using the Kaplan–Meier method. To evaluate the independent prognostic significance of PLR, multivariable Cox regression models were applied for all three different end points.Results:Univariable analysis revealed a significant association between the elevated preoperative PLR and CSS (hazard ratio (HR): 2.75, 95% confidence interval (CI): 1.57–4.83, P<0.001) that remained statistically significant in multivariable analysis (HR: 2.03, 95% CI: 1.03–4.02, P=0.042). An increased PLR was also significantly associated with decreased OS in univariable (HR: 2.45, 95% CI: 1.43–4.20, P=0.001) and in multivariable analysis (HR: 1.92, 95% CI: 1.01–3.67, P=0.047). Furthermore, univariable analysis showed a significant impact of increased PLR on DMFS (HR: 2.02, 95% CI: 1.18–3.44, P=0.010). Subgroup analysis revealed significant associations of the elevated PLR on the primary end point CSS for all breast cancer subtypes. This association retained its significance in multivariable analysis in patients with luminal B tumours (HR: 2.538, 95% CI: 1.043–6.177, P=0.040).Conclusions:In this study, we identified the preoperative PLR as an independent prognostic marker for survival in breast cancer patients. Independent validation of our findings is needed.

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.

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.

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 Harrells 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.

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

Abstract 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

PurposeTelomeres 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.MethodsBlood 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.ResultsDuring 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).ConclusionsLonger leukocyte RTL predicts higher overall mortality in patients with PCa.

210 The Development of Distant Metastases in Postmenopausal Woman with Breast Cancer in Association with VEGF Gene Polymorphisms

Background: The epithelial to mesenchymal transition (EMT) is involved in multiple aspects of cancer biology, including tumor metastasis, cancer stem cells, drug resistance, and immunosuppression. TGFb, one of the most studied regulators of EMT, is produced in a latent form that needs to be activated to enable binding to its receptor and subsequent down-stream signaling. Four of the five aVb integrin proteins have been demonstrated to induce TGFb maturation. Cross-talk between TGFb and integrin signaling can also occur downstream of initial receptor activation and regulates various cellular processes, including EMT. Materials and Methods: Lung, melanoma, and breast cancer cell lines were obtained from ATCC. Protein levels were determined by Western-blot and RNA levels were determined by q-PCR. Migration and invasion assays were carried out using trans-well system. All experiments were conducted without coating the plates with vitronectin. Results: Active TGFb1 increased integrin aV, b1, and b3 expression in lung cancer cells while integrin b5 expression was suppressed by TGFb1. This differential regulation of integrin protein expression was accompanied by a reorganization of integrin heterodimer complex between aV and b subunits. TGFb-treated cells developed a spindle-like morphology. Altered expressions of E-Cadherin, vimentin, and snail in these cells were consistent with EMT. Intetumumab (CNTO95), a monoclonal antibody that binds to aVb integrins (aVb1, aVb3, aVb5, aVb6, and aVb8), potently inhibits cellular events strongly relevant to EMT such as migration, invasion and metastasis. Co-treatment of cells with intetumumab blocked TGFb-induced EMT. Moreover, lung cancer cell lines treated with intetumumab alone underwent a mesenchymal to epithelial transition (MET), with increased expression of E-cadherin and decreased expression of vimentin and snail. The effect of intetumumab on EMT was also observed in melanoma cancer cells. Conclusions: aVb integrins are critical regulators of EMT and MET. Intetumumab activates MET and inhibits TGFb induced EMT by blocking aVb integrins, suggesting potential roles in preventing metastasis.