Previous meta-analyses have shown that the antidiabetic agent metformin is associated with reduced cancer incidence and mortality. However, this effect has not been consistently demonstrated in animal models and recent epidemiologic studies. We performed a meta-analysis with a focus on confounders and biases, including body mass index (BMI), study type, and time-related biases. We identified 71 articles published between January 1, 1966, and May 31, 2013, through Pubmed, ISI Web of Science (Science Citation Index Expanded), Embase, and the Cochrane library that were related to metformin and cancer incidence or mortality. Study characteristics and outcomes were abstracted for each study that met inclusion criteria. We included estimates from 47 independent studies and 65,540 cancer cases in patients with diabetes. Overall cancer incidence was reduced by 31% [summary relative risk (SRR), 0.69; 95% confidence interval (CI), 0.52–0.90], although between-study heterogeneity was considerable (I² = 88%). Cancer mortality was reduced by 34% (SRR, 0.66; 95% CI, 0.54–0.81; I² = 21%). BMI-adjusted studies and studies without time-related biases also showed significant reduction in cancer incidence (SRR, 0.82; 95% CI, 0.70–0.96 with I² = 76% and SRR, 0.90; 95% CI, 0.89–0.91 with I² = 56%, respectively), albeit with lesser magnitude (18% and 10% reduction, respectively). However, studies of cancer mortality and individual organ sites did not consistently show significant reductions across all types of analyses. Although these associations may not be causal, our results show that metformin may reduce cancer incidence and mortality in patients with diabetes However, the reduction seems to be of modest magnitude and not affecting all populations equally. Clinical trials are needed to determine if these observations apply to nondiabetic populations and to specific organ sites. Cancer Prev Res; 7(9); 867–85. ©2014 AACR.

Cancers often arise as the end stage of inflammation in adults, but not in children. As such there is a complex interplay between host immune cells during neoplastic development, with both an ability to promote cancer and limit or eliminate it, most often complicit with the host. In humans, defining inflammation and the presence of inflammatory cells within or surrounding the tumor is a critical aspect of modern pathology. Groups defining staging for neoplasms are strongly encouraged to assess and incorporate measures of the presence of apoptosis, autophagy, and necrosis and also the nature and quality of the immune infiltrate. Both environmental and genetic factors enhance the risk of cigarette smoking, Helicobacter pylori, hepatitis B/C, human papilloma virus, solar irradiation, asbestos, pancreatitis, or other causes of chronic inflammation. Identifying suitable genetic polymorphisms in cytokines, cytokine receptors, and Toll-like receptors among other immune response genes is also seen as high value as genomic sequencing becomes less expensive. Animal models that incorporate and assess not only the genetic anlagen but also the inflammatory cells and the presence of microbial pathogens and damage-associated molecular pattern molecules are necessary. Identifying micro-RNAs involved in regulating the response to damage or injury are seen as highly promising. Although no therapeutic strategies to prevent or treat cancers based on insights into inflammatory pathways are currently approved for the common epithelial malignancies, there remains substantial interest in agents targeting COX2 or PPARγ, ethyl pyruvate and steroids, and several novel agents on the horizon.

Although only a subset of smokers develop lung cancer, we cannot determine which smokers are at highest risk for cancer development, nor do we know the signaling pathways altered early in the process of tumorigenesis in these individuals. On the basis of the concept that cigarette smoke creates a molecular field of injury throughout the respiratory tract, this study explores oncogenic pathway deregulation in cytologically normal proximal airway epithelial cells of smokers at risk for lung cancer. We observed a significant increase in a genomic signature of phosphatidylinositol 3-kinase (PI3K) pathway activation in the cytologically normal bronchial airway of smokers with lung cancer and smokers with dysplastic lesions, suggesting that PI3K is activated in the proximal airway before tumorigenesis. Further, PI3K activity is decreased in the airway of high-risk smokers who had significant regression of dysplasia after treatment with the chemopreventive agent myo-inositol, and myo-inositol inhibits the PI3K pathway in vitro. These results suggest that deregulation of the PI3K pathway in the bronchial airway epithelium of smokers is an early, measurable, and reversible event in the development of lung cancer and that genomic profiling of these relatively accessible airway cells may enable personalized approaches to chemoprevention and therapy. Our work further suggests that additional lung cancer chemoprevention trials either targeting the PI3K pathway or measuring airway PI3K activation as an intermediate endpoint are warranted.

This article reviews progress in chemopreventive drug development, especially data and concepts that are new since the 2002 AACR report on treatment and prevention of intraepithelial neoplasia. Molecular biomarker expressions involved in mechanisms of carcinogenesis and genetic progression models of intraepithelial neoplasia are discussed and analyzed for how they can inform mechanism-based, molecularly targeted drug development as well as risk stratification, cohort selection, and end-point selection for clinical trials. We outline the concept of augmenting the risk, mechanistic, and disease data from histopathologic intraepithelial neoplasia assessments with molecular biomarker data. Updates of work in 10 clinical target organ sites include new data on molecular progression, significant completed trials, new agents of interest, and promising directions for future clinical studies. This overview concludes with strategies for accelerating chemopreventive drug development, such as integrating the best science into chemopreventive strategies and regulatory policy, providing incentives for industry to accelerate preventive drugs, fostering multisector cooperation in sharing clinical samples and data, and creating public-private partnerships to foster new regulatory policies and public education.