Optimal cut-off for neutrophil-to-lymphocyte ratio: Fact or Fantasy? A prospective cohort study in metastatic cancer patients

<div><p>This study assessed the prognostic value of pre-treatment neutrophil-to-lymphocyte ratio (NLR) in patients with metastatic solid tumors. Clinical and biological data for patients with metastatic solid tumors treated in an oncology outpatient department and prospectively followed by a call center (PROCHE program) between January 2008 and December 2011 were analyzed. All patients with an NLR value within 28 days before the first cycle of first-line of chemotherapy were included (cohort 1). To assess influence of chemotherapy line on NLR prognostic value, data from patients treated with later chemotherapy lines were also analyzed (cohort 2). Adjusted multivariate Cox regressions with or without non-linear and time-dependent effects were performed. Optimal NLR cut-off was investigated by time-dependent sensitivity analysis using several indices. There were 317 and 134 patients in cohorts 1 and 2, respectively. Elevated NLR was associated with worse survival (hazard ratio [HR] for death, 1.35 [95% confidence interval 1.19–1.54]; p<0.0001). The optimal NLR cut-off in cohort 1 was dependent on index used and time of assessment: HR values were non-significant at a cut-off of 3.0 (1.34 [0.99–1.32], but significant when the cut-off was 4.0 (1.53 [1.11–2.10]). NLR was linearly related to mortality risk; in subgroup analysis, no significant interaction was found with co-variables or tumor localization overall (cohorts 1+2). Pre-treatment NLR is a useful prognostic tool in patients with metastatic solid tumors, irrespective of primary tumor site, chemotherapy line, age, gender and performance status. However, using an NLR cut-off value for clinical decision-making requires extreme caution.</p></div

Baseline demographics and clinical characteristics.

<p>Baseline demographics and clinical characteristics.</p

Multivariate analysis in the overall cohort of patients receiving chemotherapy (cohort 1 + cohort 2, n = 451) with neutrophil-to-lymphocyte ratio as dichotomous variable.

<p>Multivariate analysis in the overall cohort of patients receiving chemotherapy (cohort 1 + cohort 2, n = 451) with neutrophil-to-lymphocyte ratio as dichotomous variable.</p

Optimal cut-off for neutrophil-to-lymphocyte ratio: Fact or Fantasy? A prospective cohort study in metastatic cancer patients - Fig 3

<p>Subgroup analysis illustrating the impact of the choice of neutrophil-to-lymphocyte ratio (NLR) cut-off value; examples with NLR ≥3.0 (<b>A</b>) and NLR ≥4.0 (<b>B</b>). The model was adjusted for age, sex, disease site and European Co-operative Oncology Group performance status, and the interaction test remained statistically non-significant across the different subgroups, irrespective of the cut-off value, in favour of a persisting negative effect of a high NLR value on prognosis. *Likelihood-ratio txt for interaction of term with NLR cut-off = 3.</p

Sensitivity analysis of the neutrophil-to-lymphocyte ratio (NLR) cut-off using 4 different indices.

<p>Using the log-rank test-base method, the NLR cut-off value displaying the greatest stability over time was determined to be between 4.0 and 4.5.</p

Multivariate analysis in the overall cohort of patients receiving chemotherapy (cohort 1 + cohort 2, n = 451) with neutrophil-to-lymphocyte ratio as a continuous variable.

<p>Multivariate analysis in the overall cohort of patients receiving chemotherapy (cohort 1 + cohort 2, n = 451) with neutrophil-to-lymphocyte ratio as a continuous variable.</p

Survival probability for patients with a neutrophil-to-lymphocyte ratio (NLR) at the cut-off value or higher versus below the cut-off value for each unit variation of NLR cut-off (Cox univariate model).

<p>Survival probability for patients with a neutrophil-to-lymphocyte ratio (NLR) at the cut-off value or higher versus below the cut-off value for each unit variation of NLR cut-off (Cox univariate model).</p

Risk of Hormone Escape in a Human Prostate Cancer Model Depends on Therapy Modalities and Can Be Reduced by Tyrosine Kinase Inhibitors

<div><p>Almost all prostate cancers respond to androgen deprivation treatment but many recur. We postulated that risk of hormone escape -frequency and delay- are influenced by hormone therapy modalities. More, hormone therapies induce crucial biological changes involving androgen receptors; some might be targets for escape prevention. We investigated the relationship between the androgen deprivation treatment and the risk of recurrence using nude mice bearing the high grade, hormone-dependent human prostate cancer xenograft PAC120. Tumor-bearing mice were treated by Luteinizing-Hormone Releasing Hormone (LHRH) antagonist alone, continuous or intermittent regimen, or combined with androgen receptor (AR) antagonists (bicalutamide or flutamide). Tumor growth was monitored. Biological changes were studied as for genomic alterations, AR mutations and protein expression in a large series of recurrent tumors according to hormone therapy modalities. Therapies targeting Her-2 or AKT were tested in combination with castration. All statistical tests were two-sided. Tumor growth was inhibited by continuous administration of the LH-RH antagonist degarelix (castration), but 40% of tumors recurred. Intermittent castration or complete blockade induced by degarelix and antiandrogens combination, inhibited tumor growth but increased the risk of recurrence (RR) as compared to continuous castration (RR_intermittent: 14.5, RR_{complete blockade}: 6.5 and 1.35). All recurrent tumors displayed <em>new</em> quantitative genetic alterations and AR mutations, whatever the treatment modalities. AR amplification was found after complete blockade. Increased expression of Her-2/neu with frequent ERK/AKT activation was detected in all variants. Combination of castration with a Her-2/neu inhibitor decreased recurrence risk (0.17) and combination with an mTOR inhibitor prevented it. Anti-hormone treatments influence risk of recurrence although tumor growth inhibition was initially similar. Recurrent tumors displayed genetic instability, AR mutations, and alterations of phosphorylation pathways. We postulated that Her-2/AKT pathways allowed salvage of tumor cells under castration and we demonstrated that their inhibition prevented tumor recurrence in our model.</p> </div

High Milk Consumption Does Not Affect Prostate Tumor Progression in Two Mouse Models of Benign and Neoplastic Lesions

<div><p>Epidemiological studies that have investigated whether dairy (mainly milk) diets are associated with prostate cancer risk have led to controversial conclusions. In addition, no existing study clearly evaluated the effects of dairy/milk diets on prostate tumor progression, which is clinically highly relevant in view of the millions of men presenting with prostate pathologies worldwide, including benign prostate hyperplasia (BPH) or high-grade prostatic intraepithelial neoplasia (HGPIN). We report here a unique interventional animal study to address this issue. We used two mouse models of fully penetrant genetically-induced prostate tumorigenesis that were investigated at the stages of benign hyperplasia (probasin-Prl mice, Pb-Prl) or pre-cancerous PIN lesions (KIMAP mice). Mice were fed high milk diets (skim or whole) for 15 to 27 weeks of time depending on the kinetics of prostate tumor development in each model. Prostate tumor progression was assessed by tissue histopathology examination, epithelial proliferation, stromal inflammation and fibrosis, tumor invasiveness potency and expression of various tumor markers relevant for each model (c-Fes, Gprc6a, activated Stat5 and p63). Our results show that high milk consumption (either skim or whole) did not promote progression of existing prostate tumors when assessed at early stages of tumorigenesis (hyperplasia and neoplasia). For some parameters, and depending on milk type, milk regimen could even exhibit slight protective effects towards prostate tumor progression by decreasing the expression of tumor-related markers like Ki-67 and Gprc6a. In conclusion, our study suggests that regular milk consumption should not be considered detrimental for patients presenting with early-stage prostate tumors.</p></div

AR gene sequence showing mutations detected in AI variants A) after treatment with single-agent degarelix, B) after antiandrogens and C) after complete androgen blockade.

<p>Full underlines show mutations found in more than one tumor treated with the same agent. Mutations depicted with a blue, green or red background have previously been described in PAIS, CAIS and PCa, respectively.</p