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Cancer Epidemiology Biomarkers & Prevention

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Cancer Epidemiology Biomarkers & Prevention

Since the introduction of mammography screening, debates about the value of screening have endured and been contentious. Recent reviews of the randomized controlled trials reach different conclusions about the absolute benefit of screening, as do evaluations of population trends in breast cancer mortality and the evaluations of service screening. Conclusions about the value of screening commonly are expressed in terms of the balance of benefits and harms, which can differ greatly even when derived seemingly from the same data. It can be shown when different estimates are adjusted to a common screening and follow-up scenario, differences in balance sheet estimates diminish substantially. The strong evidence of benefit associated with exposure to modern mammography screening suggests that it is time to move beyond the randomized controlled trial estimates of benefit and consider policy decisions on the basis of benefits and harms estimated from the evaluation of current screening programs. Cancer Epidemiol Biomarkers Prev; 23(7); 1139–46. ©2014 AACR.

Reducing colorectal cancer mortality by promoting screening has been a national goal for two decades. The NCI's Population-Based Research Optimizing Screening through Personalized Regimens (PROSPR) consortium is the first federal initiative to foster coordinated, transdisciplinary research evaluating the entire cancer screening process in community settings. PROSPR is creating a central data repository to facilitate research evaluating the breast, cervical, and colorectal cancer screening process across different patient populations, provider types, and delivery systems. Data are being collected and organized at the multiple levels in which individuals are nested (e.g., healthcare systems, facilities, providers, and patients). Here, we describe a conceptual model of the colorectal cancer screening process guiding data collection and highlight critical research questions that will be addressed through pooled data. We also describe the three research centers focused on colorectal cancer screening with respect to study populations, practice settings, and screening policies. PROSPR comprehensively elucidates the complex screening process through observational study, and has potential to improve care delivery beyond the healthcare systems studied. Findings will inform intervention designs and policies to optimize colorectal cancer screening delivery and advance the Institute of Medicine's goals of effective, efficient, coordinated, timely, and safe health care with respect to evidence-based cancer screening. Cancer Epidemiol Biomarkers Prev; 23(7); 1147–58. ©2014 AACR.

A recent comprehensive review has been carried out to quantify the benefits and harms of the European population-based mammographic screening programs. Five literature reviews were conducted on the basis of the observational published studies evaluating breast cancer mortality reduction, breast cancer overdiagnosis, and false-positive results. On the basis of the studies reviewed, the authors present a first estimate of the benefit and harm balance sheet. For every 1,000 women screened biennially from ages 50 to 51 years until ages 68 to 69 years and followed up until age 79 years, an estimated seven to nine breast cancer deaths are avoided, four cases are overdiagnosed, 170 women have at least one recall followed by noninvasive assessment with a negative result, and 30 women have at least one recall followed by invasive procedures yielding a negative result. The chance of a breast cancer death being avoided by population-based mammography screening of appropriate quality is more than that of overdiagnosis by screening. These outcomes should be communicated to women offered service screening in Europe. Cancer Epidemiol Biomarkers Prev; 23(7); 1159–63. ©2014 AACR.

Epithelial–mesenchymal transition (EMT) is thought to be an important mechanism of cancer cell metastasis. Clinical measurement of EMT markers in primary tumors could improve risk stratification and treatment decisions by identifying patients who potentially have metastatic disease. To evaluate the potential of EMT markers that could be used for risk stratification for patients with colorectal cancer, we conducted a systematic review of studies (N = 30) that measured at least one of a selection of EMT markers in primary tumors and patient outcomes. Fifteen of 30 studies (50%) reported at least one statistically significant result supporting a role for one of the selected EMT markers in identifying patients at risk for worse outcomes. Importantly, however, we identified design inconsistencies that limited inferences and prevented meta-analysis of data. We offer a number of recommendations to make future studies more informative and standardized, including consistent sampling of different parts of the primary tumor, larger sample sizes, and measurement of both protein and RNA expression of a given EMT marker in the same tumors. Strengthening the literature per our recommendations could facilitate translating EMT markers to clinical use. Cancer Epidemiol Biomarkers Prev; 23(7); 1164–75. ©2014 AACR.

Background: Light-at-night has been shown in experimental studies to disrupt melatonin production but this has only partly been confirmed in studies of night shift workers. In this cross-sectional study, we examined the circadian variation of melatonin in relation to shift status, individual levels of light-at-night exposure, and diurnal preference, an attribute reflecting personal preference for activity in the morning or evening.

Methods: One hundred and seventeen workers (75 night and 42 day) of both sexes, ages 22 to 64 years, were recruited from four companies. Participants collected urine samples from all voids over 24 hours and wore a data logger continuously recording their light exposure. Sociodemographic, occupational, lifestyle, and diurnal preference information were collected by interview. Concentrations of urinary 6-sulfatoxymelatonin (aMT6s), the main melatonin metabolite, were measured.

Results: Mean aMT6s levels were lower in night [10.9 ng/mg creatinine/hour; 95% confidence interval (CI), 9.5–12.6] compared with day workers (15.4; 95% CI, 12.3–19.3). The lowest aMT6s levels were observed in night workers with morning preference (6.4; 95% CI, 3.0–13.6). Peak time of aMT6s production occurred 3 hours later in night (08:42 hour, 95% CI, 07:48–09:42) compared with day workers (05:36 hour, 95% CI, 05:06–06:12). Phase delay was stronger among subjects with higher light-at-night exposure and number of nights worked.

Conclusions: Night shift workers had lower levels and a delay in peak time of aMT6s production over a 24-hour period. Differences were modified by diurnal preference and intensity of light-at-night exposure.

Impact: Night shift work affects levels and timing of melatonin production and both parameters may relate to future cancer risk. Cancer Epidemiol Biomarkers Prev; 23(7); 1176–86. ©2014 AACR.

Background: Arsenic is a ubiquitous, naturally occurring metalloid that poses a significant human cancer risk. While water consumption provides the majority of human exposure, millions of individuals worldwide are significantly exposed to arsenic through naturally occurring levels of arsenic in grains, vegetables, meats and fish, as well as through food processed with water containing arsenic. Thus, we estimated the global burdens of disease for bladder, lung, and skin cancers attributable to inorganic arsenic in food.

Methods: To determine foodborne inorganic arsenic exposures worldwide, we used World Health Organization estimates of food consumption in thirteen country clusters, in conjunction with reported measurements of total and inorganic arsenic in different foods. We estimated slope factors for arsenic-related bladder and lung cancers, and used the U.S. Environmental Protection Agency skin cancer slope factor, to calculate the annual risk of the cancer incidence in males and females within each country cluster.

Results: We estimated that each year 9,129 to 119,176 additional cases of bladder cancer, 11,844 to 121,442 of lung cancer, and 10,729 to 110,015 of skin cancer worldwide are attributable to inorganic arsenic in food.

Conclusions: These estimates indicate that foodborne arsenic exposure causes a significant global burden of human disease.

Impact: Estimating the global cancer burden caused by arsenic exposure in food will support policies that reduce exposure to disease-promoting environmental hazards. Cancer Epidemiol Biomarkers Prev; 23(7); 1187–94. ©2014 AACR.

Background: Epidemiologic studies indicate that infections in early childhood may protect against pediatric acute lymphoblastic leukemia (ALL).

Methods: We identified 3,402 ALL cases among children 0 to 5 years of age using the California Cancer Registry. From California birth records we randomly selected controls in a 20:1 ratio and frequency matched them to cases by birth year. We investigated markers of exposure to infections, including month of birth, timing of birth in relation to influenza and respiratory syncytial virus (RSV) seasons, and birth order based on data from California birth certificates and national infection surveillance systems.

Results: We observed an increased risk of ALL for spring and summer births, and for those first exposed to an influenza or RSV season at nine to twelve months of age compared with those exposed during the first three months of life, and this association was stronger among first born children [odds ratios (OR), 1.44 and 95% confidence intervals (CI), 1.13–1.82, for influenza exposure at nine to twelve months of age]. Decreased risk was observed with increasing birth order among non-Hispanic whites but not Hispanics (OR, 0.76 and 95% CI, 0.59–096, for fourth or higher birth order among whites).

Conclusion: Our results support the hypothesis that infections in early childhood decrease risk of ALL.

Impact: Our findings implicate early life exposure to infections as protective factors for ALL in young children. Cancer Epidemiol Biomarkers Prev; 23(7); 1195–203. ©2014 AACR.

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 (<150/150–300/>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.

Background: Nasopharyngeal carcinoma (NPC) is an Epstein–Barr virus (EBV)–associated cancer that is highly treatable when diagnosed early, with 5-year disease-free survival of approximately 90%. However, NPC is typically diagnosed at advanced stages, in which disease-free survival is <50%. There is, therefore, a need for clinical tools to assist in early NPC detection, particularly among high-risk individuals.

Methods: We evaluated the ability of anti-EBV IgA antibodies to detect incident NPC among high-risk Taiwanese individuals. NPC cases (N = 21) and age- and sex-matched controls (N = 84) were selected. Serum collected before NPC diagnosis was tested for ELISA-based IgA antibodies against the following EBV peptides: EBNA1, VCAp18, EAp138, Ead_p47, and VCAp18 + EBNA1 peptide mixture. The sensitivity, specificity, and screening program parameters were calculated.

Results: EBNA1 IgA had the best performance characteristics. At an optimized threshold value, EBNA1 IgA measured at baseline identified 80% of the high-risk individuals who developed NPC during follow-up (80% sensitivity). However, approximately 40% of high-risk individuals who did not develop NPC also tested positive (false positives). Application of EBNA1 IgA as a biomarker to detect incident NPC in a previously unscreened, high-risk population revealed that 164 individuals needed to be screened to detect 1 NPC and that 69 individuals tested positive per case detected.

Conclusions: EBNA1 IgA proved to be a sensitive biomarker for identifying incident NPC, but future work is warranted to develop more specific screening tools to decrease the number of false positives.

Impact: Results from this study could inform decisions about screening biomarkers and referral thresholds for future NPC early-detection program evaluations. Cancer Epidemiol Biomarkers Prev; 23(7); 1213–9. ©2014 AACR.

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.

Background: We describe patterns of colorectal cancer screening uptake in a U.S. insured population as individuals become newly eligible for screening at age 50 and assess temporal trends and patient characteristics with screening uptake.

Methods: We identified a cohort of 81,223 men and women who were members of Group Health and turned 50 years old from 1996 to 2010. We ascertained receipt of colorectal cancer screening within five years. Time to screening was estimated by year of cohort entry using cumulative incidence curves and Cox proportional hazards models–estimated patient characteristics associated with screening uptake.

Results: Stool-based screening tests were the most common, 72% of first screening tests. The proportion of individuals initiating colorectal cancer screening via colonoscopy increased from 8% in 1996 to 1998 to 33% in 2008 to 2010. Patient factors associated with increased colorectal cancer screening were: turning 50 more recently (2008–2010; Ptrend < 0.0001) or Asian race [HR, 1.14; 95% confidence interval (CI), 1.10–1.19]. Patient factors associated with decreased screening were: being a woman (HR, 0.70; 95% CI, 0.68–0.72), Native American (HR, 0.68; 95% CI, 0.60–0.78), or Pacific Islander race (HR, 0.82; 95% CI, 0.72–0.95), and having prevalent diabetes (HR, 0.78; 95% CI, 0.75–0.82) and higher body mass index (Ptrend < 0.0001).

Conclusions: Patient characteristics associated with initiation of colorectal cancer screening in a newly eligible population are similar to characteristics associated with overall screening participation in all age-eligible adults. Our results identify patient populations to target in outreach programs.

Impact: Disparities in receipt of colorectal cancer screening are evident from onset of an age-eligible cohort, identifying key groups for future interventions for screening. Cancer Epidemiol Biomarkers Prev; 23(7); 1230–7. ©2014 AACR.

Background: Epidemiologic studies have shown increased risks of lung cancer among adults with low blood levels of selenium, although evidence is inconsistent. In the United States, the incidence of lung cancer is higher and mean serum selenium levels lower among Blacks than Whites, but prior studies have not assessed the selenium–lung cancer association among Blacks.

Methods: From the prospective Southern Community Cohort Study, we identified 372 participants who provided blood samples and subsequently developed lung cancer. Selenoprotein P (SEPP1), the most abundant selenoprotein in plasma and a biomarker of selenium nutriture, was measured in the plasma from these individuals and from 716 matched controls.

Results: Mean SEPP1 levels were significantly (P < 0.0001) lower among Blacks than Whites. Conditional logistic regression models accounting for smoking revealed a significant trend of increasing OR of lung cancer with decreasing SEPP1 tertiles among Blacks (P = 0.0006) but not Whites (P = 0.69; Pinteraction = 0.10). The ORs and corresponding 95% confidence intervals of lung cancer risk among those with lowest versus highest tertile levels of SEPP1 were 2.4 (1.5–3.0) among Blacks and 1.1 (0.6–2.1) among Whites.

Conclusions: Among a mostly low-income population in the southeastern United States, lower levels of SEPP1 were associated with an increasing risk of lung cancer among Blacks but not Whites.

Impact: The combined findings of higher prevalence of low selenium status and higher lung cancer risk associated with low status raise the possibility that selenium deficiency may contribute to observed racial disparities in lung cancer incidence. Cancer Epidemiol Biomarkers Prev; 23(7); 1238–44. ©2014 AACR.

Background: Assessment and discussion of individual risk for breast cancer within the primary care setting are crucial to discussion of risk reduction and timely referral.

Methods: We conducted a randomized controlled trial of a multiethnic, multilingual sample of women ages 40 to 74 years from two primary care practices (one academic, one safety net) to test a breast cancer risk assessment and education intervention. Patients were randomly assigned to control or intervention group. All patients completed a baseline telephone survey and risk assessment (via telephone for controls, via tablet computer in clinic waiting room before visit for intervention). Intervention (BreastCARE) patients and their physicians received an individualized risk report to discuss during the visit. One-week follow-up telephone surveys with all patients assessed patient–physician discussion of family cancer history, personal breast cancer risk, high-risk clinics, and genetic counseling/testing.

Results: A total of 655 control and 580 intervention women completed the risk assessment and follow-up interview; 25% were high-risk by family history, Gail, or Breast Cancer Surveillance Consortium risk models. BreastCARE increased discussions of family cancer history [OR, 1.54; 95% confidence interval (CI), 1.25–1.91], personal breast cancer risk (OR, 4.15; 95% CI, 3.02–5.70), high-risk clinics (OR, 3.84; 95% CI, 2.13–6.95), and genetic counseling/testing (OR, 2.22; 95% CI, 1.34–3.68). Among high-risk women, all intervention effects were stronger.

Conclusions: An intervention combining an easy-to-use, quick risk assessment tool with patient-centered risk reports at the point of care can successfully promote discussion of breast cancer risk reduction between patients and primary care physicians, particularly for high-risk women.

Impact: Next steps include scaling and dissemination of BreastCARE with integration into electronic medical record systems. Cancer Epidemiol Biomarkers Prev; 23(7); 1245–53. ©2014 AACR.

Background: Pancreas-cancer prognosis is dismal, with 5-year survival less than 5%. Significant relationships between aspirin use and decreased pancreas-cancer incidence and mortality have been shown in four of 13 studies.

Methods: To evaluate further a possible association between aspirin use and risk of pancreatic cancer, we used data from a population-based Connecticut study conducted from January 2005 to August 2009, of 362 pancreas-cancer cases frequency matched to 690 randomly sampled controls.

Results: Overall, regular use of aspirin was associated with reduced risk of pancreatic cancer [odds ratio (OR), 0.52; 95% confidence interval (CI), 0.39–0.69]. Increments of decreasing risk of pancreatic cancer were observed for each year of low-dose or regular-dose aspirin use (OR, 0.94; 95% CI, 0.91–0.98 and OR, 0.98; 95% CI, 0.96–1.01, respectively) and for increasing years in the past that low-dose or regular-dose aspirin use had started (OR, 0.95; 95% CI, 0.92–0.99 and OR, 0.98; 95% CI, 0.96–1.00, respectively). Reduced risk of pancreatic cancer was seen in most categories of calendar time period of aspirin use, for both low-dose aspirin and regular-dose aspirin use. Relative to continuing use at the time of interview, termination of aspirin use within 2 years of interview was associated with increased risk of pancreatic cancer (OR, 3.24; 95% CI, 1.58–6.65).

Conclusions: Our results provide some support that a daily aspirin regimen may reduce risk of developing pancreatic cancer.

Impact: Long-term aspirin use has benefits for both cardiovascular disease and cancer, but appreciable bleeding complications that necessitate risk–benefit analysis for individual applications. Cancer Epidemiol Biomarkers Prev; 23(7); 1254–63. ©2014 AACR.

Background: Nondaily or intermittent smokers (ITS) are increasingly common, but how much nicotine, if any, ITS take in and how quickly they metabolize it has not yet been studied.

Methods: We compared carbon monoxide (CO), urinary cotinine, and nicotine metabolism [nicotine metabolite ratio (NMR): 3-hydroxycotinine:cotinine] in 224 ITS and 222 daily smokers (DS). Effects of gender and ethnicity were examined.

Results: DS had higher cotinine concentrations than ITS (1,396 ± 69 vs. 478 ± 44 ng/mL), attributable to higher cigarettes per day (CPD). In both groups, cotinine rose more slowly as CPD increased. There were no differences in cotinine between White (WH) and African American (AA) DS; among ITS, AA cotinine was over twice that of WH. Among DS, CO was significantly higher among WH than AA smokers, but significantly lower among WH ITS than AA ITS. Although AA ITS smoked more than WH ITS (CPD: 4.13 ± 0.55 vs. 3.31 ± 0.41), this did not account for the observed cotinine nor CO differences. There were no differences in NMR by group or race, nor any gender effects.

Conclusions: At comparable CPD, DS' and ITS' intake of nicotine per cigarette was similar, as were their rates of nicotine metabolism. Among ITS, AA smokers smoke more and take in more nicotine per cigarette than WH ITS, consistent with the view of ITS as a heterogeneous group.

Impact: Differences in nicotine intake per cigarette and metabolism likely cannot account for differences in DS and ITS smoking. Future studies should explore ethnic differences in ITS smoking. Cancer Epidemiol Biomarkers Prev; 23(7); 1264–72. ©2014 AACR.

Background: The insulin-like growth factor-I (IGFI) receptor is a potential target for breast cancer treatment and may be influenced by dietary intake.

Methods: Nested, case–control study of 265 postmenopausal breast cancer survivors; primary breast cancer tissue was stained to determine IGFI receptor status. Change in carbohydrate intake from baseline to year 1 of study was estimated from 24-hour dietary recalls. Breast cancer recurrence cases (91) were matched to two controls (n = 174) on disease and study characteristics and counter matched on change in carbohydrate intake. Weighted conditional logistic regression models fit the risk of recurrence on IGFI receptor status and dietary change.

Results: Half of the tumors were IGFI receptor positive. Increased risk of recurrence was associated with IGFI receptor–positive status [HR 1.7; 95% confidence interval (CI), 1.2–2.5] and, separately, with a stable/increased intake of carbohydrates (HR 2.0; 95% CI, 1.3–5.0). There was a borderline significant interaction between those two variables (P = 0.11). Specifically, carbohydrate intake had no significant impact on risk of recurrence among women who were receptor negative, yet increased the risk of recurrence by more than 5-fold among women who were receptor positive (HR 5.5; 95% CI, 1.8–16.3).

Conclusions: Among women whose tumor tissue is positive for the IGFI receptor, reducing carbohydrate intake after diagnosis could reduce the risk of breast cancer recurrence. These findings need replication in a larger sample.

Impact: This is the first study to suggest that it may be possible to personalize dietary recommendations for breast cancer survivors based on molecular characteristics of their primary tumor tissue. Cancer Epidemiol Biomarkers Prev; 23(7); 1273–9. ©2014 AACR.

Background: Childhood cancer survivors may be at increased risk of hospitalization because of cancer-related late effects.

Methods: Using data from population-based research resources in Utah, we identified childhood and adolescent cancer survivors who were diagnosed from 1973 to 2005 (N = 2,571). We selected a comparison cohort based on birth year and sex (N = 7,713). Hospitalizations from 1996 to 2010, excluding pregnancy and delivery, were determined from discharge records. Multivariable regressions were used to evaluate hospitalization admissions, length of stay, and diagnosis for survivors starting five years from diagnosis versus the comparison cohort.

Results: When follow-up began in 1996, there were N = 1,499 survivors and N = 7,219 comparisons who were alive and eligible for follow-up. Average follow-up for survivors was 13.5 years (SD = 8.5) and for the comparison 14.0 years (SD = 8.7; P = 0.05). Survivors were hospitalized, on average, 1.62 (SD = 3.37) times contrasted to 0.79 (SD = 1.73) for the comparison cohort. In multivariable analyses, the hazard ratio (HR) of any hospitalization since 1996 was higher for survivors than the comparison cohort [HR, 1.52, 95% confidence interval (CI), 1.31–1.66]. Survivors experienced a higher hospital admission rate [rate ratio (RR) = 1.67; 95% CI, 1.58–1.77] than the comparison cohort. The number of hospitalizations was highest for neuroblastoma (RR = 2.21; 95% CI, 1.84–2.66) and bone tumors (RR = 2.55; 95% CI, 2.14–3.02) in reference to the comparison cohort. Survivors were hospitalized because of blood disorders more often (HR, 14.2; 95% CI, 6.3–32.0).

Conclusions: The risk of hospitalization and lengths of stay are elevated among childhood cancer survivors.

Impact: Research to identify strategies to prevent and manage survivors' health problems in outpatient settings is needed. Cancer Epidemiol Biomarkers Prev; 23(7); 1280–9. ©2014 AACR.

Background: It has been hypothesized that predominance of the 2-hydroxylation estrogen metabolism pathway over the 16α-hydroxylation pathway may be inversely associated with breast cancer risk.

Methods: We examined the associations of invasive breast cancer risk with circulating 2-hydroxyestrone (2-OHE1), 16α-hydroxyestrone (16α-OHE1), and the 2-OHE1:16α-OHE1 ratio in a case–control study of postmenopausal women nested within two prospective cohorts: the New York University Women's Health Study (NYUWHS) and the Northern Sweden Mammary Screening Cohort (NSMSC), with adjustment for circulating levels of estrone, and additional analyses by tumor estrogen receptor (ER) status. Levels of 2-OHE1 and 16α-OHE1 were measured using ESTRAMET 2/16 assay in stored serum or plasma samples from 499 incident breast cancer cases and 499 controls, who were matched on cohort, age, and date of blood donation.

Results: Overall, no significant associations were observed between breast cancer risk and circulating levels of 2-OHE1, 16α-OHE1, or their ratio in either cohort and in combined analyses. For 2-OHE1, there was evidence of heterogeneity by ER status in models adjusting for estrone (P ≤ 0.03). We observed a protective association of 2-OHE1 with ER+ breast cancer [multivariate-adjusted OR for a doubling of 2-OHE1, 0.67 (95% confidence interval [CI], 0.48–0.94; P = 0.02)].

Conclusions: In this study, higher levels of 2-OHE1 were associated with reduced risk of ER+ breast cancer in postmenopausal women after adjustment for circulating estrone.

Impact: These results suggest that taking into account the levels of parent estrogens and ER status is important in studies of estrogen metabolites and breast cancer. Cancer Epidemiol Biomarkers Prev; 23(7); 1290–7. ©2014 AACR.

Background: It is important to understand the natural history of cervical cancer, which has implications for cancer prevention and management. However, a dearth of studies on the long-term development of cervical cancer exists in China.

Methods: We investigated the natural history of cervical cancer in Chinese women by creating a multistate model using 11 years of follow-up data from the Shanxi Province Cervical Cancer Screening Study I conducted from 1999 to 2010. In 1999, a total of 1,997 eligible women, ages 35 to 45 years, were enrolled in Xiangyuan County, Shanxi Province. Participants were followed up in 2005 and 2010, respectively.

Results: The average time a subject spent in CIN1 before transiting into another state was 1.4693 years [95% confidence interval (CI): 1.1215–1.9251] and the average time a subject spent in CIN2 was 2.9822 years (95% CI: 1.9790–4.4938). A subject's transition probability from CIN1 to normal increased with time. However, the transition probability from CIN1 to CIN2 was relatively lower, with 3-, 5-, and 10-year transition probabilities of 0.1415, 0.1066, and 0.0437. Comparison of 5-year transition probabilities between CIN2 to normal/CIN1 and CIN2 to CIN3+ yielded a ratio of 2.74.

Conclusions: Women with CIN1 had a substantial tendency for regression. Similarly, women with CIN2 had a higher probability of regression to normal/CIN1 than progression to CIN3+. Findings in this study may have significant implications for the development and evaluation of formal cervical cancer preventive strategies in China.

Impact: This study may serve as a valuable reference to future research on other multistate cancer processes. Cancer Epidemiol Biomarkers Prev; 23(7); 1298–305. ©2014 AACR.

Background: The intervention completion rate is an important metric in behavioral and intervention research; trials with limited intervention completion rates may have reduced internal validity. We examined intervention completion rates among 530 African Americans who had been randomized to an integrated (INT) or disease-specific (DSE) risk education protocol as part of a comparative effectiveness trial from September 2009 to August 2012.

Methods: The interventions were developed by an academic-community partnership using community-based participatory research. Intervention completion rates were determined based on attendance at all four intervention sessions. Intervention completers were participants who completed all four sessions and noncompleters were those who did not complete any session or only completed one to three sessions following randomization.

Results: Seventy-three percent of participants were intervention completers and 27% were noncompleters. There were no differences in intervention completion based on randomization to INT (72%) or DSE (75%), sociodemographic factors, or body mass index (BMI) in the total sample. Different factors were associated significantly with intervention completion within study groups. Among participants randomized to INT, the odds of intervention completion were greater with higher levels of intrinsic motivation, less exposure to information about diet and cardiovascular disease, and greater BMI. Among participants randomized to DSE, the odds of completing the intervention were associated significantly with older age and greater dietary self-efficacy.

Conclusions: Many African Americans are likely to complete risk education interventions.

Impact: Psychologic characteristics should be considered when determining intervention completion rates following randomization in behavioral and intervention trials. Cancer Epidemiol Biomarkers Prev; 23(7); 1306–13. ©2014 AACR.

Background: Mammographic density is a strong risk factor for breast cancer.

Methods: We present a novel approach to enhance area density measures that takes advantage of the relative density of the pectoral muscle that appears in lateral mammographic views. We hypothesized that the grey scale of film mammograms is normalized to volume breast density but not pectoral density and thus pectoral density becomes an independent marker of volumetric density.

Results: From analysis of data from a Swedish case–control study (1,286 breast cancer cases and 1,391 control subjects, ages 50–75 years), we found that the mean intensity of the pectoral muscle (MIP) was highly associated with breast cancer risk [per SD: OR = 0.82; 95% confidence interval (CI), 0.75–0.88; P = 6 x 10–7] after adjusting for a validated computer-assisted measure of percent density (PD), Cumulus. The area under curve (AUC) changed from 0.600 to 0.618 due to using PD with the pectoral muscle as reference instead of a standard area-based PD measure. We showed that MIP is associated with a genetic variant known to be associated with mammographic density and breast cancer risk, rs10995190, in a subset of women with genetic data. We further replicated the association between MIP and rs10995190 in an additional cohort of 2,655 breast cancer cases (combined P = 0.0002).

Conclusions: MIP is a marker of volumetric density that can be used to complement area PD in mammographic density studies and breast cancer risk assessment.

Impact: Inclusion of MIP in risk models should be considered for studies using area PD from analog films. Cancer Epidemiol Biomarkers Prev; 23(7); 1314–23. ©2014 AACR.

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.

Background: One challenge in prostate cancer is distinguishing indolent from aggressive disease at diagnosis. DNA promoter hypermethylation is a frequent epigenetic event in prostate cancer, but few studies of DNA methylation in relation to features of more aggressive tumors or prostate cancer recurrence have been completed.

Methods: We used the Infinium HumanMethylation450 BeadChip to assess DNA methylation in tumor tissue from 407 patients with clinically localized prostate cancer who underwent radical prostatectomy. Recurrence status was determined by follow-up patient surveys, medical record review, and linkage with the Surveillance, Epidemiology, and End Results (SEER) registry. The methylation status of 14 genes for which promoter hypermethylation was previously correlated with advanced disease or biochemical recurrence was evaluated. Average methylation level for promoter region CpGs in patients who recurred compared with those with no evidence of recurrence was analyzed. For two genes with differential methylation, time to recurrence was examined.

Results: During an average follow-up of 11.7 years, 104 (26%) patients recurred. Significant promoter hypermethylation in at least 50% of CpG sites in two genes, ABHD9 and HOXD3, was found in tumors from patients who recurred compared with those without recurrence. Evidence was strongest for HOXD3 (lowest P = 9.46 x 10–6), with higher average methylation across promoter region CpGs associated with reduced recurrence-free survival (P = 2 x 10–4). DNA methylation profiles did not differ by recurrence status for the other genes.

Conclusions: These results validate the association between promoter hypermethylation of ADHB9 and HOXD3 and prostate cancer recurrence.

Impact: Tumor DNA methylation profiling may help to distinguish patients with prostate cancer at higher risk for disease recurrence. Cancer Epidemiol Biomarkers Prev; 23(7); 1331–9. ©2014 AACR.

Background: Up to 70% of patients with non–muscle-invasive bladder cancer (NMIBC) experience disease recurrence, making it one of the most prevalent cancers in the United States. The purpose of this study was to test the performance of a multiplex urinary biomarker assay for the monitoring of voided urine for recurrent bladder cancer.

Methods: This retrospective, multicenter study included a total of 125 subjects with a history of bladder cancer. Voided urine specimens were collected before procedure from these subjects (53 with confirmed tumor recurrence and 72 with confirmed non-tumor recurrence) for analysis. A prediction rule generated from the performance characteristics of 10 single biomarkers (IL8, MMP9, MMP10, SERPINA1, VEGFA, ANG, CA9, APOE, SERPINE1, and SDC1) was measured using ELISA. The diagnostic performance of the biomarker panel was assessed using receiver operator curves (ROC) and descriptive statistical values (e.g., sensitivity and specificity).

Results: The combination of all 10 biomarkers outperformed any single biomarker with a calculated AUROC for the diagnostic panel of 0.904 [95% confidence interval (CI), 0.853–0.956]. The multiplex assay achieved an overall sensitivity of 79% and specificity of 88% for recurrent bladder cancer and significantly outperformed the Urovysion cytogenetic assay (sensitivity 42%, specificity 94%) and voided urinary cytology (sensitivity 33%, specificity 90%).

Conclusions: A diagnostic panel of 10 urinary biomarkers that accurately detects primary bladder cancer also performs well for the detection of recurrent bladder cancer.

Impact: The identification of a reliable urine-based surveillance and detection assay would be of benefit to both patients and the healthcare system. Cancer Epidemiol Biomarkers Prev; 23(7); 1340–5. ©2014 AACR.

Background: We (i) described variability in colorectal cancer (CRC) test use across multiple levels, including physician, clinic, and neighborhood; and (ii) compared the performance of novel cross-classified models versus traditional hierarchical models.

Methods: We examined multilevel variation in CRC test use among patients not up-to-date with screening in a large, urban safety net health system (2011–2012). Outcomes included: (i) fecal occult blood test (FOBT) or (ii) colonoscopy and were ascertained using claims data during a 1-year follow-up. We compared Bayesian (i) cross-classified four-level logistic models nesting patients within separate, nonoverlapping "levels" (physicians, clinics, and census tracts) versus (ii) three hierarchical two-level models using deviance information criterion. Models were adjusted for covariates (patient sociodemographic factors, driving time to clinic, and census tract poverty rate).

Results: Of 3,195 patients, 157 (4.9%) completed FOBT and 292 (9.1%) completed colonoscopy during the study year. Patients attended 19 clinics, saw 177 physicians, and resided in 332 census tracts. Significant variability was observed across all levels in both hierarchical and cross-classified models that was unexplained by measured covariates. For colonoscopy, variance was similar across all levels. For FOBT, physicians, followed by clinics, demonstrated the largest variability. Model fit using cross-classified models was superior or similar to 2-level hierarchical models.

Conclusions: Significant and substantial variability was observed across neighborhood, physician, and clinic levels in CRC test use, suggesting the importance of factors at each of these levels on CRC testing.

Impact: Future multilevel research and intervention should consider the simultaneous influences of multiple levels, including clinic, physician, and neighborhood. Cancer Epidemiol Biomarkers Prev; 23(7); 1346–55. ©2014 AACR.

Background: Only a minority of the genetic components of prostate cancer risk have been explained. Some observed associations of SNPs with prostate cancer might arise from associations of these SNPs with circulating prostate-specific antigen (PSA) because PSA values are used to select controls.

Methods: We undertook a genome-wide association study (GWAS) of screen-detected prostate cancer (ProtecT: 1,146 cases and 1,804 controls); meta-analyzed the results with those from the previously published UK Genetic Prostate Cancer Study (1,854 cases and 1,437 controls); investigated associations of SNPs with prostate cancer using either "low" (PSA < 0.5 ng/mL) or "high" (PSA ≥ 3 ng/mL, biopsy negative) PSA controls; and investigated associations of SNPs with PSA.

Results: The ProtecT GWAS confirmed previously reported associations of prostate cancer at three loci: 10q11.23, 17q24.3, and 19q13.33. The meta-analysis confirmed associations of prostate cancer with SNPs near four previously identified loci (8q24.21,10q11.23, 17q24.3, and 19q13.33). When comparing prostate cancer cases with low PSA controls, alleles at genetic markers rs1512268, rs445114, rs10788160, rs11199874, rs17632542, rs266849, and rs2735839 were associated with an increased risk of prostate cancer, but the effect-estimates were attenuated to the null when using high PSA controls (Pheterogeneity in effect-estimates < 0.04). We found a novel inverse association of rs9311171-T with circulating PSA.

Conclusions: Differences in effect-estimates for prostate cancer observed when comparing low versus high PSA controls may be explained by associations of these SNPs with PSA.

Impact: These findings highlight the need for inferences from genetic studies of prostate cancer risk to carefully consider the influence of control selection criteria. Cancer Epidemiol Biomarkers Prev; 23(7); 1356–65. ©2014 AACR.

Background: Serum vascular adhesion protein-1 (VAP-1) predicts cancer-related mortality in diabetic subjects. However, whether serum VAP-1 predicts cancer incidence or cancer progression remains unclear. We conducted a cohort study to investigate whether serum VAP-1 and related clinical variables predict incident cancers in type II diabetic subjects.

Methods: From 1996 to 2003, we enrolled 568 type II diabetic subjects who were free of cancer at baseline. Serum VAP-1 at enrollment was measured by time-resolved immunofluorometric assay. Chronic kidney disease (CKD) was defined as estimated glomerular filtration rate <60 mL/min per 1.73 m2. The subjects were followed until first occurrence of cancer or until December 31, 2011.

Results: During a mean follow-up of 11.3 years, 71 subjects developed incident cancers. The HRs for incident cancers in subjects with highest tertile of serum VAP-1 and in subjects with CKD were 2.95 [95% confidence interval (CI), 1.31–6.63; P = 0.009] and 2.29 (95% CI, 1.18–4.44; P = 0.015), respectively, after multivariate adjustment. There was an interaction between serum VAP-1 and CKD on the risk of incident cancers (P = 0.01 for log-transformed VAP-1 x CKD). The relationship among serum VAP-1, CKD, and incident cancers was similar if death was considered in the competing risk models or if subjects with shorter follow-up period were excluded.

Conclusions: Higher serum VAP-1 and CKD can independently predict future development of cancers in type II diabetic subjects.

Impact: Physicians should be aware of the early signs of cancer in diabetic individuals with elevated VAP-1 or renal dysfunction. More aggressive treatment strategies might be considered. Cancer Epidemiol Biomarkers Prev; 23(7); 1366–73. ©2014 AACR.

Background: Previous studies on the association between one-carbon dietary factors and gastric cancer risk have been inconsistent.

Methods: We investigated this association using data from a prospective study, the Shanghai Women's Health Study (1997–2010), including 323 distal gastric cancer cases identified from 73,009 Chinese women. HRs and 95% confidence intervals (CI) were estimated using Cox proportional hazard regression after adjusting for confounders.

Results: Overall, no statistically significant association of gastric cancer was observed with dietary intake of folate, methionine, or B vitamins. However, when stratified by menopausal status, higher intake of riboflavin was associated with decreased gastric cancer risk in premenopausal women with HR of 0.35 (95% CI, 0.17–0.73), 0.48 (0.24–0.97), 0.28 (0.12–0.65), and 0.23 (0.07–0.91), respectively, for the quintiles 2 to 5 intake groups compared with the lowest quintile intake (P for trend = 0.02). Among premenopausal women, highest intake of folate was associated with increased gastric cancer risk (HR, 2.62; 95% CI, 1.04–6.59). There were no statistically significant associations observed among postmenopausal women.

Conclusions: These results suggest that dietary factors involved in one-carbon metabolism are associated with gastric cancer risk among premenopausal women.

Impact: Riboflavin may be a protective factor and folate may be a risk factor for premenopausal gastric cancer. Cancer Epidemiol Biomarkers Prev; 23(7); 1374–82. ©2014 AACR.

Background: Serum markers are used before pelvic imaging to improve specificity and positive predictive value (PPV) of ovarian cancer multimodal screening strategies.

Methods: We conducted a randomized controlled pilot trial to estimate surgical PPV of a "2 of 3 tests positive" screening rule, and to compare use of HE4 as a first-line (Arm 1) versus a second-line (Arm 2) screen, in women at high and elevated risk for epithelial ovarian cancer (EOC) at five study sites. Semiannual screening was offered to 208 women ages 25 to 80 years with deleterious BRCA germline mutations and to 834 women ages 35 to 80 years with pedigrees suggesting inherited susceptibility. Annual screening was offered to 130 women ages 45 to 80 years (Risk Group 3) with epidemiologic and serum marker risk factors. Rising marker levels were identified using the parametric empirical Bayes algorithm.

Results: Both strategies yielded surgical PPV above 25%. Protocol-indicated surgery was performed in 6 women, identifying two ovarian malignancies and yielding a surgical PPV in both arms combined of 33% (95% confidence interval: 4%–78%), 25% in Arm 1 and 50% in Arm 2. Surgical consultation was recommended for 37 women (26 in Arm 1 and 11 in Arm 2). On the basis of 12 women with at least 2 of 3 tests positive (CA125, HE4, or imaging), an intent-to-treat analysis yielded PPV of 14% in Arm 1 and 20% in Arm 2.

Conclusions: Positive screens were more frequent when HE4 was included in the primary screen.

Impact: HE4 may be useful as a confirmatory screen when rising CA125 is used alone as a primary screen. Cancer Epidemiol Biomarkers Prev; 23(7); 1383–93. ©2014 AACR.

Background: Well-designed studies on lifestyle and health-related quality of life (HRQoL) in colorectal cancer survivors based on a biopsychosocial instead of a traditional biomedical approach are warranted. We report on the applicability of the International Classification of Functioning, Disability, and Health (ICF) as useful biopsychosocial framework to improve research on how lifestyle influences colorectal cancer survivors' HRQoL, using the Energy for life after ColoRectal cancer (EnCoRe) study as an example.

Methods: The ICF was used to develop a conceptual model for studying lifestyle and colorectal cancer survivors' HRQoL, by identifying relevant factors from literature and mapping them within the ICF. Subsequently, this model was used for selection of measurement instruments and biomarkers. By linking meaningful concepts within selected measures to the ICF, we could assess the ICF coverage of our developed conceptual model.

Results: Within selected measures, 450 meaningful concepts were identified, of which 88% were linked to the ICF. The linking process resulted in 132 distinctive ICF categories assigned (38% within "Body Functions," 2% within "Body Structures," 46% within "Activities and Participation," and 14% within "Environmental Factors").

Conclusions: The selected EnCoRe study measures broadly cover ICF domains relevant to colorectal cancer survivors, stressing the relevance of using a biopsychosocial approach for studying this population's HRQoL.

Impact: The developed conceptual model will guide data analyses and interpretation, and facilitate early transfer of results for development, evaluation, and implementation of personalized multidisciplinary lifestyle interventions. We recommend the ICF as an invaluable framework for improving the quality and scope of HRQoL studies. Cancer Epidemiol Biomarkers Prev; 23(7); 1394–405. ©2014 AACR.

Background: The incidence of rectal neuroendocrine tumors (NET) has been increasing since the implementation of the screening colonoscopy. However, very little is known about risk factors associated with rectal NETs. We examined the prevalence of and the risk factors for rectal NETs in a Korean population.

Methods: A cross-sectional study was performed on 62,171 Koreans who underwent screening colonoscopy. The clinical characteristics and serum biochemical parameters of subjects with rectal NET were compared with those of subjects without rectal NET using multivariate logistic regression.

Results: Of a total of 57,819 participants, 101 [OR, 0.17%; 95% confidence interval (CI), 0.14–0.20] had a rectal NET. Young age (<50 years; OR, 2.09; 95% CI, 1.06–4.15), male gender (OR, 1.92; 95% CI, 1.15–3.20), alcohol drinking [adjusted OR (AOR), 1.56; 95% CI, 1.01–2.42], and a low high-density lipoprotein-cholesterol (HDL-C) level (AOR, 1.85; 95% CI, 1.10–3.11) were independent risk factors for rectal NETs. Cigarette smoking, fatty liver, metabolic syndrome, higher triglyceride level (≥150 mg/dL), and higher homeostasis model assessment of insulin resistance (≥2.5) were not independently associated with rectal NETs, although these factors were more common in individuals with rectal NETs in the univariate analysis.

Conclusions: Young age (<50 years), male gender, alcohol drinking, and a low HDL-C level were risk factors for rectal NETs. Our results suggest that gender, behavioral factors, and dyslipidemia may affect the risk for developing rectal NETs.

Impact: The findings of this study contribute to a better understanding of the influence of gender, behavioral factors, and dyslipidemia in developing rectal NETs. Cancer Epidemiol Biomarkers Prev; 23(7); 1406–13. ©2014 AACR.

Epidemiologic studies have consistently found that self-reported allergies are associated with reduced risk of pancreatic cancer. Our aim was to prospectively assess the relationship between serum immunoglobulin E (IgE), a marker of allergy, and risk. This nested case–control study within the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO) included subjects enrolled in 1994 to 2001 and followed through 2010. There were 283 cases of pancreatic cancer and 544 controls matched on age, gender, race, and calendar date of blood draw. Using the ImmunoCAP system, we measured total IgE (normal, borderline, elevated), IgE to respiratory allergens, and IgE to food allergens (negative or positive) in serum collected at baseline. Odds ratios (OR) and 95% confidence intervals (CI) were estimated using conditional logistic regression. We assessed interactions with age, gender, smoking, body mass index, and time between randomization and case diagnosis. Overall, there was no association between the IgE measures and risk. We found a statistically significant interaction by baseline age: in those aged ≥65 years, elevated risks were observed for borderline total IgE (OR, 1.43; 95% CI, 0.88–2.32) and elevated total IgE (OR, 1.98; 95% CI, 1.16–3.37) and positive IgE to food allergens (OR, 2.83; 95% CI, 1.29–6.20); among participants <65 years, ORs were <1. Other interactions were not statistically significant. The reduced risk of pancreatic cancer associated with self-reported allergies is not reflected in serum IgE. Cancer Epidemiol Biomarkers Prev; 23(7); 1414–20. ©2014 AACR.

Survival in epithelial ovarian cancer (EOC) is influenced by the host immune response, yet the key genetic determinants of inflammation and immunity that affect prognosis are not known. The nuclear factor-B (NF-B) transcription factor family plays an important role in many immune and inflammatory responses, including the response to cancer. We studied common inherited variation in 210 genes in the NF-B family in 10,084 patients with invasive EOC (5,248 high-grade serous, 1,452 endometrioid, 795 clear cell, and 661 mucinous) from the Ovarian Cancer Association Consortium. Associations between genotype and overall survival were assessed using Cox regression for all patients and by major histology, adjusting for known prognostic factors and correcting for multiple testing (threshold for statistical significance, P < 2.5 x 10–5). Results were statistically significant when assessed for patients of a single histology. Key associations were with caspase recruitment domain family, member 11 (CARD11) rs41324349 in patients with mucinous EOC [HR, 1.82; 95% confidence interval (CI), 1.41–2.35; P = 4.13 x 10–6] and tumor necrosis factor receptor superfamily, member 13B (TNFRSF13B) rs7501462 in patients with endometrioid EOC (HR, 0.68; 95% CI, 0.56–0.82; P = 2.33 x 10–5). Other associations of note included TNF receptor–associated factor 2 (TRAF2) rs17250239 in patients with high-grade serous EOC (HR, 0.84; 95% CI, 0.77–0.92; P = 6.49 x 10–5) and phospholipase C, gamma 1 (PLCG1) rs11696662 in patients with clear cell EOC (HR, 0.43; 95% CI, 0.26–0.73; P = 4.56 x 10–4). These associations highlight the potential importance of genes associated with host inflammation and immunity in modulating clinical outcomes in distinct EOC histologies. Cancer Epidemiol Biomarkers Prev; 23(7); 1421–7. ©2014 AACR.

Background: The association between cell phone use and the development of parotid tumors is controversial. Because there is unequivocal evidence that the microenvironment is important for tumor formation, we investigated in the parotid glands whether cell phone use alters the expression of gene products related to cellular stress.

Methods: We used the saliva produced by the parotid glands of 62 individuals to assess molecular alterations compatible with cellular stress, comparing the saliva from the gland exposed to cell phone radiation (ipsilateral) to the saliva from the opposite, unexposed parotid gland (contralateral) of each individual. We compared salivary flow, total protein concentration, p53, p21, reactive oxygen species (ROS), and salivary levels of glutathione (GSH), heat shock proteins 27 and 70, and IgA between the ipsilateral and contralateral parotids.

Results: No difference was found for any of these parameters, even when grouping individuals by period of cell phone use in years or by monthly average calls in minutes.

Conclusion and Impact: We provide molecular evidence that the exposure of parotid glands to cell phone use does not alter parotid salivary flow, protein concentration, or levels of proteins of genes that are directly or indirectly affected by heat-induced cellular stress. Cancer Epidemiol Biomarkers Prev; 23(7); 1428–31. ©2014 AACR.

Background: The EML4-ALK fusion gene is more frequently found in younger, never smoking patients with lung cancer. Meanwhile, never smokers exposed to secondhand tobacco smoke (SHS) during childhood are diagnosed at a younger age compared with never smoking patients with lung cancer who are not exposed. We, therefore, hypothesized that SHS, which can induce DNA damage, is associated with the EML4-ALK fusion gene.

Methods: We compared the frequency of the EML4-ALK fusion gene among 197 never smoker patients with lung cancer with and without a history of exposure to SHS during childhood at Mayo Clinic.

Results: The EML4-ALK fusion gene was detected in 33% of cases from never smokers with a history of SHS exposure during childhood, whereas 47% of never smoking lung cancer cases without a history of childhood SHS exposure tested positive for the fusion gene.

Conclusions: The EML4-ALK fusion gene is not enriched in tumors from individuals exposed to SHS during childhood.

Impact: These data suggest that childhood exposure to SHS is not a significant etiologic cause of the EML4-ALK fusion gene in lung cancer. Cancer Epidemiol Biomarkers Prev; 23(7); 1432–4. ©2014 AACR.