Evolution of Risk Factors for Atherosclerotic Cardiovascular Events in Systemic Lupus Erythematosus: A Longterm Prospective Study.

OBJECTIVE: We previously reported the effect of certain factors on cardiovascular disease (CVD) in 250 women with systemic lupus erythematosus (SLE) followed for 8 years. The aim of this study was to delineate their evolution after 15 years of followup. METHODS: There were 210 women with SLE and 138 age-matched healthy women available for analysis after 15 years. Cardiovascular events (CVE) included angina pectoris, myocardial infarction (fatal and nonfatal), transient ischemic attack, and stroke (fatal and nonfatal). Analysis was performed with SAS 9.3 software; p < 0.05 was considered significant. RESULTS: CVE occurred in 41/210 patients (19.5%) and 9/138 controls (6.5%), most of them in the second part (2008-2015) of the study (24/210, 11.4% vs 17/241, 7.1% in SLE group). Coronary artery disease was more common in patients (32/210, 15.2% vs 5/138, 3.6%, p = 0.0041). There was no significant difference for cerebrovascular disease (10/210, 4.8% vs 3/138, 2.2%, p = 0.213). SLE was the most prominent CVE predictor in the first 8 years (HR 2.8, 95% CI 1.3-6.3). Hypertension and diabetes were more frequent in patients who developed CVE during the second half of the study. Thirty-one deaths occurred in patients with SLE (10 because of CVD) and 6 in controls (none because of CVD). CONCLUSION: The relative importance of atherosclerotic risk factors is significantly differentiated over time in SLE. Disease-related factors seem to dominate CV risk during the early stages while traditional factors, partially related to corticosteroid treatment, play a significant role later in the disease course.

Influence of censoring on conclusions of trials for women with metastatic breast cancer.

Progression-free survival and time-to-progression (PFS/TTP) are used commonly as primary end-points in trials evaluating treatments for metastatic breast cancer (MBC). We reviewed the impact of censoring on interpretation of these end-points. A systematic review identified phase 3 trials in MBC published between 2001 and 2012 that reported hazard ratios (HRs) for PFS/TTP and Kaplan-Meier curves indicating numbers at risk. We calculated HRs for time-to-treatment-failure (TTF) where discontinuation of treatment for any reason is considered an event. Mean HRs for PFS/TTP, TTF, and overall survival (OS) were 0.79, 0.89 and 0.91, respectively. Unbalanced censoring of patients prior to progression was prevalent, usually with more patients censored in the experimental arms. There was moderate-to-poor correlation of HRs of PFS/TTP and TTF with HRs for OS. We suggest that TTF should be reported as supportive analysis in registration trials and extent of missing data due to censoring be considered in decisions made by regulatory agencies.

Prognostic relevance of receptor tyrosine kinase expression in breast cancer: a meta-analysis.

BACKGROUND: Receptor tyrosine kinases (RTKs) may facilitate tumor progression if activated aberrantly. The prognostic impact of human epidermal growth factor receptor 2 (HER2) overexpression and effectiveness of its therapeutic targeting is well established, but the effects on prognosis of overexpression of other RTKs is unknown. Here we evaluate the association of RTK expression and survival in breast cancer. METHODS: PubMed was searched to identify studies evaluating the association between expression of RTKs other than HER2 and survival of women with breast cancer. Published data were extracted and computed into odds ratios (OR) for death at 5 years with 95% confidence intervals (CI). Data were pooled in a meta-analysis using the Mantel-Haenszel random-effect model. For studies reporting data for more than one RTK the lowest and highest OR were used for separate analyses. RESULTS: Sixteen studies comprising 11,056 patients were included in the analysis. There was an association between overexpression of RTKs and decreased 5-year OS and this was highly significant when using highest ORs from studies reporting more than one RTK (OR=2.42; 95% CI=1.92-3.06, P<0.001). Similar results were observed for 5-year BCSS. Worse OS was seen with overexpression of fibroblast growth factor receptor 2/3 (FGFR) (OR=3.81; 95% CI=1.79-8.11) and epidermal growth factor receptor (EGFR)/HER1 (OR=2.45; 95% CI=1.90-3.15). CONCLUSION: Overexpression of various RTKs is associated with poor outcomes. This data suggests the clinical evaluation of combination of agents against RTKs or relevant oncogenic nodes.

Prognostic role of platelet to lymphocyte ratio in solid tumors: a systematic review and meta-analysis.

BACKGROUND: Inflammation influences cancer development and progression. An elevated platelet to lymphocyte ratio (PLR), a marker of inflammation, has been linked to poor prognosis in several malignancies. Here, we quantify the prognostic impact of this biomarker. METHODS: A systematic review of databases was conducted to identify publications exploring the association of blood PLR and overall survival (OS) in solid tumors. Data were pooled in a meta-analysis. Pooled HRs for OS by disease group and by PLR cutoff groups were computed and weighted using generic inverse-variance and random-effect modeling. RESULTS: Twenty studies comprising 12,754 patients were assessed. Cutoffs for PLR defining risk groups ranged from 150 to 300 and were dichotomous (12 studies; group 1) or split into three groups (<150/150-300/>300, 8 studies; group 2). Higher PLR was associated with significantly worse OS in group 1 [HR = 1.87; 95% confidence interval (CI, 1.49-2.34); P < 0.001] and with a nonsignificant association in group 2 (HR per higher category = 1.21; 95%CI, 0.97-1.50; P = 0.10). The size of effect of PLR on OS was greater for metastatic disease (HR[group 1] = 2.0; 95% CI, 1.6-2.7; HR[group 2] = 1.6; 95% CI, 1.1-2.4) than for early-stage disease (HR[group 1] = 1.5; 95% CI, 1.0-2.2; HR[group 2] = 1.0; 95% CI, 0.8-1.3). A significant association was observed for colorectal, hepatocellular, gastroesophageal, ovarian, and pancreatic carcinoma in group 1 and for colorectal cancers in group 2. CONCLUSION: A high PLR is associated with worse OS in various solid tumors. Further research of its regulation and relevance in daily practice is warranted. IMPACT: PLR is a readily available and inexpensive biomarker with independent prognostic value in solid tumors.

Tranilast treatment decreases cell growth, migration and inhibits colony formation of human breast cancer cells.

In the treatment of breast cancer, although a wide of choice of drugs and treatment modalities are available, drug resistance or drug toxicity poses a considerable challenge. Tranilast is a well tolerated drug used in the treatment of allergic disorders. Previous works in various models have shown that tranilast has the potential to be used as an anti-cancer drug. Hence, in this study using human breast cancer cell lines BT-474 and MDA-MB-231, we studied the effect of tranilast on cell growth, migration and ability to prevent colony formation in vitro, properties that are relevant to a possible therapeutic effect in breast cancer. We found that tranilast inhibits the growth of both breast cancer cell lines. In the cell migration experiments, the tumor cells exhibit significantly slower wound closure after tranilast treatment, as well as reduced migration using an insert system. Downregulation of MRTF-A, a global cytoskeleton regulator was observed after tranilast treatment. Additionally, tranilast treatment increased levels of cleaved PARP in both cell lines tested indicating a stimulation of apoptosis. A significant reduction in colony size and number was observed in soft agar clonogenic assays in both cell lines after tranilast treatment. BT-474 cells were more responsive to tranilast treatment compared to MDA-MB-231 cells, suggesting a difference in modes of action, or sensitivity, possibly related to their different receptor status. Based on these changes in cancer cell lines, we conclude that tranilast exerts effects that set a rationale for future preclinical studies in animal models of breast cancer.

Breast cancer stem-like cells are inhibited by a non-toxic aryl hydrocarbon receptor agonist.

BACKGROUND: Cancer stem cells (CSCs) have increased resistance to cancer chemotherapy. They can be enriched as drug-surviving CSCs (D-CSCs) by growth with chemotherapeutic drugs, and/or by sorting of cells expressing CSC markers such as aldehyde dehydrogenase-1 (ALDH). CSCs form colonies in agar, mammospheres in low-adherence cultures, and tumors following xenotransplantation in Scid mice. We hypothesized that tranilast, a non-toxic orally active drug with anti-cancer activities, would inhibit breast CSCs. METHODOLOGY/FINDINGS: We examined breast cancer cell lines or D-CSCs generated by growth of these cells with mitoxantrone. Tranilast inhibited colony formation, mammosphere formation and stem cell marker expression. Mitoxantrone-selected cells were enriched for CSCs expressing stem cell markers ALDH, c-kit, Oct-4, and ABCG2, and efficient at forming mammospheres. Tranilast markedly inhibited mammosphere formation by D-CSCs and dissociated formed mammospheres, at pharmacologically relevant concentrations. It was effective against D-CSCs of both HER-2+ and triple-negative cell lines. Tranilast was also effective in vivo, since it prevented lung metastasis in mice injected i.v. with triple-negative (MDA-MB-231) mitoxantrone-selected cells. The molecular targets of tranilast in cancer have been unknown, but here we demonstrate it is an aryl hydrocarbon receptor (AHR) agonist and this plays a key role. AHR is a transcription factor activated by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), polycyclic aromatic hydrocarbons and other ligands. Tranilast induced translocation of the AHR to the nucleus and stimulated CYP1A1 expression (a marker of AHR activation). It inhibited binding of the AHR to CDK4, which has been linked to cell-cycle arrest. D-CSCs expressed higher levels of the AHR than other cells. Knockdown of the AHR with siRNA, or blockade with an AHR antagonist, entirely abrogated the anti-proliferative and anti-mammosphere activity of tranilast. Thus, the anti-cancer effects of tranilast are AHR dependent. CONCLUSION/SIGNIFICANCE: We show that tranilast is an AHR agonist with inhibitory effects on breast CSCs. It is effective against CSCs of triple-negative breast cancer cells selected for anti-cancer drug resistance. These results suggest it might find applications in the treatment of breast cancer.