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Cancer Epidemiology Biomarkers & Prevention

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Cancer Epidemiology Biomarkers & Prevention

Environmental risk factors for uveal melanomas (cancer of the iris, ciliary body, and choroid) have not been identified. To search for these, we examined the correlation of age-adjusted eye cancer incidence rates, a surrogate for uveal melanoma rates, in U.S. states with group level geographic and demographic factors using multivariate linear regression. Incidence rates for eye cancer were inversely correlated with the percentage of the population receiving fluoridated water; that is, higher rates were found in states with lower prevalences of fluoridation (P = 0.01). Fluoride is known to inhibit the growth of microbial agents that cause choroiditis and choroidal lesions in animals. We speculate that fluoridation protects against choroidal melanoma by inhibiting microbial agents that cause choroiditis and/or choroidal lesions in humans. Cancer Epidemiol Biomarkers Prev; 23(9); 1707–11. ©2014 AACR.

There is growing interest in early detection of colorectal cancer as current screening modalities lack compliance and specificity. This study systematically reviewed the literature to identify biomarkers for early detection of colorectal cancer and polyps. Literature searches were conducted for relevant papers since 2007. Human studies reporting on early detection of colorectal cancer and polyps using biomarkers were included. Methodologic quality was evaluated, and sensitivity, specificity, and the positive predictive value (PPV) were reported. The search strategy identified 3,348 abstracts. A total of 44 papers, examining 67 different tumor markers, were included. Overall sensitivities for colorectal cancer detection by fecal DNA markers ranged from 53% to 87%. Combining fecal DNA markers increased the sensitivity of colorectal cancer and adenoma detection. Canine scent detection had a sensitivity of detecting colorectal cancer of 99% and specificity of 97%. The PPV of immunochemical fecal occult blood test (iFOBT) is 1.26%, compared with 0.31% for the current screening method of guaiac fecal occult blood test (gFOBT). A panel of serum protein biomarkers provides a sensitivity and specificity above 85% for all stages of colorectal cancer, and a PPV of 0.72%. Combinations of fecal and serum biomarkers produce higher sensitivities, specificities, and PPVs for early detection of colorectal cancer and adenomas. Further research is required to validate these biomarkers in a well-structured population-based study. Cancer Epidemiol Biomarkers Prev; 23(9); 1712–28. ©2014 AACR.

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. Cancer Epidemiol Biomarkers Prev; 23(9); 1729–51. ©2014 AACR.

Background: Mammographic density (MD) is one of the strongest known breast cancer risk factors. Twin studies have suggested that a large part of the variation in MD is genetically determined. We hypothesized that breast cancer susceptibility variants may affect MD, and that their effects may be modified by nongenetic factors.

Methods: We assessed MD, using a computer-assisted method, on 2,348 postmenopausal Caucasian women (50–69 years) who participated in the Norwegian Breast Cancer Screening Program (NBCSP) in 2004 or 2006–07. We used linear regression (additive models) to determine the association between each SNP and MD, adjusting for age, body mass index (BMI), and study. We evaluated MD associations with 17 established breast cancer SNPs, overall, and by strata defined by non-genetic factors.

Results: Two variants, 6q25.1-rs9383938 and TXNRD2-rs8141691, were statistically significantly associated with percent MD (P = 0.019 and 0.03, respectively), with the 6q25.1-rs9383938 association being consistent with the SNP effect on breast cancer risk. The effect of 6q25.1-rs3734805 on percent MD varied between parous and nulliparous women (Pinteraction = 0.02), whereas the effects of 9q31.2-rs865686 and MRPS30:FGF10-rs4415084 differed across strata of BMI (Pinteraction = 0.01 and 0.005, respectively). There was no evidence of effect modification by estrogen and progestin therapy use or alcohol consumption.

Conclusion: This study provides novel evidence of shared genetic risk factors between MD and breast cancer and of possible MD genetic–environmental interactions.

Impact: Although the results may be chance findings, they nevertheless highlight the need to investigate interactions with nongenetic factors in studies on the genetics of MD. Cancer Epidemiol Biomarkers Prev; 23(9); 1752–63. ©2014 AACR.

Introduction: Mammographic density is a strong risk factor for breast cancer and an important determinant of screening sensitivity, but its clinical utility is hampered due to the lack of objective and automated measures. We evaluated the performance of a fully automated volumetric method (Volpara).

Methods: A prospective cohort study included 41,102 women attending mammography screening, of whom 206 were diagnosed with breast cancer after a median follow-up of 15.2 months. Percent and absolute dense volumes were estimated from raw digital mammograms. Genotyping was performed in a subset of the cohort (N = 2,122). We examined the agreement by side and view and compared density distributions across different mammography systems. We also studied associations with established density determinants and breast cancer risk.

Results: The method showed good agreement by side and view, and distributions of percent and absolute dense volume were similar across mammography systems. Volumetric density was positively associated with nulliparity, age at first birth, hormone use, benign breast disease, and family history of breast cancer, and negatively with age and postmenopausal status. Associations were also observed with rs10995190 in the ZNF365 gene (P < 1.0 x 10–6) and breast cancer risk [HR for the highest vs. lowest quartile, 2.93; 95% confidence interval, 1.73–4.96 and 1.63 (1.10–2.42) for percent and absolute dense volume, respectively].

Conclusions: In a high-throughput setting, Volpara performs well and in accordance with the behavior of established density measures.

Impact: Automated measurement of volumetric mammographic density is a promising tool for widespread breast cancer risk assessment. Cancer Epidemiol Biomarkers Prev; 23(9); 1764–72. ©2014 AACR.

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). 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.

Background: Smoking is detrimental to recovery and survival from cancer, but many cancer survivors continue to smoke. Information is lacking on smoking patterns of survivors many years after diagnosis and correlates of smoking status and patterns, likelihood of quitting, and intentions to quit.

Methods: Cross-sectional analyses were conducted among survivors of 10 cancers recruited by stratified random sampling from cancer registries in a nationwide, longitudinal, quality-of-life study (n = 2,938).

Results: Approximately 9 years after diagnosis, 9.3% of all survivors were current (past 30-day) smokers. Smoking prevalence was highest among survivors of bladder (17.2%), lung (14.9%), and ovarian (11.6%) cancers. Most current smokers (83%) smoked daily, averaging 14.7 cigarettes per day (cpd). Forty percent of daily smokers smoked more than 15 cpd. Nondaily smokers smoked a mean of 10.9 days in the last 30 days and averaged 5.7 cpd on smoking days. Current smoking was associated with younger age, lower education and income, and greater alcohol consumption. Quitting after diagnosis was associated with having a smoking-related cancer. Roughly, a third of current smokers intended to quit, 40% within the next month. The odds of intending to quit were lower if survivors were married, older, or smoked more.

Conclusions: This population-based study indicated that smoking can persist long after initial diagnosis and at high levels and identified characteristics associated with quitting and intentions to quit.

Impact: Findings can be used to identify survivors most at risk for continued smoking and to inform tailoring of cessation treatments for survivors. Cancer Epidemiol Biomarkers Prev; 23(9); 1783–92. ©2014 AACR.

Background: Despite considerable use of make your own (MYO) cigarettes worldwide and increasing use in the United States, relatively little is known about how these cigarettes are smoked and the resultant toxicant exposure.

Methods: In a laboratory study, we compared two types of MYO cigarettes—roll your own (RYO) and personal machine made (PMM)—with factory-made (FM) cigarettes in three groups of smokers who exclusively used RYO (n = 34), PMM (n = 23), or FM (n = 20). Within each group, cigarettes were smoked in three conditions: (i) after confirmed overnight tobacco abstinence; (ii) in an intense smoking paradigm; and (iii) without restrictions. All cigarettes were smoked ad lib through a smoking topography unit.

Results: Plasma nicotine significantly increased after cigarettes in all conditions except PMM in the intense smoking paradigm. Puff volume, puff duration, total puff volume, and puff velocity did not differ between cigarette types but the puffs per cigarette and time to smoke were significantly smaller for RYO compared with PMM and FM. Regardless of the cigarette, participants consumed the first three puffs more vigorously than the last three puffs.

Conclusions: Despite the belief of many of their consumers, smoking MYO cigarettes is not a safe alternative to FM cigarettes. Like FM, MYO cigarettes expose their users to harmful constituents of tobacco smoke. Despite differences in size and design their puffing profiles are remarkably similar.

Impact: These data are relevant to health and regulatory considerations on the MYO cigarettes. Cancer Epidemiol Biomarkers Prev; 23(9); 1793–803. ©2014 AACR.

Background: Because of the faltering sensitivity and/or specificity, urine-based assays currently have a limited role in the management of patients with bladder cancer. The aim of this study was to externally validate our previously reported protein biomarker panel from multiple sites in the United States and Europe.

Methods: This multicenter external validation study included a total of 320 subjects (bladder cancer = 183). The 10 biomarkers (IL8, MMP9, MMP10, SERPINA1, VEGFA, ANG, CA9, APOE, SDC1, and SERPINE1) were measured using commercial ELISA assays in an external laboratory. The diagnostic performance of the biomarker panel was assessed using receiver operator curves (ROC) and descriptive statistical values.

Results: Utilizing the combination of all 10 biomarkers, the area under the ROC for the diagnostic panel was noted to be 0.847 (95% confidence interval, 0.796–0.899), outperforming any single biomarker. The multiplex assay at optimal cutoff value achieved an overall sensitivity of 0.79, specificity of 0.79, positive prediction value of 0.73, and negative prediction value of 0.84 for bladder cancer classification. Sensitivity values of the diagnostic panel for high-grade bladder cancer, low-grade bladder cancer, muscle invasive bladder cancer, and non-muscle invasive bladder cancer were 0.81, 0.90, 0.95, and 0.77, respectively.

Conclusions: Urinary levels of the biomarker panel enabled discrimination of patients with bladder cancer and controls, and the levels of biomarker subsets were associated with advancing tumor grade and stage.

Impact: If proven to be reliable, urinary diagnostic biomarker assays can detect bladder cancer in a timely manner such that the patient can expect improvements in overall survival and quality of life. Cancer Epidemiol Biomarkers Prev; 23(9); 1804–12. ©2014 AACR.

Background: We investigated whether prediagnostic reported intake of dairy products and dietary calcium is associated with colorectal cancer survival.

Methods: Data from 3,859 subjects with colorectal cancer (42.1% male; mean age at diagnosis, 64.2 ± 8.1 years) in the European Investigation into Cancer and Nutrition cohort were analyzed. Intake of dairy products and dietary calcium was assessed at baseline (1992–2000) using validated, country-specific dietary questionnaires. Multivariable Cox regression models were used to calculate HR and corresponding 95% confidence intervals (CI) for colorectal cancer–specific death (n = 1,028) and all-cause death (n = 1,525) for different quartiles of intake.

Results: The consumption of total dairy products was not statistically significantly associated with risk of colorectal cancer–specific death (adjusted HR Q4 vs. Q1, 1.17; 95% CI, 0.97–1.43) nor that of all-cause death (Q4 vs. Q1, 1.16; 95% CI, 0.98–1.36). Multivariable-adjusted HRs for colorectal cancer–specific death (Q4 vs. Q1) were 1.21 (95% CI, 0.99–1.48) for milk, 1.09 (95% CI, 0.88–1.34) for yoghurt, and 0.93 (95% CI, 0.76–1.14) for cheese. The intake of dietary calcium was not associated with the risk of colorectal cancer–specific death (adjusted HR Q4 vs. Q1, 1.01; 95% CI, 0.81–1.26) nor that of all-cause death (Q4 vs. Q1, 1.01; 95% CI, 0.84–1.21).

Conclusions: The prediagnostic reported intake of dairy products and dietary calcium is not associated with disease-specific or all-cause risk of death in patients diagnosed with colorectal cancer.

Impact: The impact of diet on cancer survival is largely unknown. This study shows that despite its inverse association with colorectal cancer risk, the prediagnostic intake of dairy and dietary calcium does not affect colorectal cancer survival. Cancer Epidemiol Biomarkers Prev; 23(9); 1813–23. ©2014 AACR.

Background: Genome-wide association studies have identified several single nucleotide polymorphisms (SNPs) that are associated with risk of colorectal cancer. Prior research has evaluated the presence of gene–environment interaction involving the first 10 identified susceptibility loci, but little work has been conducted on interaction involving SNPs at recently identified susceptibility loci, including: rs10911251, rs6691170, rs6687758, rs11903757, rs10936599, rs647161, rs1321311, rs719725, rs1665650, rs3824999, rs7136702, rs11169552, rs59336, rs3217810, rs4925386, and rs2423279.

Methods: Data on 9,160 cases and 9,280 controls from the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO) and Colon Cancer Family Registry (CCFR) were used to evaluate the presence of interaction involving the above-listed SNPs and sex, body mass index (BMI), alcohol consumption, smoking, aspirin use, postmenopausal hormone (PMH) use, as well as intake of dietary calcium, dietary fiber, dietary folate, red meat, processed meat, fruit, and vegetables. Interaction was evaluated using a fixed effects meta-analysis of an efficient Empirical Bayes estimator, and permutation was used to account for multiple comparisons.

Results: None of the permutation-adjusted P values reached statistical significance.

Conclusions: The associations between recently identified genetic susceptibility loci and colorectal cancer are not strongly modified by sex, BMI, alcohol, smoking, aspirin, PMH use, and various dietary factors.

Impact: Results suggest no evidence of strong gene–environment interactions involving the recently identified 16 susceptibility loci for colorectal cancer taken one at a time. Cancer Epidemiol Biomarkers Prev; 23(9); 1824–33. ©2014 AACR.

Background: The sensitivity of mammography for the detection of small lesions, including node-negative early-stage (T1N0) primary breast cancer (PBC) and ductal carcinoma in situ (DCIS), is significantly decreased in young patients. From a clinical standpoint, an inconclusive mammogram reflects the inability of clinicians to confidently decide whether patients should be referred for biopsy or for follow-up with repeat imaging.

Methods: Specific ELISAs were developed for a panel of 13 well-recognized breast autoantigens (HSP60, FKBP52, PRDX2, PPIA, MUC1, GAL3, PAK2, P53, CCNB1, PHB2, RACK1, RUVBL1, and HER2). Circulating autoantibody levels were measured in a cohort of 396 serum samples from histologically confirmed DCIS (n = 87) or T1N0 PBC (n = 153) and healthy controls (n = 156).

Results: Individually, antibodies against CCNB1, FKBP52, GAL3, PAK2, PRDX2, PPIA, P53, and MUC1 demonstrated discriminatory power between breast cancer and healthy control groups. At 90% sensitivity, the overall combined specificity of the autoantibody serum screening test was 42%. Adjustment for higher sensitivities of 95% and 99% resulted in 30% and 21% specificities, respectively (33% and 18% in T1N0 PBC and 28% and 21% in DCIS). Finally, in patients with node-negative early-stage breast cancer younger than 50 years, the autoantibody assay exhibited 59% specificity with a fixed sensitivity at 90%.

Conclusions: Our autoantibody panel allows accurate detection of early breast cancer and DCIS, notably in younger patients.

Impact: Clinical assessment of this autoantibody panel displays a potential to facilitate clinical management of early-stage breast cancer detection in cases of inconclusive mammogram. Cancer Epidemiol Biomarkers Prev; 23(9); 1834–42. ©2014 AACR.

Background: Dysregulated insulin signaling is thought to contribute to cancer risk.

Methods: To determine if insulin-related serum factors are associated with colon polyps, 126 asymptomatic men (48–65 years) were recruited at colonoscopy. Blood was collected. Odds ratios were determined using polytomous logistic regression for polyp number and type.

Results: Males with serum C-peptide concentration >3.3 ng/mL were 3.8 times more likely to have an adenoma relative to no polyp than those with C-peptide ≤1.8 ng/mL. As C-peptide tertile increased, an individual was 2 times more likely to have an adenoma (P = 0.01) than no polyp. There were no associations between insulin-like growth factor or its binding proteins with polyp number or type. Males with soluble receptor for advanced glycation end products (sRAGE) concentration >120.4 pg/mL were 0.25 times less likely to have ≥3 polyps relative to no polyps compared with males with sRAGE ≤94.5 pg/mL. For each increase in sRAGE tertile, a man was 0.5 times less likely to have ≥3 polyps than no polyps (P = 0.03). Compared with males with a serum vascular endothelial growth factor (VEGF) concentration ≤104.7 pg/mL, males with a serum VEGF concentration >184.2 pg/mL were 3.4 times more likely to have ≥3 polyps relative to no polyps. As the VEGF tertile increased, a man was 1.9 times more likely to have ≥3 polyps than no polyps (P = 0.049).

Conclusions: Serum concentrations of C-peptide, sRAGE, and VEGF may indicate which men could benefit most from colonoscopy.

Impact: Identification of biomarkers could reduce medical costs through the elimination of colonoscopies on low-risk individuals. Cancer Epidemiol Biomarkers Prev; 23(9); 1843–51. ©2014 AACR.

Background: We investigated body size, physical activity, and early-life energy restriction in relation to colorectal tumors with and without methylated insulin-like growth factor–binding protein (IGFBP) genes, which are putative tumor-suppressor genes.

Methods: We determined IGFBP2, IGFBP3, and IGFBP7 promoter CpG island hypermethylation in tumors of 733 colorectal cancer cases from the Netherlands Cohort Study (N = 120,852). Participants self-reported lifestyle and dietary factors at baseline in 1986. Using a case–cohort approach (N subcohort = 5,000), we estimated hazard ratios (HR) for colorectal cancer by extent of IGFBP methylation.

Results: Comparison of the highest versus lowest sex-specific tertiles of adult body mass index (BMI) gave multivariable-adjusted HRs [95% confidence intervals (CI)] for colorectal cancers with 0 (18.7%), 1 (29.5%), 2 (32.4%), and 3 (19.5%) methylated genes of 1.39 (0.88–2.19), 1.11 (0.77–1.62), 1.67 (1.17–2.38), and 2.07 (1.29–3.33), respectively. Other anthropometric measures and physical activity were not associated with colorectal cancer risk by extent of IGFBP methylation, except height in sex-specific analyses for women. Exposure to energy restriction during the Dutch Hunger Winter versus nonexposure gave HRs (95% CIs) for colorectal cancers with 0, 1, 2, and 3 methylated genes of 1.01 (0.67–1.53), 1.03 (0.74–1.44), 0.72 (0.52–0.99), and 0.50 (0.32–0.78), respectively.

Conclusions: Adult BMI, height (in women only), and early-life energy restriction were associated with the risk of having a colorectal tumor characterized by IGFBP methylation.

Impact: Body size may particularly increase the risk of IGFBP gene–methylated colorectal tumors; this finding might facilitate more targeted approaches to prevent obesity-related colorectal cancers. Cancer Epidemiol Biomarkers Prev; 23(9); 1852–62. ©2014 AACR.

Background: Occupational exposure to extremely low-frequency magnetic fields (ELF) is a suspected risk factor for brain tumors, however the literature is inconsistent. Few studies have assessed whether ELF in different time windows of exposure may be associated with specific histologic types of brain tumors. This study examines the association between ELF and brain tumors in the large-scale INTEROCC study.

Methods: Cases of adult primary glioma and meningioma were recruited in seven countries (Australia, Canada, France, Germany, Israel, New Zealand, and the United Kingdom) between 2000 and 2004. Estimates of mean workday ELF exposure based on a job exposure matrix were assigned. Estimates of cumulative exposure, average exposure, maximum exposure, and exposure duration were calculated for the lifetime, and 1 to 4, 5 to 9, and 10+ years before the diagnosis/reference date.

Results: There were 3,761 included brain tumor cases (1,939 glioma and 1,822 meningioma) and 5,404 population controls. There was no association between lifetime cumulative ELF exposure and glioma or meningioma risk. However, there were positive associations between cumulative ELF 1 to 4 years before the diagnosis/reference date and glioma [odds ratio (OR) ≥ 90th percentile vs. < 25th percentile, 1.67; 95% confidence interval (CI), 1.36–2.07; PLinear trend < 0.0001], and, somewhat weaker associations with meningioma (OR ≥ 90th percentile vs. < 25th percentile, 1.23; 95% CI, 0.97–1.57; PLinear trend = 0.02).

Conclusions: Results showed positive associations between ELF in the recent past and glioma.

Impact: Occupational ELF exposure may play a role in the later stages (promotion and progression) of brain tumorigenesis. Cancer Epidemiol Biomarkers Prev; 23(9); 1863–72. ©2014 AACR.

Background: Breast cancer is the most frequently diagnosed cancer and the second leading cause of cancer death in American women. Postsurgery adjuvant radiotherapy (RT) significantly reduced the local recurrence rate. However, many patients develop early adverse skin reactions (EASR) that impact quality of life and treatment outcomes.

Methods: We evaluated an inflammatory biomarker, C-reactive protein (CRP), in predicting RT-induced EASRs in 159 patients with breast cancer undergoing RT. In each patient, we measured pre- and post-RT plasma CRP levels using a highly sensitive ELISA CRP assay. RT-induced EASRs were assessed at weeks 3 and 6 using the National Cancer Institute Common Toxicity Criteria (v3.0). Associations between EASRs and CRP levels were assessed using logistic regression models after adjusting for potential confounders.

Results: RT-induced grade 2+ EASRs were observed in 8 (5%) and 80 (50%) patients at weeks 3 and 6 (end of RT), respectively. At the end of RT, a significantly higher proportion of African Americans developed grade 3 EASRs (13.8% vs. 2.3% in others); grade 2+ EASRs were significantly associated with: change of CRP > 1 mg/L [odds ratio (OR), 2.51; 95% confidence interval (CI), 1.06–5.95; P = 0.04], obesity (OR, 2.08; 95% CI, 1.03–4.21; P = 0.04), or combined both factors (OR, 5.21; 95% CI, 1.77–15.38; P = 0.003).

Conclusion: This is the first study to demonstrate that an inflammatory biomarker CRP is associated with RT-induced EASRs, particularly combined with obesity.

Impact: Future larger studies are warranted to validate our findings and facilitate the discovery and development of anti-inflammatory agents to protect normal tissue from RT-induced adverse effects and improve quality of life in patients with breast cancer undergoing RT. Cancer Epidemiol Biomarkers Prev; 23(9); 1873–83. ©2014 AACR.

Background: Fecal immunochemical test (FIT) diagnostic accuracy for colorectal adenoma detection in colorectal cancer screening is limited.

Methods: We analyzed 474 asymptomatic subjects with adenomas detected on colonoscopy in two blinded diagnostic tests studies designed to assess FIT diagnostic accuracy. We determined the characteristics of adenomas (number, size, histology, morphology, and location) and the risk of metachronous lesions (according to European guidelines). Finally, we performed a logistic regression to identify those variables independently associated with a positive result.

Results: Advanced adenomas were found in 145 patients (75.6% distal and 24.3% only proximal to splenic flexure). Patients were classified as low (59.5%), intermediate (30.2%), and high risk (10.3%) according to European guidelines. At a 100-ng/mL threshold, FIT was positive in 61 patients (12.8%). Patients with advanced adenomas [odds ratio (OR), 8.8; 95% confidence interval (CI), 4.76–16.25], distal advanced adenomas (OR, 6.7; 95% CI, 1.9–8.8), high risk (OR, 20.1; 95% CI, 8.8–45.8), or intermediate risk lesions (OR, 6; 95% CI, 2.9–12.4) had more probabilities to have a positive test. The characteristics of adenomas independently associated were number of adenomas (OR, 1.22; 95% CI, 1.04–1.42), distal flat adenomas (OR, 0.44; 95% CI, 0.21–0.96), pedunculated adenomas (OR, 2.28; 95% CI, 1.48–3.5), and maximum size of distal adenomas (mm; OR, 1.24; 95% CI, 1.16–1.32).

Conclusions: European guidelines classification and adenoma location correlates with the likelihood of a positive FIT result.

Impact: This information allows us to understand the FIT impact in colorectal cancer prevention. Likewise, it should be taken into account in the development of new colorectal adenomas biomarkers. Cancer Epidemiol Biomarkers Prev; 23(9); 1884–92. ©2014 AACR.

Background: Physical activity probably protects against the risk of breast cancer after menopause, but questions remain about how rapidly and for how long this protective effect exists.

Methods: We analyzed data from 59,308 postmenopausal women (2,155 incident invasive breast cancers) followed between 1993 and 2005 (8.5 years postmenopause on average) through biennial questionnaires. Multivariable Cox models included time-varying exposure data, using levels of recreational physical activity self-reported in 1993, 1997, and 2002.

Results: Women with recent (within the previous 4 years) recreational physical activity levels ≥12 metabolic equivalent task-hours (MET-h)/week had a lower risk of invasive breast cancer than women with lower levels [HR, 0.90; 95% confidence interval (CI), 0.82–0.99], with no apparent dose–response relation beyond 12 MET-h/week. Associations did not vary significantly across ER/PR subtypes. Risk reductions were of the same magnitude order regardless of weight change, body mass index, waist circumference, or less recent (5–9 years earlier) physical activity levels. Among women with levels of physical activity ≥12 MET-h/week 5 to 9 years earlier, those who became less active (<12 MET-h/week) had a significantly increased risk of breast cancer compared with those who did not (HR, 1.16; 95% CI, 1.01–1.35). And, compared with the least active women at both time points, they had no significantly decreased risk of breast cancer (HR, 1.06; 95% CI, 0.87–1.29).

Conclusions: Our results suggest a decrease in risk associated with recent recreational physical activity even of modest levels.

Impact: Starting or maintaining physical activity after menopause may be beneficial regarding breast cancer risk. Cancer Epidemiol Biomarkers Prev; 23(9); 1893–902. ©2014 AACR.

Background: Allergic diseases signify immune dysregulation attributable to underlying genetics and environmental exposures. Associations between various allergies and hematopoietic cancers have been observed, albeit inconsistently; however, few prospective studies have examined the risk, and even fewer among older adults.

Methods: We examined risk of incident hematopoietic cancers in those reporting allergic diseases in a population-based cohort of 22,601 older women (Iowa Women's Health Study). Self-reported allergic status, including asthma, hay fever, eczema, and/or other allergies, was determined via questionnaire in 1997 (mean age, 72 years; range, 63–81 years). Incident cancers were ascertained by linkage with the Iowa Cancer Registry from 1997 to 2011. Cox proportional hazards regression was performed to estimate multivariate-adjusted HR and 95% confidence intervals (CI) for myeloid (N = 177) and lymphoid (N = 437) malignancies, respectively.

Results: Allergic diseases were not associated with risk of myeloid (HR, 1.00; 95% CI, 0.72–1.37) or lymphoid (HR, 0.99; 95% CI, 0.81–1.22) malignancies overall, or for most allergic and malignant subtypes examined. Self-reported asthma was positively associated with development of myelodysplastic syndrome (MDS; HR, 2.00; 95% CI, 0.93–4.32). In addition, there was a 30% to 40% decrease in risk of both lymphoid and myeloid cancers in those reporting rural residences but no association in those reporting urban residences; the interaction between residence and allergy was statistically significant for lymphoid malignancies (Pinteraction = 0.05).

Conclusions and Impact: These results suggest that asthma may contribute to the pathogenesis of MDS, a finding consistent with the chronic antigen stimulation hypothesis. Susceptibility differences by location of residence are concordant with the hygiene hypothesis and merit additional exploration. Cancer Epidemiol Biomarkers Prev; 23(9); 1903–12. ©2014 AACR.

Background: Childhood cancer survivors (CCS) receiving packed red blood cell (PRBC) transfusions may have increased risk for vital organ iron deposition causing serious late effects.

Methods: This cross-sectional cohort study of a CCS cohort quantified organ iron content by magnetic resonance imaging. Iron status by serum markers and hemochromatosis gene mutation status were assessed.

Results: Seventy-five patients who had received a range (0–392 mL/kg) of cumulative PRBC transfusion volumes were enrolled (median age 14 years, range 8–25.6 years at evaluation). Median follow-up time was 4.4 years, and median time since last transfusion was 4.9 years. Cancer diagnoses included acute lymphoblastic or myelogenous leukemia (ALL/AML; n = 33) and solid tumors (n = 42). Liver and pancreatic iron concentrations were elevated in 36 of 73 (49.3%) and 19 of 72 (26.4%) subjects, respectively. Cardiac iron concentration was not increased in this cohort. In multivariate analysis, cumulative PRBC volume (P < 0.0001) and older age at diagnosis (P < 0.0001) predicted elevated liver iron concentration.

Conclusions: Iron overload (IO) may occur in children and adolescents/young adults treated for cancer and is associated with cumulative PRBC transfusion volume and age at diagnosis.

Impact: These findings have implications for development of monitoring and management guidelines for cancer patients and survivors at risk for IO, exploration of the additive risk of liver/pancreatic damage from chemotherapeutic exposures, and health education to minimize further liver/pancreatic damage from exposures such as excessive alcohol intake and hepatotoxic medications. Cancer Epidemiol Biomarkers Prev; 23(9); 1913–9. ©2014 AACR.

Background: Most colorectal cancers develop from adenomas. We aimed to estimate sex- and age-specific incidence rates of colorectal adenomas and to assess their potential implications for colorectal cancer screening strategies.

Methods: Sex- and age-specific incidence rates of colorectal adenomas were derived by a birth cohort analysis using data from 4,322,085 screening colonoscopies conducted in Germany and recorded in a national database in 2003–2012. In addition, cumulative risks of colorectal cancer among colonoscopically neoplasm-free men and women were estimated by combining adenoma incidence rates with previously derived adenoma-colorectal cancer transition rates.

Results: Estimated annual incidence in percentage (95% confidence interval) in age groups 55–59, 60–64, 65–69, 70–74, and 75–79 was 2.4 (2.2–2.6), 2.3 (2.1–2.6), 2.4 (2.1–2.6), 2.2 (1.8–2.5), and 1.8 (1.2–2.3) among men, and 1.4 (1.3–1.5), 1.5 (1.4–1.7), 1.6 (1.4–1.8), 1.6 (1.3–1.8), and 1.2 (0.8–1.6) among women. Estimated 10- and 15-year risks of clinically manifest colorectal cancer were 0.1% and 0.5% or lower, respectively, in all groups assessed.

Conclusions: Annual incidence rates of colorectal adenomas are below 2.5% and 2% among men and women, respectively, and show little variation by age.

Impact: Risk of clinically manifest colorectal cancer is expected to be very small within 10 years and beyond after negative colonoscopy for men and women at all ages. The use of rescreening after a negative screening colonoscopy above 60 years of age may be very limited. Cancer Epidemiol Biomarkers Prev; 23(9); 1920–7. ©2014 AACR.

Genetic variation at insulin-like growth factor 1 (IGF1) has been linked to prostate cancer risk. However, the specific predisposing variants have not been identified. In this study, we fine-mapped the IGF1 locus for prostate cancer risk in African Americans. We conducted targeted Roche GS-Junior 454 resequencing of a 156-kb region of IGF1 in 80 African American aggressive prostate cancer cases. Three hundred and thirty-four IGF1 SNPs were examined for their association with prostate cancer risk in 1,000 African American prostate cancer cases and 991 controls. The top associated SNP in African Americans, rs148371593, was examined in an additional 3,465 prostate cancer cases and 3,425 controls of non-African American ancestry—European Americans, Japanese Americans, Latinos, and Native Hawaiians. The overall association of 334 IGF1 SNPs and prostate cancer risk was assessed using logistic kernel-machine methods. The association between each SNP and prostate cancer risk was evaluated through unconditional logistic regression. A false discovery rate threshold of q < 0.1 was used to determine statistical significance of associations. We identified 8 novel IGF1 SNPs. The cumulative effect of the 334 IGF1 SNPs was not associated with prostate cancer risk (P = 0.13) in African Americans. Twenty SNPs were nominally associated with prostate cancer at P < 0.05. The top associated SNP among African Americans, rs148371593 [minor allele frequency (MAF) = 0.03; P = 0.0014; q > 0.1], did not reach our criterion of statistical significance. This polymorphism was rare in non-African Americans (MAF < 0.003) and was not associated with prostate cancer risk (P = 0.98). Our findings do not support the role of IGF1 variants and prostate cancer risk among African Americans. Cancer Epidemiol Biomarkers Prev; 23(9); 1928–32. ©2014 AACR.

Primary screening for high-risk human papillomavirus (hrHPV) requires a triage protocol. Repeat cytology testing at baseline and after 6 to 12 months has emerged as a reasonable triage approach, but carries the risk of loss to follow-up. Repeat cytology testing may be omitted if cytology is supplemented with another, complementary triage test at baseline. In this study, the performance of combined triage by cytology and DNA methylation analysis was assessed. In hrHPV-positive cervical scrapes (n = 250), cytology [threshold: atypical squamous cells of undetermined significance (ASCUS)], bi-marker CADM1/MAL methylation testing (at different assay thresholds), and combinations of both were evaluated for endpoints cervical intraepithelial neoplasia grade 2 or worse (CIN2+) and grade 3 or worse (CIN3+). At a predefined methylation threshold of 70% specificity for CIN3+, combined triage revealed a CIN3+ sensitivity of 86.8% [95% confidence interval (CI), 76.1–97.6] compared with 65.8% (95% CI, 50.7–80.9) for sole cytology triage testing. Corresponding CIN3+ specificity was 64.8% (95% CI, 58.1–71.5) for combined triage and 78.6% (95% CI, 72.8–84.3) for sole cytology triage testing. For CIN2+, the sensitivity of combined triage testing was 84.5% (95% CI, 75.2–93.8) compared with 65.5% (95% CI, 53.3–77.7) for sole cytology triage, with corresponding specificities of 69.9% (95% CI, 63.1–76.6) and 83.5% (95% CI, 78.0–89.0), respectively. In conclusion, combined triage reached substantially higher CIN2+/3+ sensitivities compared with sole cytology at a slight drop in specificity. Therefore, it is an attractive triage strategy for colposcopy of hrHPV-positive women with a high reassurance for cervical cancer and advanced CIN lesions. Cancer Epidemiol Biomarkers Prev; 23(9); 1933–7. ©2014 AACR.

Treatments for childhood cancer can impair pulmonary function. We assessed the potential impact of cigarette smoking on pulmonary function in 433 adult childhood cancer survivors (CCS) who received pulmonary-toxic therapy, using single breath diffusion capacity for carbon monoxide corrected for hemoglobin (DLCOcorr), forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), and total lung capacity (TLC). FEV1/FVC median values among current [1.00; interquartile range (IQR): 0.94–1.04] and former smokers (0.98; IQR: 0.93–1.04) were lower than those who had never smoked (1.02; IQR: 0.96–1.06; P = 0.003). Median FEV1/FVC values were lower among those who smoked ≥ 6 pack-years (0.99; IQR: 0.92–1.03) and those who smoked <6 pack-years (1.00; IQR: 0.94–1.04), than among those who had never smoked (P = 0.005). Our findings suggest that CCSs have an increased risk for future obstructive and restrictive lung disease. Follow-up is needed to determine whether smoking imparts more than additive risk. Smoking prevention and cessation need to be a priority in this population. Cancer Epidemiol Biomarkers Prev; 23(9); 1938–43. ©2014 AACR.

Background: Black men exhibit a high prevalence of vitamin D deficiency as well as a higher incidence of prostate cancer and higher mortality rates from prostate cancer than Whites. There are few data about the effect of vitamin D3 (cholecalciferol) supplementation on prostate-specific antigen (PSA) in healthy Black men.

Methods: During three winters from 2007 to 2010, 105 Black men (median age, 48.9 years) of Boston, MA were randomized into a four-arm, double-blind trial for 3 months of placebo, 1,000, 2,000, or 4,000 U of vitamin D3. At baseline and 3 months, free and total PSA was measured.

Results: With vitamin D supplementation, no significant differences in free and total PSA were observed; free PSA, –0.0004 ng/mL (P = 0.94) and total PSA, –0.004 ng/mL (P = 0.92) for each additional 1,000 U/d of vitamin D3.

Conclusion: Within an unselected population of healthy Black men without a cancer diagnosis, we found no effect of vitamin D supplementation on free or total PSA.

Impact: These findings support prior findings of no change in PSA with vitamin D supplementation and emphasize the need for new methods to assess the influence of vitamin D supplementation on prostate cancer prevention. Cancer Epidemiol Biomarkers Prev; 23(9); 1944–7. ©2014 AACR.

Social media are now used by a majority of American internet users. Social media platforms encourage participants to share information with their online social connections and exchange user-generated content. Significant numbers of people are already using social media to share health-related information. As such, social media provide an opportunity for "user-generated" cancer control and prevention interventions that employ users' behavior, knowledge, and existing social networks for the creation and dissemination of interventions. These interventions also enable novel data collection techniques and research designs that will allow investigators to examine real-time behavioral responses to interventions. Emerging social media-based interventions for modifying cancer-related behaviors have been applied to such domains as tobacco use, diet, physical activity, and sexual practices, and several examples are discussed for illustration purposes. Despite some promising early findings, challenges including inadequate user engagement, privacy concerns, and lack of internet access among some groups need to be addressed in future research. Recommendations for advancing the field include stronger partnerships with commercial technology companies, utilization of rapid and adaptive designs to identify successful strategies for user engagement, rigorous and iterative efficacy testing of these strategies, and inclusive methods for intervention dissemination. Cancer Epidemiol Biomarkers Prev; 23(9); 1953–6. ©2014 AACR.