David W. Cescon

Functional variants of OCTN cation transporter genes are associated with Crohn disease

Crohn disease is a chronic, inflammatory disease of the gastrointestinal tract. A locus of ∼250 kb at 5q31 (IBD5) was previously associated with susceptibility to Crohn disease, as indicated by increased prevalence of a risk haplotype of 11 single-nucleotide polymorphisms among individuals with Crohn disease, but the pathogenic lesion in the region has not yet been identified. We report here that two variants in the organic cation transporter cluster at 5q31 (a missense substitution in SLC22A4 and a G→C transversion in the SLC22A5 promoter) form a haplotype associated with susceptibility to Crohn disease. These variants alter transcription and transporter functions of the organic cation transporters and interact with variants in another gene associated with Crohn disease, CARD15, to increase risk of Crohn disease. These results suggest that SLC22A4, SLC22A5 and CARD15 act in a common pathogenic pathway to cause Crohn disease.

Evolution of the Randomized Controlled Trial in Oncology Over Three Decades

PURPOSE The randomized controlled trial (RCT) is the gold standard for establishing new therapies in clinical oncology. Here we document changes with time in design, sponsorship, and outcomes of oncology RCTs. METHODS Reports of RCTs evaluating systemic therapy for breast, colorectal (CRC), and non-small-cell lung cancer (NSCLC) published 1975 to 2004 in six major journals were reviewed. Two authors abstracted data regarding trial design, results, and conclusions. Conclusions of authors were graded using a 7-point Likert scale. For each study the effect size for the primary end point was converted to a summary measure. RESULTS A total of 321 eligible RCTs were included (48% breast, 24% CRC, 28% NSCLC). Over time, the number and size of RCTs increased considerably. For-profit/mixed sponsorship increased substantially during the study period (4% to 57%; P < .001). There was increasing use of time-to-event measures (39% to 78%) and decreasing use of response rate (54% to 14%) as primary end point (P < .001). Effect size remained stable over the study period. Authors have become more likely to strongly endorse the experimental arm (P = .017). A significant P value for the primary end point and industry sponsorship were each independently associated with endorsement of the experimental agent (odds ratio [OR] = 19.6, 95% CI, 8.9 to 43.1, and OR = 3.5, 95% CI, 1.6 to 7.5, respectively). CONCLUSION RCTs in oncology have become larger and are more likely to be sponsored by industry. Authors of modern RCTs are more likely to strongly endorse novel therapies. For-profit sponsorship and statistically significant results are independently associated with endorsement of the experimental arm.

APOBEC3B expression in breast cancer reflects cellular proliferation, while a deletion polymorphism is associated with immune activation

Significance Somatic mutagenesis is fundamental to the development and evolution of cancers. APOBEC3B (A3B) is a cellular deaminase, which is overexpressed in cancers and believed to be an important cause of cancer-associated mutations. The factors responsible for A3B up-regulation are unknown. Interestingly, a germ-line deletion polymorphism exists, such that a significant proportion of the global population does not express A3B protein. Using large human cancer datasets, we show that A3B expression is strongly associated with cellular proliferation. Furthermore, we identify a pattern of immune activation related to hypermutation in tumors arising in A3B deletion carriers suggesting that these patients could respond differently to immune-directed therapies. These results provide important context for the ongoing study of A3B as a therapeutic target or biomarker. Genomic sequencing studies of breast and other cancers have identified patterns of mutations that have been attributed to the endogenous mutator activity of APOBEC3B (A3B), a member of the AID/APOBEC family of cytidine deaminases. A3B gene expression is increased in many cancers, but its upstream drivers remain undefined. Furthermore, there exists a common germ-line deletion polymorphism (A3Bdel), which has been associated with a paradoxical increase in breast cancer risk. To examine causes and consequences of A3B expression and its constitutive absence in breast cancer, we analyzed two large clinically annotated genomic datasets [The Cancer Genome Atlas (TCGA) and the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC)]. We confirmed that A3B expression is associated with aggressive clinicopathologic characteristics and adverse outcomes and show that A3B expression is highly correlated with proliferative features (mitosis and cell cycle-related gene expression) in breast and 15 of 16 other solid tumor types. However, breast cancers arising in homozygous A3Bdel individuals with A3B absent did not differ in these features, indicating that A3B expression is a reflection rather than a direct cause of increased proliferation. Using gene set enrichment analysis (GSEA), we detected a pattern of immune activation in A3Bdel breast cancers, which seems to be related to hypermutation arising in A3Bdel carriers. Together, these results provide an explanation for A3B overexpression and its prognostic effect, giving context to additional study of this mutator as a cancer biomarker or putative drug target. In addition, although immune features of A3Bdel require additional study, these findings nominate the A3Bdel polymorphism as a potential predictor for cancer immunotherapy.

Genetic Polymorphisms and Head and Neck Cancer Outcomes: A Review

Head and neck cancer (HNC) patients have variable prognoses even within the same clinical stage and while receiving similar treatments. The number of studies of genetic polymorphisms as prognostic factors of HNC outcomes is growing. Candidate polymorphisms have been evaluated in DNA repair, cell cycle, xenobiotic metabolism, and growth factor pathways. Polymorphisms of XRCC1, FGFR, and CCND1 have been consistently associated with HNC survival in at least two studies, whereas most of the other polymorphisms have either conflicting data or were from single studies. Heterogeneity and lack of description of patient populations and lack of accounting for multiple comparisons were common problems in a significant proportion of studies. Despite a large number of exploratory studies, large replication studies in well-characterized HNC populations are warranted. (Cancer Epidemiol Biomarkers Prev 2008;17(3):490–9)

Extended Adjuvant Tamoxifen for Early Breast Cancer: A Meta-Analysis

Background Hormone receptor positive breast cancer is characterized by the potential for disease recurrence many years after initial diagnosis. Endocrine therapy has been shown to reduce the risk of such recurrence, but the optimal duration of endocrine therapy remains unclear. Methods We conducted a systematic review and meta-analysis to quantify the benefits and harms of extended adjuvant tamoxifen (>5 years of therapy) compared with adjuvant tamoxifen (5 years of therapy). Odds ratios (ORs) and 95% confidence intervals (CIs) were computed for disease recurrence, death and adverse events. Subgroup analyses by timing of recurrence and baseline lymph node and menopause status were carried. Results Five trials comprising 21,554 patients were included. Extended adjuvant tamoxifen was not associated with a significant reduction in the risk of recurrence (OR:0.89, 95% CI 0.76–1.05, p = 0.17). There was no association between extended adjuvant tamoxifen and all-cause death (OR:0.99, 95% CI 0.84–1.16, p = 0.88). There was an apparent reduction in risk of recurrence occurring after completion of extended adjuvant tamoxifen with little evidence of effect during therapy, however, this difference was not significant (p for difference 0.10). Subgroup analysis suggested that a greater effect size among lymph node positive patients compared with those who are lymph node negative (NNT: 25 vs. 49). There was no apparent difference in the effect between pre- and post-menopausal patients. Endometrial carcinoma was substantially more frequent with extended adjuvant tamoxifen (OR:2.06, 95% CI 1.65–2.58, p<0.001, number needed to harm:89). Conclusion In unselected patients, extended adjuvant tamoxifen is not associated with a significant reduction in recurrence, or a reduction in all-cause death. Patients with lymph node positive breast cancer may derive some benefit. Reduction in the risk of recurrence appears to occur only after completion of extended adjuvant therapy.

p53 Arg72Pro and MDM2 T309G Polymorphisms, Histology, and Esophageal Cancer Prognosis

Purpose: This study aimed to evaluate the prognostic significance of two functional single nucleotide polymorphisms (SNP) in the p53 pathway (p53 Arg72Pro and MDM2 T309G) in patients with esophageal cancer, and to determine the importance of histologic subtype in the SNP-outcome relationships. Experimental Design: A cohort of 371 patients with esophageal carcinoma enrolled in Boston, USA from 1999 to 2004 were genotyped for the p53 and MDM2 SNPs. Associations between genotypes and overall survival (OS; the primary outcome) and progression-free survival (PFS) were assessed using the Kaplan-Meier method. Cox proportional hazard models, adjusted for age, stage, performance status, and smoking were developed. Interaction analyses were done for histology (adenocarcinoma versus squamous cell carcinoma). Results: At the median follow-up of 33 months, median survival (MS) and PFS were 29.1 and 15.7 months, respectively. p53 Pro/Pro was strongly associated with shorter survival in the entire cohort (MS of 11.8 versus 29.1 months, P < 0.0001; adjusted hazard ratio for death, 2.05; 95% confidence interval, 1.30-3.24; P = 0.002 for Pro/Pro versus Arg/Arg). MDM2 G/G was associated with markedly reduced survival in squamous cell carcinoma (MS of 10.3 versus 49.4 months; adjusted hazard ratio for death, 7.9; 95% confidence interval, 2.4-26.0; P = 0.0007 for G/G versus T/T) but not in adenocarcinoma (SNP-histology interaction P = 0.004). Conclusions: In a large prospective cohort, p53 Arg72Pro Pro/Pro was associated with a 2-fold increased risk of death in all esophageal cancers, whereas MDM2 T309G G/G was associated with a 7-fold increased risk of death in squamous cell carcinoma.

Pharmacogenetic and Germline Prognostic Markers of Lung Cancer

Introduction: Lung cancer is the leading global cause of cancer-related mortality. Interindividual variability in treatment response and cancer outcomes has focused attention on genetic polymorphisms as prognostic markers. We evaluated the overall contribution of candidate polymorphism association studies to our current understanding of the genetic predictors of lung cancer outcomes. Methods: We examined the results of 90 studies that evaluated associations between genetic polymorphisms and lung cancer outcomes published between January 1990 and May 2009. Results: A total of 170 genetic variations in 90 studies were identified. Overall survival was a primary outcome in 81% of the studies and toxicity in 19%. Candidate polymorphisms in the DNA repair/synthesis pathway were the most frequently studied. Strong evidence in large-scale confirmatory studies of any single polymorphism was lacking. Polymorphisms of EGFR, XRCC1, and ERCC1 were associated with pharmacogenetic outcomes, whereas polymorphisms of MDM2, p53, and GSTM1 were associated with prognostic outcomes. All remaining polymorphisms had results lacking or failing replication testing. Heterogeneity in study populations, incomplete reporting of important population or study characteristics, inadequate power, and inconsistencies in methodology were common. Conclusions: Although the quality of existing studies involving the candidate polymorphism approach is highly variable, a small set of candidate polymorphisms was identified as potential biomarkers of clinical or pharmacogenetic outcome and would benefit from further replication testing. Newer approaches including haplotype tagging, pathway, genome-wide association, and combination methods with validative approaches may facilitate a more accurate prediction of lung cancer outcomes by genetic variation.

Barcoded Medication Administration: A Last Line of Defense

PREVENTABLE ADVERSE DRUG EVENTS (ADES) GENERate an estimated

Absolute benefits of medical therapies in phase III clinical trials for breast and colorectal cancer

2 billion in direct hospital costs each year and are a substantial source of morbidity and mortality. The 2 processes from which preventable ADEs most commonly arise are medication prescribing and administration. A physician order for penicillin for a patient with a known penicillin allergy is an example of the former, whereas the latter is illustrated by the erroneous administration of 100 units of insulin when 10 were ordered. There has been considerable attention devoted to reducing prescribing error with systematic solutions such as computerized physician order entry, electronic decision support, and pharmacist presence during physician rounds. None of these solutions, however, reduces medication administration errors, which account for 34% of preventable ADEs. Although occasionally attracting media attention, fines, and legal action, these errors are difficult to identify and almost never intercepted. Traditionally, the vigilance of nurses has been the predominant protection against medication administration errors, without any systematic safeguard to ensure that the “5 rights” (right patient, right drug, right dose, right route, and right time) are achieved for billions of medication doses each year. When they do occur, errors in medication administration can be traumatic experiences for the nurses involved, with significant personal and professional consequences. Barcoded medication administration (BCMA) systems are a last line of defense against medication errors and warrant greater advocacy and implementation. Just as couriers are empowered with barcodes to track their packages to safe delivery, so too can nurses be empowered with barcodes to ensure the safe administration of medications to patients.

Toxicity of Extended Adjuvant Therapy With Aromatase Inhibitors in Early Breast Cancer: A Systematic Review and Meta-analysis

BACKGROUND Phase III randomized clinical trials (RCTs) have become larger and are powered to detect small absolute benefits. Temporal changes in absolute benefits of experimental medical therapies reported in RCTs are unknown. METHODS We identified all RCTs with sample size > or =200 evaluating experimental medical therapies for breast and colorectal cancer published from 1975 to 2007. We assessed changes over three decades in absolute differences in time-to-event end points between experimental and control arms by (i) the usual method (i.e. at one point) and (ii) as the area between time-to-event curves up to a predefined time. RESULTS We identified 236 eligible RCTs of which 57% (N = 135) evaluated adjuvant treatments. Experimental treatments became more often compared with active treatments (48% versus 59% versus 81%; P < 0.0001). Median absolute benefits of experimental adjuvant treatments decreased but outcomes in control arms improved with time. For RCTs evaluating metastatic disease, there were no changes in absolute benefit over time but incremental monthly costs of new approved treatments increased with time by 100-fold (P < 0.0001). CONCLUSION In RCTs of breast and colorectal cancer, new effective adjuvant treatments show decreasing absolute benefit, while new treatments of metastatic disease show unchanging levels of benefit at rapidly escalating costs.