Showing papers in "Cancer Epidemiology, Biomarkers & Prevention in 2014"

Gastric Cancer: Descriptive Epidemiology, Risk Factors, Screening, and Prevention

Abstract: Less than a century ago, gastric cancer (GC) was the most common cancer in the United States and perhaps throughout the world. Despite its worldwide decline in incidence over the past century, GC remains a major killer across the globe. This article reviews the epidemiology, screening, and prevention of gastric cancer. We first discuss the descriptive epidemiology of GC, including its incidence, survival, and mortality, including trends over time. Next, we characterize the risk factors for gastric cancer, both environmental and genetic. Serological markers and histological precursor lesions of GC and early detection of GC of using these markers is reviewed. Finally, we discuss prevention strategies and provide suggestions for further research.

Epidemiologic and Molecular Prognostic Review of Glioblastoma

Abstract: Glioblastoma multiforme (GBM) is the most common and aggressive primary central nervous system malignancy with a median survival of 15 months. The average incidence rate of GBM is 3.19/100,000 population, and the median age of diagnosis is 64 years. Incidence is higher in men and individuals of white race and non-Hispanic ethnicity. Many genetic and environmental factors have been studied in GBM, but the majority are sporadic, and no risk factor accounting for a large proportion of GBMs has been identified. However, several favorable clinical prognostic factors are identified, including younger age at diagnosis, cerebellar location, high performance status, and maximal tumor resection. GBMs comprise of primary and secondary subtypes, which evolve through different genetic pathways, affect patients at different ages, and have differences in outcomes. We report the current epidemiology of GBM with new data from the Central Brain Tumor Registry of the United States 2006 to 2010 as well as demonstrate and discuss trends in incidence and survival. We also provide a concise review on molecular markers in GBM that have helped distinguish biologically similar subtypes of GBM and have prognostic and predictive value.

Prognostic Role of Platelet to Lymphocyte Ratio in Solid Tumors: A Systematic Review and Meta-Analysis

Abstract: 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 ( 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. Cancer Epidemiol Biomarkers Prev; 23(7); 1204–12. ©2014 AACR . This article is featured in Highlights of This Issue, [p. 1137][1] [1]: /lookup/volpage/23/1137?iss=7

Programmed Cell Death 1 (PD-1) and Its Ligand (PD-L1) in Common Cancers and Their Correlation with Molecular Cancer Type

Abstract: Cancer cells expressing PD-1 ligands (PD-L1/PD-L2) inhibit immune-modulatory T-cell activation facilitating disease progression. Preliminary clinical trials exploring interruption of PD-1/PD-L1 signaling showed benefit in several cancer types. We analyzed the distribution of PD-1-positive tumor-infiltrating lymphocytes (TIL) and cancer cells' expression of PD-L1 in a molecularly profiled cohort of 437 malignancies (380 carcinomas, 33 sarcomas, and 24 melanomas). We showed that the presence of PD-1(+) TILs significantly varied among cancer types (from 0% in extraskeletal myxoid chondrosarcomas to 93% in ovarian cancer), and was generally associated with the increased number of mutations in tumor cells (P = 0.029). Cancer cell expression of PD-L1 varied from absent (in Merkel cell carcinomas) to 100% (in chondro- and liposarcomas), but showed the inverse association with the number of detected mutations (P = 0.004). Both PD-1 and PD-L1 expression were significantly higher in triple-negative breast cancers (TNBC) than in non-TNBC (P < 0.001 and 0.017, respectively). Similarly, MSI-H colon cancers had higher PD-1 and PD-L1 expression than the microsatellite stable tumors (P = 0.002 and 0.02, respectively). TP53-mutated breast cancers had significantly higher PD-1 positivity than those harboring other driver mutations (e.g., PIK3CA; P = 0.002). In non-small cell lung cancer, PD-1/PD-L1 coexpression was identified in 8 cases (19%), which lacked any other targetable alterations (e.g., EGFR, ALK, or ROS1). Our study demonstrated the utility of exploring the expression of two potentially targetable immune checkpoint proteins (PD-1/PD-L1) in a substantial proportion of solid tumors, including some aggressive subtypes that lack other targeted treatment modalities.

Childhood brain tumor epidemiology: a brain tumor epidemiology consortium review.

Abstract: Childhood brain tumors are the most common pediatric solid tumor and include several histological subtypes. Although progress has been made in improving survival rates for some subtypes, understanding of risk factors for childhood brain tumors remains limited to a few genetic syndromes and ionizing radiation to the head and neck. In this report, we review descriptive and analytical epidemiology childhood brain tumor studies from the past decade and highlight priority areas for future epidemiology investigations and methodological work that is needed to advance our understanding of childhood brain tumor causes. Specifically, we summarize the results of a review of studies published since 2004 that have analyzed incidence and survival in different international regions and that have examined potential genetic, immune system, developmental and birth characteristics, and environmental risk factors.

Cancer in Africa 2012

Abstract: Background:Non-communicable diseases, and especially cancers, are recognized as an increasing problem for low- and middle income countries. Effective control programmes require adequate information on the size, nature, and evolution of the health problem which they pose. Methods:We present estimates of the incidence and mortality of cancer in Africa in 2012, derived from "Globocan 2012", published by the International Agency for Research on Cancer. Results: There were 847,000 new cancer cases (6% of the world total) and 591,000 deaths (7.2% of the world total) in the 54 countries of Africa in 2012. While the cancer profiles often differ markedly between regions, the most common cancers in men were prostate (16.4% of new cancers), liver (10.7%) and Kaposi sarcoma (6.7%); in women, by far the most important are cancers of the breast (27.6% of all cancers) and cervix uteri (20.4%). Conclusions: These results are based on the best data currently available, and provide a reasonable appraisal of the cancer situation in Africa. With the number of annual cancer cases and deaths likely to increase by at least 70% by 2030 there is a pressing need for a coordinated approach to improving the extent and quality of services for cancer control in Africa, and better surveillance systems with which they can be planned and monitored. Impact:The need for developing cancer surveillance systems in Africa for planning and monitoring cancer prevention and control in the region.

Iron and Cancer Risk—A Systematic Review and Meta-analysis of the Epidemiological Evidence

Abstract: Iron has been suggested as a risk factor for different types of cancers mainly due to its prooxidant activity, which can lead to oxidative DNA damage. Furthermore, subjects with hemochromatosis or iron overload have been shown to have a higher risk of developing liver cancer. We have systematically reviewed 59 epidemiologic studies, published between 1995 and 2012, reporting information on total iron, dietary iron, heme iron, and biomarkers of iron status and cancer risk. Furthermore we conducted meta-analysis for colorectal [relative risk (RR), 1.08; 95% confidence interval (CI), 1.00-1.17], colon (RR = 1.12; 95% CI, 1.03-1.22), breast (RR = 1.03; 95% CI, 0.97-1.09), and lung cancer (RR = 1.12; 95% CI, 0.98-1.29), for an increase of 1 mg/day of heme iron intake. Globally, on the basis of the systematic review and the meta-analysis results, a higher intake of heme iron has shown a tendency toward a positive association with cancer risk. Evidence regarding high levels of biomarkers of iron stores (mostly with serum ferritin) suggests a negative effect toward cancer risk. More prospective studies combining research on dietary iron intake, iron biomarkers, genetic susceptibility, and other relevant factors need to be conducted to clarify these findings and better understand the role of iron in cancer development.

Chronic Inflammation in Benign Prostate Tissue Is Associated with High-Grade Prostate Cancer in the Placebo Arm of the Prostate Cancer Prevention Trial

Abstract: Background: Chronic inflammation is hypothesized to influence prostate cancer development, although a definitive link has not been established. Methods: Prostate cancer cases ( N = 191) detected on a for-cause (clinically indicated) or end-of-study (protocol directed) biopsy, and frequency-matched controls ( N = 209), defined as negative for cancer on an end-of-study biopsy, were sampled from the placebo arm of the Prostate Cancer Prevention Trial. Inflammation prevalence and extent in benign areas of biopsy cores were visually assessed using digital images of hematoxylin and eosin–stained sections. Logistic regression was used to estimate associations. Results: Of note, 86.2% of cases and 78.2% of controls had at least one biopsy core (of three assessed) with inflammation in benign areas, most of which was chronic. Men who had at least one biopsy core with inflammation had 1.78 [95% confidence interval (CI), 1.04–3.06] times the odds of prostate cancer compared with men who had zero cores with inflammation. The association was stronger for high-grade disease (Gleason sum 7–10, N = 94; OR, 2.24; 95% CI, 1.06–4.71). These patterns were present when restricting to cases and controls in whom intraprostatic inflammation was the least likely to have influenced biopsy recommendation because their prostate-specific antigen (PSA) was low (<2 ng/mL at biopsy). Conclusion: Inflammation, most of which was chronic, was common in benign prostate tissue, and was positively associated with prostate cancer, especially high grade. The association did not seem to be due to detection bias. Impact: This study supports an etiologic link between inflammation and prostate carcinogenesis, and suggests an avenue for prevention by mitigating intraprostatic inflammation. Cancer Epidemiol Biomarkers Prev; 23(5); 847–56. ©2014 AACR .

The Detection of Hepatocellular Carcinoma Using a Prospectively Developed and Validated Model Based on Serological Biomarkers

Abstract: Background: Hepatocellular carcinoma is a common complication of chronic liver disease (CLD), and is conventionally diagnosed by radiological means. We aimed to build a statistical model that could determine the risk of hepatocellular carcinoma in individual patients with CLD using objective measures, particularly serological tumor markers. Methods: A total of 670 patients with either CLD alone or hepatocellular carcinoma were recruited from a single UK center into a case–control study. Sera were collected prospectively and specifically for this study. A logistic regression analysis was used to determine independent factors associated with hepatocellular carcinoma and a model built and assessed in terms of sensitivity, specificity, and proportion of correct diagnoses. Results: The final model involving gender, age, AFP-L3, α fetoprotein (AFP), and des-carboxy-prothrombin (“GALAD”) was developed in a “discovery” data set and validated in independent data sets both from the same institution and from an external institution. When optimized for sensitivity and specificity, the model gave values of more than 0.88 irrespective of the disease stage. Conclusions: The presence of hepatocellular carcinoma can be detected in patients with CLD on the basis of a model involving objective clinical and serological factors. It is now necessary to test the model's performance in a prospective manner and in a routine clinical practice setting, to determine if it may replace or, more likely, enhance current radiological approaches. Impact: Our data provide evidence that an entirely objective serum biomarker–based model may facilitate the detection and diagnosis of hepatocellular carcinoma and form the basis for a prospective study comparing this approach with the standard radiological approaches. Cancer Epidemiol Biomarkers Prev; 23(1); 144–53. ©2013 AACR .

A Web Tool for Age–Period–Cohort Analysis of Cancer Incidence and Mortality Rates

Abstract: Background: Age–period–cohort (APC) analysis can inform registry-based studies of cancer incidence and mortality, but concerns about statistical identifiability and interpretability, as well as the learning curves of statistical software packages, have limited its uptake. Methods: We implemented a panel of easy-to-interpret estimable APC functions and corresponding Wald tests in R code that can be accessed through a user-friendly Web tool. Results: Input data for the Web tool consist of age-specific numbers of events and person-years over time, in the form of a rate matrix of paired columns. Output functions include model-based estimators of cross-sectional and longitudinal age-specific rates, period and cohort rate ratios that incorporate the overall annual percentage change (net drift), and estimators of the age-specific annual percentage change (local drifts). The Web tool includes built-in examples for teaching and demonstration. User data can be input from a Microsoft Excel worksheet or by uploading a comma-separated–value file. Model outputs can be saved in a variety of formats, including R and Excel. Conclusions: APC methodology can now be carried out through a freely available user-friendly Web tool. The tool can be accessed at . Impact: The Web tool can help cancer surveillance researchers make important discoveries about emerging cancer trends and patterns. Cancer Epidemiol Biomarkers Prev; 23(11); 2296–302. ©2014 AACR .

The Heritability of Prostate Cancer in the Nordic Twin Study of Cancer

Abstract: Background: Prostate cancer is thought to be the most heritable cancer, although little is known about how this genetic contribution varies across age. Methods: To address this question, we undertook the world's largest prospective study in the Nordic Twin Study of Cancer cohort, including 18,680 monozygotic (MZ) and 30,054 dizygotic (DZ) same-sex male twin pairs. We incorporated time-to-event analyses to estimate the risk concordance and heritability while accounting for censoring and competing risks of death, essential sources of biases that have not been accounted for in previous twin studies modeling cancer risk and liability. Results: The cumulative risk of prostate cancer was similar to that of the background population. The cumulative risk for twins whose co-twin was diagnosed with prostate cancer was greater for MZ than for DZ twins across all ages. Among concordantly affected pairs, the time between diagnoses was significantly shorter for MZ than DZ pairs (median, 3.8 versus 6.5 years, respectively). Genetic differences contributed substantially to variation in both the risk and the liability [heritability = 58% (95% confidence interval, 52%–63%)] of developing prostate cancer. The relative contribution of genetic factors was constant across age through late life with substantial genetic heterogeneity even when diagnosis and screening procedures vary. Conclusions: Results from the population-based twin cohort indicate a greater genetic contribution to the risk of developing prostate cancer when addressing sources of bias. The role of genetic factors is consistently high across age. Impact: Findings affect the search for genetic and epigenetic markers and frame prevention efforts. Cancer Epidemiol Biomarkers Prev; 23(11); 2303–10. ©2014 AACR . This article is featured in Highlights of This Issue, [p. 2199][1] [1]: /lookup/volpage/23/2199?iss=11

Increased Lung and Bladder Cancer Incidence in Adults after In Utero and Early-Life Arsenic Exposure

Abstract: Background: From 1958 to 1970, >100,000 people in northern Chile were exposed to a well-documented, distinct period of high drinking water arsenic concentrations. We previously reported ecological evidence suggesting that early-life exposure in this population resulted in increased mortality in adults from several outcomes, including lung and bladder cancer. Methods: We have now completed the first study ever assessing incident cancer cases after early-life arsenic exposure, and the first study on this topic with individual participant exposure and confounding factor data. Subjects included 221 lung and 160 bladder cancer cases diagnosed in northern Chile from 2007 to 2010, and 508 age and gender-matched controls. Results: ORs adjusted for age, sex, and smoking in those only exposed in early life to arsenic water concentrations of ≤110, 110 to 800, and >800 μg/L were 1.00, 1.88 [95% confidence interval (CI), 0.96–3.71], and 5.24 (3.05–9.00; P trend 800 μg/L) involved exposures that started 49 to 52 years before, and ended 37 to 40 years before the cancer cases were diagnosed. Conclusion: Lung and bladder cancer incidence in adults was markedly increased following exposure to arsenic in early life, even up to 40 years after high exposures ceased. Such findings have not been identified before for any environmental exposure, and suggest that humans are extraordinarily susceptible to early-life arsenic exposure. Impact: Policies aimed at reducing early-life exposure may help reduce the long-term risks of arsenic-related disease. Cancer Epidemiol Biomarkers Prev; 23(8); 1529–38. ©2014 AACR .

Dietary Inflammatory Index and Risk of Colorectal Cancer in the Iowa Women's Health Study

Abstract: Background: Colorectal cancer, the third most common cancer in the United States, has a natural history that usually encompasses several decades. Dietary components have been implicated in the etiology of colorectal cancer, perhaps through their effect on inflammation. Methods: We examined the ability of the dietary inflammatory index (DII) to predict colorectal cancer in the Iowa Women's Health Study. The DII was computed based on dietary intake assessed by a 121-item food frequency questionnaire in this cohort of 34,703 women, ages 55 to 69 years, free of any self-reported prior malignancy at enrollment in 1986. Incident colorectal cancer cases were identified through linkage with the State Health Registry of Iowa (a Surveillance, Epidemiology, and End Results program member). Cox proportional hazards regression was used to estimate HRs. Through the end of 2010, 1,636 incident colorectal cancers were identified, including 1,329 colon and 325 rectal cancers. Results: Multivariable analysis, adjusting for body mass index, smoking status, pack-years of smoking, hormone replacement therapy, education, diabetes, and total energy intake, revealed positive associations between higher DII and colorectal cancer risk [HR for DIIcontinuous: 1.07 per unit increase in DII (corresponding to 0.5 SD unit increase); 95% confidence interval (CI), 1.01–1.13; HR for DIIquintiles: Q5 vs. Q1 = 1.20; 95% CI, 1.01–1.43]. HRs for DII were similar for colon cancer and rectal cancer, though not statistically significant for rectal cancer. Conclusions: These results indicate that a proinflammatory diet, as indicated by higher DII scores, was associated with higher risk of developing colorectal cancer. Impact: Proinflammatory diets are associated with increased risk of colorectal cancer. Cancer Epidemiol Biomarkers Prev; 23(11); 2383–92. ©2014 AACR .

Attribution of 12 High-Risk Human Papillomavirus Genotypes to Infection and Cervical Disease

Abstract: Background: We estimated the prevalence and incidence of 14 human papillomavirus (HPV) types (6/11/16/18/31/33/35/39/45/51/52/56/58/59) in cervicovaginal swabs, and the attribution of these HPV types in cervical intraepithelial neoplasia (CIN), and adenocarcinoma in situ (AIS), using predefined algorithms that adjusted for multiple-type infected lesions. Methods: A total of 10,656 women ages 15 to 26 years and 1,858 women ages 24 to 45 years were enrolled in the placebo arms of one of three clinical trials of a quadrivalent HPV vaccine. We estimated the cumulative incidence of persistent infection and the proportion of CIN/AIS attributable to individual carcinogenic HPV genotypes, as well as the proportion of CIN/AIS lesions potentially preventable by a prophylactic 9-valent HPV6/11/16/18/31/33/45/52/58 vaccine. Results: The cumulative incidence of persistent infection with ≥1 of the seven high-risk types included in the 9-valent vaccine was 29%, 12%, and 6% for women ages 15 to 26, 24 to 34, and 35 to 45 years, respectively. A total of 2,507 lesions were diagnosed as CIN or AIS by an expert pathology panel. After adjusting for multiple-type infected lesions, among women ages 15 to 45 years, these seven high-risk types were attributed to 43% to 55% of CIN1, 70% to 78% of CIN2, 85% to 91% of CIN3, and 95% to 100% of AIS lesions, respectively. The other tested types (HPV35/39/51/56/59) were attributed to 23% to 30% of CIN1, 7% to 14% of CIN2, 3% to 4% of CIN3, and 0% of AIS lesions, respectively. Conclusions: Approximately 85% or more of CIN3/AIS, >70% CIN2, and approximately 50% of CIN1 lesions worldwide are attributed to HPV6/11/16/18/31/33/45/52/58. Impact: If 9-valent HPV vaccination programs are effectively implemented, the majority of CIN2 and CIN3 lesions worldwide could be prevented, in addition to approximately one-half of CIN1. Cancer Epidemiol Biomarkers Prev; 23(10); 1997–2008. ©2014 AACR . This article is featured in Highlights of This Issue, [p. 1957][1] [1]: /lookup/volpage/23/1957?iss=10

Long-term Ultraviolet Flux, Other Potential Risk Factors, and Skin Cancer Risk: A Cohort Study

Abstract: Background: Few prospective studies have examined the relationship between sun exposure, other potential risk factors, and risk of different skin cancers [including basal cell carcinoma (BCC), squamous cell carcinoma (SCC), and melanoma] simultaneously. Methods: We evaluated the association between a number of potential risk factors and skin cancer risk in a cohort of 108,916 US women, the Nurses' Health Study II (1989–2009). Results: During 2.05 million years of follow-up, we identified 6,955, 880, and 779 diagnoses of BCC, SCC, and melanoma, respectively. Compared with participants in the lowest quintile of cumulative ultraviolet flux in adulthood, participants in the highest quintile had multivariable-adjusted relative risks (RR) of 2.35 ( P trend < 0.0001) for BCC, 2.53 ( P trend = 0.009) for SCC, and 0.68 ( P trend = 0.38) for melanoma. In contrast, the RRs were 1.68 (95% CI, 1.55–1.82) for BCC, 1.68 (95% CI, 1.34–2.11) for SCC, and 1.80 (95% CI, 1.42–2.28) for melanoma for participants with ≥5 blistering sunburns when compared with participants without sunburn between ages 15 and 20 years. We found significant interactions between family history of melanoma, number of blistering sunburns between ages 15 and 20 years and BCC risk, and between sunburn reaction as a child/adolescent and SCC risk (all P interaction < 0.05). Conclusion: In a cohort of U.S. women, we found that sun exposures in both early life and adulthood were predictive of BCC and SCC risks, whereas melanoma risk was predominantly associated with sun exposure in early life. Impact: Our results may have potential implications for the prevention of skin cancers. Cancer Epidemiol Biomarkers Prev; 23(6); 1080–9. ©2014 AACR .

A Review of the Application of Inflammatory Biomarkers in Epidemiologic Cancer Research

Abstract: Inflammation is a facilitating process for multiple cancer types. It is believed to affect cancer development and progression through several etiologic pathways, including increased levels of DNA adduct formation, increased angiogenesis, and altered antiapoptotic signaling. This review highlights the application of inflammatory biomarkers in epidemiologic studies and discusses the various cellular mediators of inflammation characterizing the innate immune system response to infection and chronic insult from environmental factors. Included is a review of six classes of inflammation-related biomarkers: cytokines/chemokines, immune-related effectors, acute-phase proteins, reactive oxygen and nitrogen species, prostaglandins and cyclooxygenase-related factors, and mediators such as transcription factors and growth factors. For each of these biomarkers, we provide a brief overview of the etiologic role in the inflammation response and how they have been related to cancer etiology and progression within the literature. We provide a discussion of the common techniques available for quantification of each marker, including strengths, weaknesses, and potential pitfalls. Subsequently, we highlight a few under-studied measures to characterize the inflammatory response and their potential utility in epidemiologic studies of cancer. Finally, we suggest integrative methods for future studies to apply multifaceted approaches to examine the relationship between inflammatory markers and their roles in cancer development.

Intrinsic Subtypes from PAM50 Gene Expression Assay in a Population-Based Breast Cancer Cohort: Differences by Age, Race, and Tumor Characteristics

Abstract: Background: Data are lacking to describe gene expression–based breast cancer intrinsic subtype patterns for population-based patient groups. Methods: We studied a diverse cohort of women with breast cancer from the Life After Cancer Epidemiology and Pathways studies. RNA was extracted from 1 mm punches from fixed tumor tissue. Quantitative reverse-transcriptase PCR was conducted for the 50 genes that comprise the PAM50 intrinsic subtype classifier. Results: In a subcohort of 1,319 women, the overall subtype distribution based on PAM50 was 53.1% luminal A, 20.5% luminal B, 13.0% HER2-enriched, 9.8% basal-like, and 3.6% normal-like. Among low-risk endocrine-positive tumors (i.e., estrogen and progesterone receptor positive by immunohistochemistry, HER2 negative, and low histologic grade), only 76.5% were categorized as luminal A by PAM50. Continuous-scale luminal A, luminal B, HER2-enriched, and normal-like scores from PAM50 were mutually positively correlated. Basal-like score was inversely correlated with other subtypes. The proportion with non-luminal A subtype decreased with older age at diagnosis, P Trend < 0.0001. Compared with non-Hispanic Whites, African American women were more likely to have basal-like tumors, age-adjusted OR = 4.4 [95% confidence intervals (CI), 2.3–8.4], whereas Asian and Pacific Islander women had reduced odds of basal-like subtype, OR = 0.5 (95% CI, 0.3–0.9). Conclusions: Our data indicate that over 50% of breast cancers treated in the community have luminal A subtype. Gene expression–based classification shifted some tumors categorized as low risk by surrogate clinicopathologic criteria to higher-risk subtypes. Impact: Subtyping in a population-based cohort revealed distinct profiles by age and race. Cancer Epidemiol Biomarkers Prev; 23(5); 714–24. ©2014 AACR . See related article by Caan et al., [p. 725][1] This article is featured in Highlights of This Issue, [p. 685][2] [1]: /lookup/volpage/23/725?iss=5 [2]: /lookup/volpage/23/685?iss=5

Association between Upper Digestive Tract Microbiota and Cancer-Predisposing States in the Esophagus and Stomach

Abstract: Background: The human upper digestive tract microbial community (microbiota) is not well characterized and few studies have explored how it relates to human health. We examined the relationship between upper digestive tract microbiota and two cancer-predisposing states, serum pepsinogen I/pepsinogen II ratio (PGI/II; predictor of gastric cancer risk) and esophageal squamous dysplasia (ESD; the precursor lesion of esophageal squamous cell carcinoma; ESCC) in a cross-sectional design. Methods: The Human Oral Microbe Identification Microarray was used to test for the presence of 272 bacterial species in 333 upper digestive tract samples from a Chinese cancer screening cohort. Serum PGI and PGII were determined by ELISA. ESD was determined by chromoendoscopy with biopsy. Results: Lower microbial richness (number of bacterial genera per sample) was significantly associated with lower PGI/II ratio ( P = 0.034) and the presence of ESD ( P = 0.018). We conducted principal component (PC) analysis on a β-diversity matrix (pairwise difference in microbiota), and observed significant correlations between PC1, PC3, and PGI/II ( P = 0.004 and 0.009, respectively), and between PC1 and ESD ( P = 0.003). Conclusions: Lower microbial richness in upper digestive tract was independently associated with both cancer-predisposing states in the esophagus and stomach (presence of ESD and lower PGI/II). Impact: These novel findings suggest that the upper digestive tract microbiota may play a role in the etiology of chronic atrophic gastritis and ESD, and therefore in the development of gastric and esophageal cancers. Cancer Epidemiol Biomarkers Prev; 23(5); 735–41. ©2014 AACR . This article is featured in Highlights of This Issue, [p. 685][1] [1]: /lookup/volpage/23/685?iss=5

Risk Prediction Models for Melanoma: A Systematic Review

Abstract: Melanoma incidence is increasing rapidly worldwide among white-skinned populations. Earlier diagnosis is the principal factor that can improve prognosis. Defining high-risk populations using risk prediction models may help targeted screening and early detection approaches. In this systematic review, we searched Medline, EMBASE, and the Cochrane Library for primary research studies reporting or validating models to predict risk of developing cutaneous melanoma. A total of 4,141 articles were identified from the literature search and six through citation searching. Twenty-five risk models were included. Between them, the models considered 144 possible risk factors, including 18 measures of number of nevi and 26 of sun/UV exposure. Those most frequently included in final risk models were number of nevi, presence of freckles, history of sunburn, hair color, and skin color. Despite the different factors included and different cutoff values for sensitivity and specificity, almost all models yielded sensitivities and specificities that fit along a summary ROC with area under the ROC (AUROC) of 0.755, suggesting that most models had similar discrimination. Only two models have been validated in separate populations and both also showed good discrimination with AUROC values of 0.79 (0.70-0.86) and 0.70 (0.64-0.77). Further research should focus on validating existing models rather than developing new ones.

The Changing Public Image of Smoking in the United States: 1964–2014

Abstract: Tobacco use behaviors in the U.S. have changed significantly over the past century. After a steep increase in cigarette use rates over the first half of the 20th century, adult smoking prevalence rates started declining from their peak reached in 1964. Improved understanding of the health risks of smoking has been aided by the U.S. Surgeon General's Reports, issued on a nearly annual basis starting in 1964. Among the many forces driving down smoking prevalence were the recognition of tobacco use as an addiction and cause of cancer, along with concerns about the ill effects of breathing secondhand smoke. These factors contributed to the declining social acceptance of smoking, especially with the advent of legal restrictions on smoking in public spaces, mass media counter-marketing campaigns, and higher taxes on cigarettes. This article reviews some of the forces that have helped change the public image of smoking, focusing on the 50 years since the 1964 Surgeon General's Report on smoking and health.

Serum Lipid Profile and Risk of Prostate Cancer Recurrence: Results from the SEARCH Database

Abstract: Background:Evidenceforanassociationbetweentotalcholesterol,low-andhigh-densitylipoproteins(LDL and HDL, respectively), triglycerides, and prostate cancer is conflicting. Given that prostate cancer and dyslipidemia affect large proportions of Western society, understanding these associations has public health importance. Methods: We conducted a retrospective cohort analysis of 843 radical prostatectomy (RP) patients who never used statins before surgery within the Shared Equal Access Regional Cancer Hospital (SEARCH) database. Multivariable Cox proportional hazards analysis was used to investigate the association between cholesterol, LDL, HDL, and triglycerides and biochemical recurrence risk. In secondary analysis, we explored these associations in patients with dyslipidemia, defined using National Cholesterol Education Program guidelines. Results: Elevated serum triglycerides were associated with increased risk of prostate cancer recurrence [HRper 10 mg/dl, 1.03; 95% confidence interval (CI), 1.01‐1.05] but associations between total cholesterol, LDL and HDL, and recurrence risk were null. However, among men with dyslipidemia, each 10 mg/dl increase in cholesterol and HDL was associated with 9% increased recurrence risk (HR, 1.09; 95% CI, 1.01‐1.17) and 39% reduced recurrence risk (HR, 0.61; 95% CI, 0.41‐0.91), respectively. Conclusions: Elevated serum triglycerides were associated with increased risk of prostate cancer recurrence. Cholesterol, LDL, or HDL were not associated with recurrence risk among all men. However, among men with dyslipidemia, elevated cholesterol and HDL levels were associated with increased and decreased risk of recurrence, respectively. Impact: These findings, coupled with evidence that statin use is associated with reduced recurrence risk, suggest that lipid levels should be explored as a modifiable risk factor for prostate cancer recurrence. Cancer Epidemiol Biomarkers Prev; 23(11); 2349–56. � 2014 AACR.

Risk of Prostate Cancer in Lynch Syndrome: A Systematic Review and Meta-analysis

Abstract: It has been controversial that men carrying a DNA mismatch repair (MMR) gene mutation (Lynch syndrome) are at heightened risk of prostate cancer given that an increased risk is likely to be modest and the prevalence of prostate cancer is high. We used PubMed to search for "molecular studies" that reported MMR-deficiency status of prostate cancer tumors in men with an MMR gene mutation, and "risk studies" that reported prostate cancer risk for men known or suspected to have an MMR gene mutation relative to that for noncarriers or the general population. Of the six molecular studies, 32 of 44 [73%, 95% confidence intervals (CI), 57%-85%] prostate cancer tumors in carriers were MMR deficient, which equates to carriers having a 3.67-fold increased risk of prostate cancer (95% CI, 2.32-6.67). Of the 12 risk studies, we estimated a 2.13-fold increased risk of prostate cancer (95% CI, 1.45-2.80) for male carriers in clinic-based retrospective cohorts, 2.11 (95% CI, 1.27-2.95) for male carriers with a prior diagnosis of colorectal cancer, and 2.28 (95% CI, 1.37-3.19) for all men from mutation-carrying families. The combination of evidence from molecular and risk studies in the current literature supports consideration of prostate cancer as part of Lynch syndrome.

Maternal Smoking and DNA Methylation in Newborns: In Utero Effect or Epigenetic Inheritance?

Abstract: Background: Maternal smoking in pregnancy is associated with adverse health outcomes in children, including cancers; underlying mechanisms may include epigenetic modifications. Using Illumina's 450K array, we previously identified differential DNA methylation related to maternal smoking during pregnancy at 26 CpG sites (CpGs) in 10 genes in newborn cord bloods from the Norwegian Mother and Child Cohort Study (MoBa). Whether these methylation signals in newborns reflect in utero exposure only or possibly epigenetic inheritance of smoking-related modifications is unclear. Methods: We therefore evaluated the impact of the timing of mother's smoking (before or during pregnancy using cotinine measured at 18 weeks gestation), the father's smoking before conception, and the grandmother's smoking during her pregnancy with the mother on methylation at these 26 CpGs in 1,042 MoBa newborns. We used robust linear regression, adjusting for covariates, applying Bonferroni correction. Results: The strongest and only statistically significant associations were observed for sustained smoking by the mother during pregnancy through at least gestational week 18 ( P < 1.6 × 10−5 for all 26 CpGs). We observed no statistically significant differential methylation due to smoking by the mother before pregnancy or that ceased by week 18, father's smoking before conception, or grandmother's smoking while pregnant with the mother. Conclusions: Differential methylation at these CpGs in newborns seems to reflect sustained in utero exposure rather than epigenetic inheritance. Impact: Smoking cessation in early pregnancy may negate effects on methylation. Analyses of maternal smoking during pregnancy and offspring health outcomes, including cancer, limited to ever smoking might miss true associations. Cancer Epidemiol Biomarkers Prev; 23(6); 1007–17. ©2014 AACR .

Known and Novel Sources of Variability in the Nicotine Metabolite Ratio in a Large Sample of Treatment-Seeking Smokers

Abstract: Background: The ratio of 3′hydroxycotinine to cotinine, or nicotine metabolite ratio (NMR), is strongly associated with CYP2A6 genotype, CYP2A6-mediated nicotine and cotinine metabolism, and nicotine clearance. Higher NMR (faster nicotine clearance) is associated retrospectively with heavier smoking and lower cessation rates. Methods: NMR as a predictive biomarker of cessation outcomes is being investigated ([NCT01314001][1]). In addition to strong CYP2A6 genetic influences on NMR, demographic and hormonal factors alter NMR. Here, we analyzed, for the first time together, these sources of variation on NMR in smokers screened for this clinical trial ( N = 1,672). Results: Participants (mean age = 45.9) were 65.1% Caucasian, 34.9% African American, and 54.8% male. Mean NMR (SD) was higher in Caucasians versus African Americans [0.41 (0.20) vs. 0.33 (0.21); P < 0.001], and in females versus males [0.41 (0.22) vs. 0.37 (0.20); P < 0.001]. Among females, birth control pill use ( N = 17) and hormone replacement therapy ( N = 14) were associated with 19.5% ( P = 0.09) and 29.3% ( P = 0.06) higher mean NMR, respectively, albeit nonsignificantly. BMI was negatively associated with NMR (Rho = −0.14; P < 0.001), whereas alcohol use (Rho = 0.11; P < 0.001) and cigarette consumption (Rho = 0.12; P < 0.001) were positively associated with NMR. NMR was 16% lower in mentholated cigarette users ( P < 0.001). When analyzed together in a linear regression model, these predictors (each ≤2%) accounted for <8% of total NMR variation. Conclusions: Although these factors significantly affected NMR, they contributed little (together <8%; each ≤2%) to total NMR variation. Impact: Thus, when using NMR, for example, to prospectively guide smoking cessation therapy, these sources of variation are unlikely to cause NMR misclassification. Cancer Epidemiol Biomarkers Prev; 23(9); 1773–82. ©2014 AACR . This article is featured in Highlights of This Issue, [p. 1705][2] [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT01314001&atom=%2Fcebp%2F23%2F9%2F1773.atom [2]: /lookup/volpage/23/1705?iss=9

Prospective Examination of Objectively Assessed Physical Activity and Sedentary Time after Breast Cancer Treatment: Sitting on the Crest of the Teachable Moment

Abstract: Background: This study prospectively examined patterns of objectively assessed sedentary time and moderate-to-vigorous physical activity (MVPA) during a 1-year period following completion of primary treatment among breast cancer survivors. The potential moderating effect of weight status on sedentary and MVPA time was also examined. Methods: Breast cancer survivors [ n = 177; M(SD)age = 54.9 (11.1) years, 85% White/Caucasian; 82% stage I or II cancer; M(SD)time since treatment = 3.5 (2.4) months] who were recruited into a convenience sample had weight, height, and waist circumference measured and wore Actigraph GT3X accelerometers for 1 week every 3 months for 1 year. Data were analyzed using repeated measures ANOVA. Results: Survivors spent nearly 78% of their day sedentary across all time points compared with less than 2% of their day engaged in MVPA. Sedentary time remained fairly stable over 12 months, whereas MVPA levels significantly decreased. Survivors with an overweight body mass index and unhealthy waist-to-height ratio engaged in significantly less MVPA than healthy weight survivors, with significant waist-to-height ratio moderator effects for both sedentary and MVPA. Conclusions: Sedentary time remains high in the first year following treatment for breast cancer, and MVPA decreases. These trends are more pronounced for survivors who are overweight, with stronger effects noted when waist-to-height ratio was examined compared with body mass index. Impact: These findings suggest that breast cancer survivors may be doing very little to improve their lifestyle behaviors following a cancer diagnosis and treatments. Cancer Epidemiol Biomarkers Prev; 23(7); 1324–30. ©2014 AACR .

Impact of Neighborhood and Individual Socioeconomic Status on Survival after Breast Cancer Varies by Race/Ethnicity: The Neighborhood and Breast Cancer Study

Abstract: Background: Research is limited on the independent and joint effects of individual- and neighborhood-level socioeconomic status (SES) on breast cancer survival across different racial/ethnic groups. Methods: We studied individual-level SES, measured by self-reported education, and a composite neighborhood SES (nSES) measure in females (1,068 non-Hispanic whites, 1,670 Hispanics, 993 African-Americans, and 674 Asian-Americans), ages 18 to 79 years and diagnosed 1995 to 2008, in the San Francisco Bay Area. We evaluated all-cause and breast cancer–specific survival using stage-stratified Cox proportional hazards models with cluster adjustment for census block groups. Results: In models adjusting for education and nSES, lower nSES was associated with worse all-cause survival among African-Americans ( P trend = 0.03), Hispanics ( P trend = 0.01), and Asian-Americans ( P trend = 0.01). Education was not associated with all-cause survival. For breast cancer–specific survival, lower nSES was associated with poorer survival only among Asian-Americans ( P trend = 0.01). When nSES and education were jointly considered, women with low education and low nSES had 1.4 to 2.7 times worse all-cause survival than women with high education and high nSES across all races/ethnicities. Among African-Americans and Asian-Americans, women with high education and low nSES had 1.6 to 1.9 times worse survival, respectively. For breast cancer–specific survival, joint associations were found only among Asian-Americans with worse survival for those with low nSES regardless of education. Conclusions: Both neighborhood and individual SES are associated with survival after breast cancer diagnosis, but these relationships vary by race/ethnicity. Impact: A better understanding of the relative contributions and interactions of SES with other factors will inform targeted interventions toward reducing long-standing disparities in breast cancer survival. Cancer Epidemiol Biomarkers Prev; 23(5); 793–811. ©2014 AACR .

Plasma Vitamin D and Prostate Cancer Risk: Results from the Selenium and Vitamin E Cancer Prevention Trial

Abstract: Background: In vitro , animal, and ecological studies suggest that inadequate vitamin D intake could increase prostate cancer risk, but results of biomarker-based longitudinal studies are inconsistent. Methods: Data for this case ( n = 1,731) and cohort ( n = 3,203) analysis are from the Selenium and Vitamin E Cancer Prevention Trial. Cox proportional hazard models were used to test whether baseline plasma vitamin D (25-hydroxy) concentration, adjusted for season of blood collection, was associated with the risk of total and Gleason score 2–6, 7–10, and 8–10 prostate cancer. Results: There were U-shaped associations of vitamin D with total cancer risk: compared with the first quintile, HRs were 0.83 [95% confidence interval (CI), 0.66–1.03; P = 0.092], 0.74 (95% CI, 0.59–0.92; P = 0.008), 0.86 (95% CI, 0.69–1.07; P = 0.181), and 0.98 (95% CI, 0.78–1.21; P = 0.823), for the second through fifth quintiles, respectively. For Gleason 7–10 cancer, corresponding HRs were 0.63 (95% CI, 0.45–0.90; P = 0.010), 0.66 (95% CI, 0.47–0.92; P = 0.016), 0.79 (95% CI, 0.56–1.10; P = 0.165), and 0.88 (95% CI, 0.63–1.22; P = 0.436). Among African American men ( n = 250 cases), higher vitamin D was associated with reduced risk of Gleason 7–10 cancer only: in the a posteriori contrast of quintiles 1–2 versus 3–5, the HR was 0.55 (95% CI, 0.31–0.97; P = 0.037), with no evidence of dose–response or a U-shaped association. Conclusions: Both low and high vitamin D concentrations were associated with increased risk of prostate cancer, and more strongly for high-grade disease. Impact: The optimal range of circulating vitamin D for prostate cancer prevention may be narrow. Supplementation of men with adequate levels may be harmful. Cancer Epidemiol Biomarkers Prev; 23(8); 1494–504. ©2014 AACR . This article is featured in Highlights of This Issue, [p. 1443][1] See related commentary by Schwartz, [p. 1447][2], and article by Schenk et al., [p. 1484][3] [1]: /lookup/volpage/23/1443?iss=8 [2]: /lookup/volpage/23/1447?iss=8 [3]: /lookup/volpage/23/1484?iss=8

Obesity Increases the Risk for High-Grade Prostate Cancer: Results from the REDUCE Study

Abstract: Background: Studies suggest obesity is associated with lower risk of prostate cancer (PC) but more aggressive cancers. As obesity lowers PSA levels, these observations may be influenced by detection bias. We examined the association between obesity and risk of low- and high-grade PC in REDUCE, where biopsies were largely independent of PSA. Methods: The REDUCE study tested dutasteride for PC risk reduction in men with a PSA of 2.5-10.0 ng/mL and a negative biopsy. Study participants included 6,729 men who underwent at least one on-study biopsy. The association between baseline body mass index (BMI 7) or low-grade PC (Gleason <7) vs. no PC was examined using multinomial logistic regression. Results: Overall, 1,739 men (27%) were normal weight, 3,384 (53%) overweight, and 1,304 (20%) were obese. Obesity was associated with lower risk of low-grade PC in both univariable (OR 0.74, p=0.001) and multivariable analyses (OR 0.79, p=0.01). In univariable analysis, obesity was not associated with high-grade PC (OR 1.08, p=0.50). However, in multivariable analysis, obesity was associated with increased risk of high-grade PC (OR 1.28, p=0.042). The current analysis was not able to address how obesity may influence prostate cancer progression. Conclusions: Obesity is associated with decreased risk of low-grade and increased risk of high-grade PC. These data provide further support to the hypothesis that obesity is associated with aggressive PC. Impact: Obesity is linked with aggressive PC. Avoiding obesity may prevent the risk of developing high-grade PC.

Prospective Population-Based Study of the Association between Serum 25-Hydroxyvitamin-D Levels and the Incidence of Specific Types of Cancer

Abstract: Background: Observational studies have suggested an inverse association between vitamin D status and cancer. We investigated the prospective associations between vitamin D status and the total and specific type of cancer in three cohorts from the general Danish population. Methods: A total of 12,204 individuals 18 to 71 years old were included. The level of 25-hydroxyvitamin D was measured at baseline, and information about cancer was obtained from the Danish Cancer Registry. Results: During the 11.3-year median follow-up time, there were 1,248 incident cancers. HRs [95% confidence intervals (CI)] per 10 nmol/L higher baseline vitamin D level were: for all cancers (HR = 1.02; 95% CI, 0.99–1.04), all cancers excluding non-melanoma skin cancer, NMSC (HR = 1.00; 95% CI, 0.97–1.03), head and neck cancer (HR = 0.97; 95% CI, 0.84–1.12), colorectal cancer (HR = 0.95; 95% CI, 0.88–1.02), cancer of bronchus and lung (HR = 0.98; 95% CI, 0.91–1.05), breast cancer (HR = 1.02; 95% CI, 0.96–1.09), cancer of the uterus (HR = 1.10; 95% CI, 0.95–1.27), prostate cancer (HR = 1.00; 95% CI, 0.93–1.08), cancer of the urinary organs (HR = 1.01; 95% CI, 0.90–1.14), NMSC (HR = 1.06; 95% CI, 1.02–1.10), and malignant melanoma (HR = 1.06; 95% CI, 0.95–1.17). Conclusions: Apart from a significantly higher risk for NMSC with higher vitamin D status, we found no statistically significant associations between vitamin D status and total or specific cancers. Impact: Our results do not indicate that there is an impact of vitamin D on total cancer incidence. Cancer Epidemiol Biomarkers Prev; 23(7); 1220–9. ©2014 AACR .

Metabolic Health Reduces Risk of Obesity-Related Cancer in Framingham Study Adults

Abstract: Background. It is unknown whether the risk for obesity-related cancers between metabolically unhealthy and healthy overweight/obese adults. Methods. Data on body mass index (BMI), waist circumference (WC), waist-to-height ratio (WHtR), and random blood glucose in Framingham Heart Study adults (n=3763) ages 55-69 were used to estimate risks of obesity-related cancers (n=385) including post-menopausal breast, female reproductive, colon, liver, gallbladder, pancreas, and kidney cancers, as well as esophageal adenocarcinomas. Multivariable-adjusted Cox proportional hazards models were used to estimate risk for obesity-related cancers associated with body fat and metabolic health (as defined by glucose levels) among subjects in three risk groups (vs. referent group with normal-weight/normal glucose): normal-weight/elevated glucose; overweight/normal glucose; and overweight/elevated glucose. Results. Overweight adults (BMI≥25 or WHtR≥0.51 (men) and ≥0.57 (women)) with elevated glucose (≥125 mg/dL) had a statistically significant two-fold increased risk of developing obesity-related cancer while overweight adults with normal glucose had a 50% increased risk. Normal-weight adults with elevated glucose had no excess cancer risk. The effects of BMI and WHtR were independent of one another. Finally, overweight women with elevated blood glucose had a 2.6-fold increased risk (95% CI: 1.4-4.9) of female reproductive (cervical, endometrial, uterine cancers) and post-menopausal breast cancers while overweight women with normal glucose levels had only a 70% increased risk (95% CI: 1.1-2.5). Conclusion. These results suggest that cancer risk may be lower among metabolically-healthy overweight/obese older adults than among overweight/obese adults with metabolic dysfunction. Impact. Metabolic dysfunction and obesity act synergistically to increase cancer risk.