A Bayesian adaptive marker‐stratified design for molecularly targeted agents with customized hierarchical modeling

It is well known that the treatment effect of a molecularly targeted agent (MTA) may vary dramatically, depending on each patient's biomarker profile. Therefore, for a clinical trial evaluating MTA, it is more reasonable to evaluate its treatment effect within different marker subgroups rather than evaluating the average treatment effect for the overall population. The marker‐stratified design (MSD) provides a useful tool to evaluate the subgroup treatment effects of MTAs. Under the Bayesian framework, the beta‐binomial model is conventionally used under the MSD to estimate the response rate and test the hypothesis. However, this conventional model ignores the fact that the biomarker used in the MSD is, in general, predictive only for the MTA. The response rates for the standard treatment can be approximately consistent across different subgroups stratified by the biomarker. In this paper, we proposed a Bayesian hierarchical model incorporating this biomarker information into consideration. The proposed model uses a hierarchical prior to borrow strength across different subgroups of patients receiving the standard treatment and, therefore, improve the efficiency of the design. Prior informativeness is determined by solving a “customized” equation reflecting the physician's professional opinion. We developed a Bayesian adaptive design based on the proposed hierarchical model to guide the treatment allocation and test the subgroup treatment effect as well as the predictive marker effect. Simulation studies and a real trial application demonstrate that the proposed design yields desirable operating characteristics and outperforms the existing designs

Methyl-CpG-binding domain sequencing reveals a prognostic methylation signature in neuroblastoma

Accurate assessment of neuroblastoma outcome prediction remains challenging. Therefore, this study aims at establishing novel prognostic tumor DNA methylation biomarkers. In total, 396 low- and high-risk primary tumors were analyzed, of which 87 were profiled using methyl-CpG-binding domain (MBD) sequencing for differential methylation analysis between prognostic patient groups. Subsequently, methylation-specific PCR (MSP) assays were developed for 78 top-ranking differentially methylated regions and tested on two independent cohorts of 132 and 177 samples, respectively. Further, a new statistical framework was used to identify a robust set of MSP assays of which the methylation score (i.e. the percentage of methylated assays) allows accurate outcome prediction. Survival analyses were performed on the individual target level, as well as on the combined multimarker signature. As a result of the differential DNA methylation assessment by MBD sequencing, 58 of the 78 MSP assays were designed in regions previously unexplored in neuroblastoma, and 36 are located in non-promoter or non-coding regions. In total, 5 individual MSP assays (located in CCDC177, NXPH1, lnc-MRPL3-2, lnc-TREX1-1 and one on a region from chromosome 8 with no further annotation) predict event-free survival and 4 additional assays (located in SPRED3, TNFAIP2, NPM2 and CYYR1) also predict overall survival. Furthermore, a robust 58-marker methylation signature predicting overall and event-free survival was established. In conclusion, this study encompasses the largest DNA methylation biomarker study in neuroblastoma so far. We identified and independently validated several novel prognostic biomarkers, as well as a prognostic 58-marker methylation signature

Biomarkers in acute coronary syndromes and their role in diabetic patients

Diabetic patients with acute coronary syndromes are at high risk for cardiovascular complications but risk stratification in these patients remains challenging. Regularly, diabetic patients have a less typical clinical presentation, which could lead to delayed diagnosis and subsequent delayed initiation of treatment. Since diabetic patients derive particular benefit from aggressive anti-platelet therapy, early diagnostic and therapeutic risk stratification of these patients is of critical importance to improve their adverse outcome. Although the electrocardiogram remains a pivotal diagnostic tool in the evaluation of patients suspected of having an acute coronary syndrome, only significant STsegment changes provide reasonable prognostic information. Therefore, repeated assessment of circulating protein biomarkers represents a valuable diagnostic tool for improving efficacy and safety of decision-making in these patients. The combined use of biomarkers reflecting distinct pathophysiological aspects, such as myocardial necrosis, vascular inflammation, oxidative stress and neurohumoral activation, may significantly improve triage of patients with chest pain. These tools may identify those patients that are at particularly high risk for short-term and/or long-term cardiovascular events. Eventually, tailored medical and interventional treatment of diabetic patients should help to prevent these cardiac events in a cost-effective manner

Follow-up after curative resection for gastric cancer. Is it time to tailor it?

There is still no consensus on the follow-up frequency and regimen after curative resection for gastric cancer. Moreover, controversy exists regarding the utility of follow-up in improving survival, and the recommendations of experts and societies vary considerably. The main reason to establish surveillance programs is to diagnose tumor recurrence or metachronous cancers early and to thereby provide prompt treatment and prolong survival. In the setting of gastric malignancies, other reasons have been put forth: (1) the detection of adverse effects of a previous surgery, such as malnutrition or digestive sequelae; (2) the collection of data; and (3) the identification of psychological and/or social problems and provision of appropriate support to the patients. No randomized controlled trials on the role of follow-up after curative resection of gastric carcinoma have been published. Herein, the primary retrospective series and systematic reviews on this subject are analyzed and discussed. Furthermore, the guidelines from international and national scientific societies are discussed. Follow-up is recommended by the majority of institutions; however, there is no real evidence that follow-up can improve long-term survival rates. Several studies have demonstrated that it is possible to stratify patients submitted to curative gastrectomy into different classes according to the risk of recurrence. Furthermore, promising studies have identified several molecular markers that are related to the risk of relapse and to prognosis. Based on these premises, a promising strategy will be to tailor follow-up in relation to the patient and tumor characteristics, molecular marker status, and individual risk of recurrence

Preoperative CYFRA 21-1 and CEA as Prognostic Factors in Patients with Stage I Non-Small Cell Lung Cancer

Objective: To validate the prognostic value of preoperative levels of CYFRA 21-1, CEA and the corresponding tumor marker index (TMI) in patients with stage I non-small cell lung cancer (NSCLC). Methods: Two hundred forty stage I NSCLC patients (80 in pT1 and 160 in pT2; 100 squamous cell carcinomas, 91 adenocarcinomas, 32 large-cell carcinomas, 17 with other histologies; 171 males and 69 females) who had complete resection (R0) between 1986 and 2004 were included in the analysis. CYFRA 21-1 and CEA were measured using the Elecsys system (Roche) and AxSym-System (Abbott), respectively. Univariate analysis was performed using the Kaplan-Meier method to identify potential associations between survival and age, gender, CYFRA 21-1, CEA and TMI. Results: Overall 3- and 5-year survival rates were 74 and 64%, respectively. Male gender (p = 0.0009) and age 1 70 years (p = 0.0041) were associated with a worse prognosis; there were no differences between pT1 and pT2 nor between histological subtypes. Three- year survival was 72% for CYFRA 21-1 levels > 3.3 ng/ml versus 75% for levels 6.7 ng/ ml versus 75% for CEA 70 years were associated with a worse outcome, but elevated levels of CEA and CYFRA 21-1, and TMI risk were not. Copyright (C) 2008 S. Karger AG, Basel

HAGE (DDX43) is a biomarker for poor prognosis and a predictor of chemotherapy response in breast cancer

Background: HAGE protein is a known immunogenic cancer-specific antigen. Methods: The biological, prognostic and predictive values of HAGE expression was studied using immunohistochemistry in three cohorts of patients with BC (n=2147): early primary (EP-BC; n=1676); primary oestrogen receptor-negative (PER-BC; n=275) treated with adjuvant anthracycline-combination therapies (Adjuvant-ACT); and primary locally advanced disease (PLA-BC) who received neo-adjuvant anthracycline-combination therapies (Neo-adjuvant-ACT; n=196). The relationship between HAGE expression and the tumour-infiltrating lymphocytes (TILs) in matched prechemotherapy and postchemotherapy samples were investigated. Results: Eight percent of patients with EP-BC exhibited high HAGE expression (HAGEþ) and was associated with aggressive clinico-pathological features (Ps<0.01). Furthermore, HAGEþexpression was associated with poor prognosis in both univariate and multivariate analysis (Ps<0.001). Patients with HAGE+ did not benefit from hormonal therapy in high-risk ER-positive disease. HAGE+ and TILs were found to be independent predictors for pathological complete response to neoadjuvant-ACT; P<0.001. A statistically significant loss of HAGE expression following neoadjuvant-ACT was found (P=0.000001), and progression-free survival was worse in those patients who had HAGE+ residual disease (P=0.0003). Conclusions: This is the first report to show HAGE to be a potential prognostic marker and a predictor of response to ACT in patients with BC

The prognostic role of VEGF in head and neck squamous cell carcinoma

Emerging from potentially malignant disorders that in most cases will never become cancerous, head and neck squamous cell carcinoma (HNSCC) is a cancer that is extremely difficult to diagnose early. This late stage diagnosis has allowed limited improvements in overall survival (OS) as patients are prone to local recurrence, secondary primary tumors, and distant metastasis. As a result, it has become vitally important to assess the prognostic value of biological marker screening to provide an avenue for early diagnosis and identification of local recurrence or residual secondary tumor sites. Many characteristic markers such as EGFR, p16, p53 and VEGF that are constitutively mutated in HNSCC have been identified. However, the dysregulation of VEGF marks a landmark mutation that accelerates the diseases progression and spread. An angiogenic protein normally expressed in response to hypoxic conditions, VEGF allows the creation of new vasculature to remove catabolites and bestows resistance to normal cellular apoptotic signals; pathways often employed by chemotherapeutics. Therefore, early identification of VEGF poses a unique opportunity to employ aggressive therapeutic regimens in combination with precision surgical resection to eliminate the cancer before neovascualture invasion has occurred and the tumor has expanded significantly. For this reason, this review will examine the current literature available on VEGFs role in HNSCC, its value as a prognostic marker

A multi-factorial genetic model for prognostic assessment of high risk melanoma patients receiving adjuvant interferon

Purpose: IFNa was the first cytokine to demonstrate anti-tumor activity in advanced melanoma. Despite the ability of high-dose IFNa reducing relapse and mortality by up to 33%, large majority of patients experience side effects and toxicity which outweigh the benefits. The current study attempts to identify genetic markers likely to be associated with benefit from IFN-a2b treatment and predictive for survival. Experimental design: We tested the association of variants in FOXP3 microsatellites, CTLA4 SNPs and HLA genotype in 284 melanoma patients and their association with prognosis and survival of melanoma patients who received IFNa adjuvant therapy. Results: Univariate survival analysis suggested that patients bearing either the DRB1*15 or HLA-Cw7 allele suffered worse OS while patients bearing either HLA-Cw6 or HLA-B44 enjoyed better OS. DRB1*15 positive patients suffered also worse RFS and conversely HLA-Cw6 positive patients had better RFS. Multivariate analysis revealed that a five-marker genotyping signature was prognostic of OS independent of disease stage. In the multivariate Cox regression model, HLA-B38 (p = 0.021), HLA-C15 (p = 0.025), HLA-C3 (p = 0.014), DRB1*15 (p = 0.005) and CT60*G/G (0.081) were significantly associated with OS with risk ratio of 0.097 (95% CI, 0.013-0.709), 0.387 (95% CI, 0.169-0.889), 0.449 (95% CI, 0.237-0.851), 1.948 (95% CI, 1.221-3.109) and 1.484 (95% IC, 0.953-2.312) respectively. Conclusion: These results suggest that gene polymorphisms relevant to a biological occurrence are more likely to be informative when studied in concert to address potential redundant or conflicting functions that may limit each gene individual contribution. The five markers identified here exemplify this concept though prospective validation in independent cohorts is needed

ST2 in Stable and Unstable Ischemic Heart Diseases

Circulating suppression of tumorigenicity 2 (ST2) predicts cardiovascular outcomes and mortality in ischemic heart disease (IHD). ST2 does not correlate with traditional risk indicators as closely as N-terminal pro–brain natriuretic peptide (NT-proBNP) and is only weakly correlated with other biomarkers, indicating distinct pathways for stimulus and release. Although of little diagnostic utility in IHD, ST2 does offer prognostic information. In ST elevation myocardial infarction, ST2 levels increase to peak above the normal reference range (within 6 to 18 hours of symptom onset) in about half of patients. Levels in the upper quartile observed in IHD independently predict cardiovascular death and heart failure with an approximate doubling of risk. Similar but weaker associations have been reported in non–ST elevation myocardial infarction, in which ST2 predicts short-term (30-day) and long-term (>1-year) death and heart failure independent of clinical indicators, but these relations are lost if Global Registry of Acute Coronary Events (GRACE) score and NT-proBNP are added to multivariate models. Early postinfarction levels of ST2 (i.e., <24 hours after admission) have the greatest prognostic utility. Early postinfarction ST2 levels and change over 24 weeks are related to infarct extent and remodeling to a similar extent as NT-proBNP and aldosterone, and ST2 may have a significant pathophysiological role in these postinfarction processes. In long-term follow-up of stable IHD, ST2 is predictive of all-cause and cardiovascular mortality independent of accepted clinical indicators and other biomarkers, including NT-proBNP, high-sensitivity C-reactive protein, interleukin-6, high-sensitivitiy cardiac troponin T, and galectin-3. In conclusion, ST2 in combination with NT-proBNP consistently improves risk stratification compared with either marker alone

Death receptor 5 expression is inversely correlated with prostate cancer progression.

Prostate carcinoma (PCa) is one of the most common cancers in men. Prostate-specific antigen (PSA) has been widely used to predict the outcome of PCa and screening with PSA has resulted in a decline in mortality. However, PSA is not an optimal prognostic tool as its sensitivity may be too low to reduce morbidity and mortality. Consequently, there is a demand for additional robust biomarkers for prostate cancer. Death receptor 5 (DR5) has been implicated in the prognosis of several cancers and it has been previously shown that it is negatively regulated by Yin Yang 1 (YY1) in prostate cancer cell lines. The present study investigated the clinical significance of DR5 expression in a prostate cancer patient cohort and its correlation with YY1 expression. Immunohistochemical analysis of protein expression distribution was performed using tissue microarray constructs from 54 primary PCa and 39 prostatic intraepithelial neoplasia (PIN) specimens. DR5 expression was dramatically reduced as a function of higher tumor grade. By contrast, YY1 expression was elevated in PCa tumors as compared with that in PIN, and was increased with higher tumor grade. DR5 had an inverse correlation with YY1 expression. Bioinformatic analyses corroborated these data. The present findings suggested that DR5 and YY1 expression levels may serve as progression biomarkers for prostate cancer