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Cancer Epidemiology Biomarkers & Prevention

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Cancer Epidemiology Biomarkers & Prevention

The Asian American, Native Hawaiian, and Pacific Islander population is large, growing, and extremely heterogeneous. Not only do they bear unique burdens of incidence and outcomes for certain cancer types, they exhibit substantial variability in cancer incidence and survival patterns across the ethnic groups. By acknowledging and leveraging this heterogeneity through investing in cancer research within these populations, we have a unique opportunity to accelerate the availability of useful and impactful cancer knowledge.

See all the articles in this CEBP Focus section, "Cancer in Asian and Pacific Islander Populations."

Cancer Epidemiol Biomarkers Prev; 23(11); 2202–5. ©2014 AACR.



Background: Routinely recommended screening for breast, cervical, and colorectal cancers can significantly reduce mortality from these types of cancer, yet screening is underutilized among Asians. Surveys rely on self-report and often are underpowered for analysis by Asian ethnicities. Electronic health records (EHR) include validated (as opposed to recall-based) rates of cancer screening. In this article, we seek to better understand cancer screening patterns in a population of insured Asian Americans.

Methods: We calculated rates of compliance with cervical, breast, and colorectal cancer screening among Asians from an EHR population and compared them with non-Hispanic whites. We performed multivariable modeling to evaluate potential predictors (at the provider- and patient-level) of screening completion among Asian patients.

Results: Aggregation of Asian subgroups masked heterogeneity in screening rates. Asian Indians and native Hawaiians and Pacific Islanders had the lowest rates of screening in our sample, well below that of non-Hispanic whites. In multivariable analyses, screening completion was negatively associated with patient–physician language discordance for mammography [OR, 0.81; 95% confidence interval (CI), 0.71–0.92] and colorectal cancer screening (OR, 0.79; CI, 0.72–0.87) and positively associated with patient–provider gender concordance for mammography (OR, 1.16; CI, 1.00–1.34) and cervical cancer screening (OR, 1.66; CI, 1.51–1.82). In addition, patient enrollment in online health services increased mammography (OR, 1.32; CI, 1.20–1.46) and cervical cancer screening (OR, 1.31; CI, 1.24–1.37).

Conclusions: Language- and gender-concordant primary care providers and culturally tailored online health resources may help improve preventive cancer screening in Asian patient populations.

Impact: This study demonstrates how the use of EHR data can inform investigations of primary prevention practices within the healthcare delivery setting.

See all the articles in this CEBP Focus section, "Cancer in Asian and Pacific Islander Populations."

Cancer Epidemiol Biomarkers Prev; 23(11); 2208–17. ©2014 AACR.


Background: The Asian American and Pacific Islander (AAPI) population is heterogeneous and rapidly growing in the United States, with a high proportion concentrated in California. Although traditionally assumed to have lower rates of breast cancer than non-Hispanic white women, recent studies have suggested considerable variation in incidence by AAPI ethnic group, with rates in some exceeding those in non-Hispanic whites. The potential role of environmental toxicants has not been well explored and may provide insights into these patterns.

Methods: We created an exposure potential index (EPI) score for 24 hazardous air pollutants modeled by the U.S. Environmental Protection Agency National-Scale Air Toxics Assessment considered to be mammary gland carcinogens, and compared values at the census tract level for "geographically concentrated" AAPI groups throughout the State. "Geographically concentrated" populations were defined as census tracts with at least 100 individuals from a specified racial/ethnic population as enumerated by the 2000 Census.

Results: Although EPI scores differed little between census tracts with aggregated AAPI (mean EPI = 0.53) and non-Hispanic white women (mean EPI = 0.63), there was substantial variation between tracts for disaggregated AAPI groups, with notably higher EPI scores for tracts enumerated for Korean or Japanese women (mean EPI of 0.78 and 0.77, respectively) compared with other AAPI groups.

Conclusions: Our findings underscore the importance of disaggregating data for the heterogeneous AAPI population to identify differences in potential environmental exposures across groups.

Impact: Future cancer etiology studies should examine environmental exposure differences within and across groups for the diverse AAPI population.

See all the articles in this CEBP Focus section, "Cancer in Asian and Pacific Islander Populations."

Cancer Epidemiol Biomarkers Prev; 23(11); 2218–28. ©2014 AACR.


Background: Hepatitis B virus (HBV) infection, the predominant cause of hepatocellular carcinoma (HCC) worldwide, disproportionately affects Asian Americans. Limited data exist on the variability and characteristics of infection that determine disease progression risk within U.S. Asian ethnic subgroups.

Methods: Retrospective analyses were conducted on a large, community-based HBV screening and treatment program in New York City (NYC). From 2004 to 2008, the program enrolled 7,272 Asian-born individuals. Determinants of HBV seroprevalence were calculated and risk factors for HCC progression were compared across Asian subgroups.

Results: Among newly tested individuals, 13% were HBV positive. Seroprevalence varied significantly with age, gender, education, birthplace, and family history of infection. Chinese-born individuals, particularly from the Fujian province, had the highest seroprevalence (23.2% and 33.1%, respectively). Clinical and virologic characteristics placed HBV-infected individuals at significant risk for HCC. Significant differences in HCC risk existed among Asian subgroups in bivariate analysis, including age, gender, HBV viral load, and HBeAg status. Differences in HBV genotype and family history of HCC may further HCC risk among subgroups.

Conclusions: Asian immigrants in NYC have a high prevalence of HBV infection and are at significant risk of disease progression and HCC. Although heterogeneity in HBV seroprevalence was found by Asian subgroups, HCC risk among infected individuals was primarily explained by age and gender differences. Country and province of birth, age, and gender may further explain seroprevalence differences.

Impact: Findings provide estimates of HBV burden in Asian ethnic subgroups and identify high-risk groups to target for screening and treatment that can prevent HCC.

See all the articles in this CEBP Focus section, "Cancer in Asian and Pacific Islander Populations."

Cancer Epidemiol Biomarkers Prev; 23(11); 2229–39. ©2014 AACR.


Background: We hypothesize that the differences in lung cancer risk in Native Hawaiians, whites, and Japanese Americans may, in part, be due to variation in the metabolism of 1,3-butadiene, one of the most abundant carcinogens in cigarette smoke.

Methods: We measured two biomarkers of 1,3-butadiene exposure, monohydroxybutyl mercapturic acid (MHBMA) and dihydroxybutyl mercapturic acid (DHBMA), in overnight urine samples among 584 Native Hawaiians, Japanese Americans, and white smokers in Hawaii. These values were normalized to creatinine levels. Ethnic-specific geometric means were compared adjusting for age at urine collection, sex, body mass index, and nicotine equivalents (a marker of total nicotine uptake).

Results: We found that mean urinary MHBMA differed by race/ethnicity (P = 0.0002). The values were highest in whites and lowest in Japanese Americans. This difference was only observed in individuals with the GSTT1-null genotype (P = 0.0001). No difference across race/ethnicity was found among those with at least one copy of the GSTT1 gene (P ≥ 0.72). Mean urinary DHBMA did not differ across racial/ethnic groups.

Conclusions: The difference in urinary MHBMA excretion levels from cigarette smoking across three ethnic groups is, in part, explained by the GSTT1 genotype. Mean urinary MHBMA levels are higher in whites among GSTT1-null smokers.

Impact: The overall higher excretion levels of MHBMA in whites and lower levels of MHBMA in Japanese Americans are consistent with the higher lung cancer risk in the former. However, the excretion levels of MHBMA in Native Hawaiians are not consistent with their disease risk and thus unlikely to explain their high risk of lung cancer.

See all the articles in this CEBP Focus section, "Cancer in Asian and Pacific Islander Populations."

Cancer Epidemiol Biomarkers Prev; 23(11); 2240–9. ©2014 AACR.


Background: Lung cancer is one of the leading cancer sites diagnosed among Asian Americans, Pacific Islanders, and Native Hawaiians (AANHPI). To better understand the patterns of lung cancer incidence among AANHPIs, we examined the incidence trends of five histologic cell types of lung cancer across ten AANHPI populations in comparison with non-Hispanic Whites.

Methods: Lung cancer incidence data from 1990 through 2010 were obtained from 13 U.S. population-based cancer registries. Age-adjusted histologic cell-type–specific incidence rates and 95% confidence intervals were calculated. Joinpoint regression models and annual percentage change (APC) statistics were used to characterize the magnitude and direction of trends.

Results: From 1990 through 2010, incidence rates of adenocarcinoma increased significantly for Filipino and Korean women with a 2.6% and 3.0% annual percentage increase, respectively. More recently, a significant rise in the incidence of adenocarcinoma was observed for Chinese men (1996–2010; APC = 1.3%). Squamous cell carcinoma (SCC) increased 2.4% per year among Japanese women. For SCC, small cell lung carcinoma, large cell and other specified carcinoma, and unspecified types, stable or decreasing trends were observed in most AANHPI groups and non-Hispanic Whites.

Conclusions: AANHPIs demonstrate a range in the burden of lung cancer across histologies and specific populations.

Impact: These findings illustrate the importance of disaggregating AANHPIs into their specific populations. The rise in incidence of adenocarcinoma and SCC among certain AANHPIs demonstrates the need for research into non-tobacco associated risk factors for these populations and targeted efforts for tobacco prevention.

See all the articles in this CEBP Focus section, "Cancer in Asian and Pacific Islander Populations."

Cancer Epidemiol Biomarkers Prev; 23(11); 2250–65. ©2014 AACR.


The goal of health equity requires the collection and reporting of disaggregated data in underrepresented populations such as Asian American (AA) and Native Hawaiian and Other Pacific Islander (NHOPI) communities. A recent Department of Health and Human Services report outlines the necessity for disaggregated data, which would offer communities, providers, and planners better tools to address health problems. In a recent collaboration, the National Cancer Institute (NCI) and several registries published a series of articles tracking cancer incidence data on AA and NHOPI communities using data from the NCI's Surveillance, Epidemiology, and End Results (SEER) program. The findings indicate a need for concentrated focus and planning for the next stages of cancer prevention and control for AA and NHOPI subpopulations. In this article, we provide (i) the context for the perpetuation of the model minority myth as well as historical and sociocultural factors that have shaped health and disease for AA and NHOPI subgroups; (ii) potential strategies for research and public health policy for AA and NHOPI groups using subpopulation-based approaches while addressing challenges and limitations; and (iii) a portfolio analysis of currently funded projects within the NCI/DCCPS to identify gaps and areas of potential research.

See all the articles in this CEBP Focus section, "Cancer in Asian and Pacific Islander Populations."

Cancer Epidemiol Biomarkers Prev; 23(11); 2266–72. ©2014 AACR.


Implementation science is a set of tools, principles, and methodologies that can be used to bring scientific evidence into action, improve health care quality and delivery, and improve public health. As the burden of cancer increases in low- and middle-income countries, it is important to plan cancer control programs that are both evidence based and delivered in ways that are feasible, cost-effective, contextually appropriate, and sustainable. This review presents a framework for using implementation science for cancer control planning and implementation and discusses potential areas of focus for research and programs in low- and middle-income countries interested in integrating research into practice and policy. Cancer Epidemiol Biomarkers Prev; 23(11); 2273–84. ©2014 AACR.


Human epididymis protein 4 (HE4) has received major attention as a potential tumor marker in epithelial ovarian cancer; however, evidence of significant overexpression of HE4 in several other human cancers is expanding. To assess the possible limitations or benefits of HE4 in a clinical setting, this review aims to systematically outline published results of HE4 tissue expression and serum HE4 levels in healthy individuals and patients with benign or malignant tumors. Our findings suggest scientific basis for a potential diagnostic ability of HE4 in gynecologic cancer and lung cancer, and further research is needed regarding other cancers. Yet, it is important to recognize that other malignancies can cause increased HE4 levels. Furthermore, attention should be paid to the influence of age and renal function on HE4 serum levels in future studies as well as in the clinic for proper interpretation of serum HE4 test results. Cancer Epidemiol Biomarkers Prev; 23(11); 2285–95. ©2014 AACR.


Background: Age–period–cohort (APC) analysis can inform registry-based studies of cancer incidence and mortality, but concerns about statistical identifiability and interpretability, as well as the learning curves of statistical software packages, have limited its uptake.

Methods: We implemented a panel of easy-to-interpret estimable APC functions and corresponding Wald tests in R code that can be accessed through a user-friendly Web tool.

Results: Input data for the Web tool consist of age-specific numbers of events and person-years over time, in the form of a rate matrix of paired columns. Output functions include model-based estimators of cross-sectional and longitudinal age-specific rates, period and cohort rate ratios that incorporate the overall annual percentage change (net drift), and estimators of the age-specific annual percentage change (local drifts). The Web tool includes built-in examples for teaching and demonstration. User data can be input from a Microsoft Excel worksheet or by uploading a comma-separated–value file. Model outputs can be saved in a variety of formats, including R and Excel.

Conclusions: APC methodology can now be carried out through a freely available user-friendly Web tool. The tool can be accessed at http://analysistools.nci.nih.gov/apc/.

Impact: The Web tool can help cancer surveillance researchers make important discoveries about emerging cancer trends and patterns. Cancer Epidemiol Biomarkers Prev; 23(11); 2296–302. ©2014 AACR.


Background: Prostate cancer is thought to be the most heritable cancer, although little is known about how this genetic contribution varies across age.

Methods: To address this question, we undertook the world's largest prospective study in the Nordic Twin Study of Cancer cohort, including 18,680 monozygotic (MZ) and 30,054 dizygotic (DZ) same-sex male twin pairs. We incorporated time-to-event analyses to estimate the risk concordance and heritability while accounting for censoring and competing risks of death, essential sources of biases that have not been accounted for in previous twin studies modeling cancer risk and liability.

Results: The cumulative risk of prostate cancer was similar to that of the background population. The cumulative risk for twins whose co-twin was diagnosed with prostate cancer was greater for MZ than for DZ twins across all ages. Among concordantly affected pairs, the time between diagnoses was significantly shorter for MZ than DZ pairs (median, 3.8 versus 6.5 years, respectively). Genetic differences contributed substantially to variation in both the risk and the liability [heritability = 58% (95% confidence interval, 52%–63%)] of developing prostate cancer. The relative contribution of genetic factors was constant across age through late life with substantial genetic heterogeneity even when diagnosis and screening procedures vary.

Conclusions: Results from the population-based twin cohort indicate a greater genetic contribution to the risk of developing prostate cancer when addressing sources of bias. The role of genetic factors is consistently high across age.

Impact: Findings affect the search for genetic and epigenetic markers and frame prevention efforts. Cancer Epidemiol Biomarkers Prev; 23(11); 2303–10. ©2014 AACR.


Background: Receptor-defined breast cancer proportions vary across Africa. They have important implications for survival prospects and research priorities.

Methods: We studied estrogen receptor (ER), progesterone receptor (PR), and HER2 receptor statuses in two multiracial Southern African countries with routine diagnostic immunohistochemistry. A total of 12,361 women with histologically confirmed breast cancer diagnosed at age ≥20 years during (i) 2009–2011 from South Africa's national cancer registry (public sector) and (ii) 2011–2013 from Namibia's only cancer hospital were included. Crude, age, and age + laboratory–adjusted ORs of receptor status were analyzed using logistic regression, and age–incidence curves were analyzed using Poisson regression.

Results: A total of 10,047 (81%) women had known ER status. Ranking of subtypes was consistent across races: ER+/PR+HER2 was most common (race-specific percentage range, 54.6%–64.8%), followed by triple-negative (17.4%–21.9%), ER+/PR+HER2+ (9.6%–13.9%), and ERPRHER2+ (7.8%–10.9%). Percentages in black versus white women were 33.8% [95% confidence (CI), 32.5–35.0] versus 26.0% (24.0–27.9) ER; 20.9% (19.7–22.1) versus 17.5% (15.4–19.6) triple-negative; and 10.7% (9.8–11.6) versus 7.8% (6.3–9.3) ERPRHER2+. Indian/Asian and mixed-ancestry women had intermediate values. Age–incidence curves had similar shapes across races: rates increased by 12.7% per year (12.2–13.1) across ER subtypes under the age of 50 years, and thereafter slowed for ER+ (1.95%) and plateaued for ER disease (–0.1%).

Conclusions: ER+ breast cancer dominates in all Southern African races, but black women have a modest excess of aggressive subtypes.

Impact: On the basis of the predominant receptor-defined breast tumors in Southern Africa, improving survival for the growing breast cancer burden should be achievable through earlier diagnosis and appropriate treatment. Cancer Epidemiol Biomarkers Prev; 23(11); 2311–21. ©2014 AACR.


Background: There is uncertainty about the benefits of using genome-wide sequencing to implement personalized preventive strategies at the population level, with some projections suggesting little benefit. We used data for all currently known breast cancer susceptibility variants to assess the benefits and harms of targeting preventive efforts to a population subgroup at highest genomic risk of breast cancer.

Methods: We used the allele frequencies and effect sizes of 86 known breast cancer variants to estimate the population distribution of breast cancer risks and evaluate the strategy of targeting preventive efforts to those at highest risk. We compared the efficacy of this strategy with that of a "best-case" strategy based on a risk distribution estimated from breast cancer concordance in monozygous twins, and with strategies based on previously estimated risk distributions.

Results: Targeting those in the top 25% of the risk distribution would include approximately half of all future breast cancer cases, compared with 70% captured by the best-case strategy and 35% based on previously known variants. In addition, current evidence suggests that reducing exposure to modifiable nongenetic risk factors will have greatest benefit for those at highest genetic risk.

Conclusions: These estimates suggest that personalized breast cancer preventive strategies based on genome sequencing will bring greater gains in disease prevention than previously projected. Moreover, these gains will increase with increased understanding of the genetic etiology of breast cancer.

Impact: These results support the feasibility of using genome-wide sequencing to target the women who would benefit from mammography screening. Cancer Epidemiol Biomarkers Prev; 23(11); 2322–7. ©2014 AACR.


Background: Although colorectal cancer is a disease characterized by sequential accumulation of mutations in epithelial cells, mechanisms leading to genomic vulnerability contributing to tumor initiation remain undefined. GUCY2C has emerged as an intestine-specific tumor suppressor controlling epithelial homeostasis through circuits canonically disrupted in cancer. Surprisingly, the GUCY2C tumor suppressor is universally overexpressed by human colorectal cancer cells. This apparent paradox likely reflects silencing of GUCY2C through loss of its paracrine hormone guanylin. Here, we quantified expression of guanylin mRNA and protein in tumors and normal epithelia from patients with colorectal cancer.

Methods: Guanylin mRNA was quantified in tumors and normal adjacent epithelia from 281 patients by the reverse transcriptase-polymerase chain reaction. Separately, the guanylin protein was quantified by immunohistochemistry in 54 colorectal tumors and 30 specimens of normal intestinal epithelium.

Results: Guanylin mRNA in colorectum varied more than a 100-fold across the population. Guanylin mRNA was reduced 100- to 1,000-fold in >85% of tumors compared with matched normal adjacent mucosa (P < 0.001). Loss of guanylin mRNA was greatest in tumors from patients <50 years old (P < 0.005) and with the highest expression in normal adjacent mucosa (Spearman correlation coefficient = 0.61; P < 0.001). In a separate validation cohort, guanylin protein was detected in all 30 normal colorectal mucosa specimens, but in none of 54 colorectal tumors.

Conclusions: Colorectal cancer may initiate as a disease of paracrine hormone insufficiency through loss of guanylin expression, silencing the GUCY2C tumor suppressor and disrupting homeostatic mechanisms regulating colorectal epithelia cells.

Impact: Intestinal tumorigenesis may be prevented by oral GUCY2C hormone replacement therapy. Cancer Epidemiol Biomarkers Prev; 23(11); 2328–37. ©2014 AACR.


Background: Mammographic density (MD), the area of non–fatty-appearing tissue divided by total breast area, is a strong breast cancer risk factor. Most MD analyses have used visual categorizations or computer-assisted quantification, which ignore breast thickness. We explored MD volume and area, using a volumetric approach previously validated as predictive of breast cancer risk, in relation to risk factors among women undergoing breast biopsy.

Methods: Among 413 primarily white women, ages 40 to 65 years, undergoing diagnostic breast biopsies between 2007 and 2010 at an academic facility in Vermont, MD volume (cm3) was quantified in craniocaudal views of the breast contralateral to the biopsy target using a density phantom, whereas MD area (cm2) was measured on the same digital mammograms using thresholding software. Risk factor associations with continuous MD measurements were evaluated using linear regression.

Results: Percent MD volume and area were correlated (r = 0.81) and strongly and inversely associated with age, body mass index (BMI), and menopause. Both measures were inversely associated with smoking and positively associated with breast biopsy history. Absolute MD measures were correlated (r = 0.46) and inversely related to age and menopause. Whereas absolute dense area was inversely associated with BMI, absolute dense volume was positively associated.

Conclusions: Volume and area MD measures exhibit some overlap in risk factor associations, but divergence as well, particularly for BMI.

Impact: Findings suggest that volume and area density measures differ in subsets of women; notably, among obese women, absolute density was higher with volumetric methods, suggesting that breast cancer risk assessments may vary for these techniques. Cancer Epidemiol Biomarkers Prev; 23(11); 2338–48. ©2014 AACR.


Background: Evidence for an association between total cholesterol, low- and high-density lipoproteins (LDL and HDL, respectively), triglycerides, and prostate cancer is conflicting. Given that prostate cancer and dyslipidemia affect large proportions of Western society, understanding these associations has public health importance.

Methods: We conducted a retrospective cohort analysis of 843 radical prostatectomy (RP) patients who never used statins before surgery within the Shared Equal Access Regional Cancer Hospital (SEARCH) database. Multivariable Cox proportional hazards analysis was used to investigate the association between cholesterol, LDL, HDL, and triglycerides and biochemical recurrence risk. In secondary analysis, we explored these associations in patients with dyslipidemia, defined using National Cholesterol Education Program guidelines.

Results: Elevated serum triglycerides were associated with increased risk of prostate cancer recurrence [HRper 10 mg/dl, 1.03; 95% confidence interval (CI), 1.01–1.05] but associations between total cholesterol, LDL and HDL, and recurrence risk were null. However, among men with dyslipidemia, each 10 mg/dl increase in cholesterol and HDL was associated with 9% increased recurrence risk (HR, 1.09; 95% CI, 1.01–1.17) and 39% reduced recurrence risk (HR, 0.61; 95% CI, 0.41–0.91), respectively.

Conclusions: Elevated serum triglycerides were associated with increased risk of prostate cancer recurrence. Cholesterol, LDL, or HDL were not associated with recurrence risk among all men. However, among men with dyslipidemia, elevated cholesterol and HDL levels were associated with increased and decreased risk of recurrence, respectively.

Impact: These findings, coupled with evidence that statin use is associated with reduced recurrence risk, suggest that lipid levels should be explored as a modifiable risk factor for prostate cancer recurrence. Cancer Epidemiol Biomarkers Prev; 23(11); 2349–56. ©2014 AACR.


Background: Mitochondria play an important role in cellular energy metabolism, free radical production, and apoptosis, and thus may be involved in cancer development.

Methods: We evaluated mitochondrial DNA (mtDNA) copy number in peripheral leukocytes in relation to colorectal cancer risk in a case–control study of 444 colorectal cancer cases and 1,423 controls nested in the Shanghai Women's Health Study, a population-based, prospective cohort study. Relative mtDNA copy number was determined by a quantitative real-time PCR assay using peripheral leukocyte DNA samples collected at the time of study enrollment, before cancer diagnosis.

Results: We found that baseline mtDNA copy number was lower among women who subsequently developed colorectal cancer [geometric mean, 0.277; 95% confidence interval (CI), 0.269–0.285] than among women who remained cancer-free (geometric mean, 0.288; 95% CI, 0.284–0.293; P = 0.0153). Multivariate adjusted ORs were 1.26 (95% CI, 0.93–1.70) and 1.44 (95% CI, 1.06–1.94) for the middle and lower tertiles of mtDNA copy number, respectively, compared with the upper tertile (highest mtDNA copy number; Ptrend = 0.0204). The association varied little by the interval between blood collection and cancer diagnosis.

Conclusions: Our data suggest that mtDNA copy number measured in peripheral leukocytes may be a potential biomarker useful for colorectal cancer risk assessment.

Impact: If confirmed, mtDNA copy number measured in peripheral leukocytes may be a biomarker useful for colorectal cancer risk assessment. Cancer Epidemiol Biomarkers Prev; 23(11); 2357–65. ©2014 AACR.


Background: Previous surveys reported declining cervical cancer screening rates from 2000 to 2010, but trends by key demographic and age groups are less clear.

Methods: We examined 3-year Papanicolaou (Pap) test rates among 4.2 million women enrolled in a large national health plan during 2001 to 2010. We calculated and plotted adjusted 3-year rates stratified by age and key neighborhood-level socioeconomic characteristics including poverty level and race/ethnicity (white, black, Hispanic, and mixed ethnicity neighborhood). We fitted trends in 2001–2010 screening rates and socioeconomic disparities as annual percentage changes (APC) using joinpoint analysis.

Results: Women ages 21 to 29 years had estimated 3-year Pap testing rates of 81.3% to 81.4% over the decade. Estimated disparities by low–high poverty level were 3.1% and 2.0% in 2001–2003 and 2008–2010, respectively, a nonsignificant decline. Initial white–black disparities were 4.0% and declined significantly from 2005–2007 to 2008–2010 to 2.8% at an APC of –0.65% (P = 0.021). White–Hispanic disparities declined from 4.3% to 0.8% over the decade, a –0.50% APC (P = 0.024). Among women ages 30 to 64 years, estimated 3-year Pap testing rates trended down from 76.1% to 71.8% over the decade [–0.94% APC (P < 0.001) until 2005–2007]. This pattern was similar among women from most categories of poverty and race/ethnicity.

Conclusions: Among commercially insured women ages 21 to 29 years, 3-year Pap testing rates remained stable at 81% over the decade; disparities were small and improved for Hispanic women to a greater degree than for black women. Among women ages 30 to 64 years, 3-year Pap testing rates declined from 2001 to 2010.

Impact: Cervical cancer screening should be promoted to achieve Healthy People 2020 goals. Cancer Epidemiol Biomarkers Prev; 23(11); 2366–73. ©2014 AACR.


Background: The combined action of androgens and estrogens—specifically their balance—may play a role in prostate carcinogenesis, but existing evidence is sparse and inconsistent. We investigated associations between serum sex steroid hormones, including estrogen metabolites, and risk of aggressive prostate cancer.

Methods: In a case–control study nested within the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial cohort, we measured serum estrone, estradiol, and 13 estrogen metabolites, in the 2-, 4-, or 16-hydroxylation pathways, using an LC/MS-MS assay. Cases (n = 195) were non-Hispanic white men ages 55 to 70 years when diagnosed with aggressive prostate cancer (stage III or IV and/or Gleason ≥7). Controls (n = 195) were non-Hispanic white men without prostate cancer who were frequency matched to cases by age and year at blood draw, and time since baseline screen. Only men with serum testosterone and sex hormone-binding globulin measured previously were eligible. Logistic regression models were used to estimate ORs and 95% confidence intervals (95% CI).

Results: Risk of aggressive prostate cancer was strongly inversely associated with estradiol:testosterone ratio (OR4th quartile vs. 1st = 0.27; 95% CI, 0.12–0.59, Ptrend = 0.003) and positively associated with 2:16α-hydroxyestrone ratio (OR4th quartile vs. 1st = 2.44; 95% CI, 1.34–4.45, Ptrend = 0.001). Individual estrogen metabolites were unrelated to risk.

Conclusions: Our findings suggest that sex steroid hormones, specifically the estrogen-androgen balance, may be important in the development of aggressive prostate cancer.

Impact: Improved understanding of the hormonal etiology of prostate cancer is critical for prevention and therapeutic interventions. Cancer Epidemiol Biomarkers Prev; 23(11); 2374–82. ©2014 AACR.


Background: Colorectal cancer, the third most common cancer in the United States, has a natural history that usually encompasses several decades. Dietary components have been implicated in the etiology of colorectal cancer, perhaps through their effect on inflammation.

Methods: We examined the ability of the dietary inflammatory index (DII) to predict colorectal cancer in the Iowa Women's Health Study. The DII was computed based on dietary intake assessed by a 121-item food frequency questionnaire in this cohort of 34,703 women, ages 55 to 69 years, free of any self-reported prior malignancy at enrollment in 1986. Incident colorectal cancer cases were identified through linkage with the State Health Registry of Iowa (a Surveillance, Epidemiology, and End Results program member). Cox proportional hazards regression was used to estimate HRs. Through the end of 2010, 1,636 incident colorectal cancers were identified, including 1,329 colon and 325 rectal cancers.

Results: Multivariable analysis, adjusting for body mass index, smoking status, pack-years of smoking, hormone replacement therapy, education, diabetes, and total energy intake, revealed positive associations between higher DII and colorectal cancer risk [HR for DIIcontinuous: 1.07 per unit increase in DII (corresponding to 0.5 SD unit increase); 95% confidence interval (CI), 1.01–1.13; HR for DIIquintiles: Q5 vs. Q1 = 1.20; 95% CI, 1.01–1.43]. HRs for DII were similar for colon cancer and rectal cancer, though not statistically significant for rectal cancer.

Conclusions: These results indicate that a proinflammatory diet, as indicated by higher DII scores, was associated with higher risk of developing colorectal cancer.

Impact: Proinflammatory diets are associated with increased risk of colorectal cancer. Cancer Epidemiol Biomarkers Prev; 23(11); 2383–92. ©2014 AACR.


Background: Persons with Barrett's esophagus experience increased risk of esophageal adenocarcinoma. Prediagnostic inflammation markers predict several cancers, but their role in predicting esophageal adenocarcinoma is unknown.

Methods: We investigated whether biomarkers of inflammation [C-reactive protein (CRP), interleukin-6 (IL6), soluble tumor necrosis factor (sTNF) receptors I and II], and of oxidative stress (F2-isoprostanes) predicted progression to esophageal adenocarcinoma in a prospective cohort of 397 patients with Barrett's esophagus, 45 of whom developed esophageal adenocarcinoma. Biomarkers were measured in stored plasma samples from two time points during follow-up, the mean of which served as the primary predictor. Adjusted hazard ratios (HR) and 95% confidence intervals (CI) were estimated using Cox regression.

Results: CRP level above the median was associated with an 80% increased risk of esophageal adenocarcinoma. The HR and 95% CI adjusted for age, gender, and further adjusted for waist–hip ratio and smoking were 1.98 (1.05–3.73) and 1.77 (0.93–3.37), respectively, with Ptrend for continuous CRP = 0.04. Persons with IL6 levels above the median also had almost 2-fold increased risk [HR and 95% CI adjusted for age and gender, and further adjusted for waist–hip ratio and smoking were 1.95 (1.03–3.72) and 1.79 (0.93–3.43), respectively, but no evidence of a trend was observed]. Concentrations of TNF receptors and F2-isoprostanes were not associated with esophageal adenocarcinoma risk.

Conclusions: Further research is needed to evaluate the role of inflammation and associated markers in esophageal adenocarcinoma development in persons with Barrett's esophagus.

Impact: This prospective study suggests that inflammation markers, particularly CRP and IL6, may help identify persons at higher risk of progression to esophageal adenocarcinoma. Cancer Epidemiol Biomarkers Prev; 23(11); 2393–403. ©2014 AACR.


Background: Although elevated body mass index (BMI) has been associated with increased risk of aggressive prostate cancer, the importance of adipose tissue distribution is not well understood. We examined associations between overall and visceral obesity and aggressive prostate cancer risk. Moreover, given racial differences in adipose tissue distribution, we examined whether race modified these associations.

Methods: We conducted a cross-sectional analysis of 308 radiotherapy-treated patients with prostate cancer within the Durham VA from 2005 to 2011. Multivariable logistic regression examined the association between BMI categories and tertiles of waist circumference (WC), visceral fat area (VFA), and periprostatic adipose tissue area (PPAT) with high-grade prostate cancer risk (Gleason score ≥7 vs. ≤6). Models stratified by race examined whether these associations differed between black and nonblack men.

Results: Both elevated BMI (Ptrend = 0.054) and WC (Ptrend = 0.040) were associated with increased high-grade prostate cancer risk, with similar results between races, although the association with BMI was not statistically significant. In contrast, elevated VFA was associated with increased aggressive prostate cancer risk in black men (Ptrend = 0.002) but not nonblack men (Ptrend = 0.831), with a significant interaction between race and VFA (Pinteraction = 0.035). Though similar patterns were observed for PPAT, none was statistically significant.

Conclusions: Among men undergoing radiotherapy for prostate cancer, visceral obesity is associated with increased aggressive prostate cancer risk, particularly among black men. If confirmed in future studies, these results suggest that adipose tissue distribution differences may contribute to prostate cancer racial disparity.

Impact: These findings highlight the need to elucidate mechanisms contributing to racial differences in the association between visceral obesity and aggressive prostate cancer. Cancer Epidemiol Biomarkers Prev; 23(11); 2404–12. ©2014 AACR.


Background: We have previously reported that colonic pericryptal microvascular blood flow is augmented in the premalignant colonic epithelium, highlighting the increased metabolic demand of the proliferative epithelium as a marker of field carcinogenesis. However, its molecular basis is unexplored. In this study, we assessed the expression of a regulator of the "lipogenic switch," fatty acid synthase (FASN), in early colon carcinogenesis for its potential biomarker utility for concurrent neoplasia.

Methods: FASN expression (IHC) in the colonic epithelium from azoxymethane and polyposis in rat colon (Pirc) models of colorectal cancer was studied. FASN mRNA expression from endoscopically normal rectal mucosa was evaluated and correlated with colonoscopic findings (pathologic confirmation of neoplasia).

Results: FASN expression progressively increased from premalignant to malignant stage in the azoxymethane model (1.9- to 2.5-fold; P < 0.0001) and was also higher in the adenomas compared with adjacent uninvolved mucosa (1.8- to 3.4-fold; P < 0.001) in the Pirc model. Furthermore, FASN was significantly overexpressed in rectal biopsies from patients harboring adenomas compared with those with no adenomas. These effects were accentuated in male (~2-fold) and obese patients (1.4-fold compared with those with body mass index < 30). Overall, the performance of rectal FASN was excellent (AUROC of 0.81).

Conclusions: FASN is altered in the premalignant colonic mucosa and may serve as a marker for colonic neoplasia present elsewhere. The enhanced effects in men and obesity may have implications for identifying patient subgroups at risk for early-onset neoplasia.

Impact: These findings support the role of rectal FASN expression as a reliable biomarker of colonic neoplasia. Cancer Epidemiol Biomarkers Prev; 23(11); 2413–21. ©2014 AACR.


Background: The association between body size and head and neck cancers (HNCA) is unclear, partly because of the biases in case–control studies.

Methods: In the prospective NIH–AARP cohort study, 218,854 participants (132,288 men and 86,566 women), aged 50 to 71 years, were cancer free at baseline (1995 and 1996), and had valid anthropometric data. Cox proportional hazards regression was used to examine the associations between body size and HNCA, adjusted for current and past smoking habits, alcohol intake, education, race, and fruit and vegetable consumption, and reported as HR and 95% confidence intervals (CI).

Results: Until December 31, 2006, 779 incident HNCAs occurred: 342 in the oral cavity, 120 in the oro- and hypopharynx, 265 in the larynx, 12 in the nasopharynx, and 40 at overlapping sites. There was an inverse association between HNCA and body mass index, which was almost exclusively among current smokers (HR = 0.76 per each 5 U increase; 95% CI, 0.63–0.93), and diminished as initial years of follow-up were excluded. We observed a direct association with waist-to-hip ratio (HR = 1.16 per 0.1 U increase; 95% CI, 1.03–1.31), particularly for cancers of the oral cavity (HR, 1.40; 95% CI, 1.17–1.67). Height was also directly associated with total HNCAs (P = 0.02), and oro- and hypopharyngeal cancers (P < 0.01).

Conclusions: The risk of HNCAs was associated inversely with leanness among current smokers, and directly with abdominal obesity and height.

Impact: Our study provides evidence that the association between leanness and risk of HNCAs may be due to effect modification by smoking. Cancer Epidemiol Biomarkers Prev; 23(11); 2422–9. ©2014 AACR.


Background: Gastric cancer represents a major health burden worldwide and is often diagnosed at an advanced stage. Biomarkers for screening and prevention of gastric cancer are missing. Changes in peripheral blood mitochondrial DNA (mtDNA) have emerged as a potential preventive/diagnosis biomarker for cancer risk. We aimed to determine whether peripheral leukocytes mtDNA levels are associated with stages of the gastric carcinogenesis cascade.

Methods: We measured mtDNA by quantitative real-time PCR assay in peripheral leukocytes of 28 patients with non-atrophic gastritis (NAG), 74 patients with gastric cancer, and 48 matched asymptomatic controls. In parallel, the serologic level of IL8 was determined.

Results: Mean mtDNA level was higher in patients with gastric cancer (P = 0.0095) than in controls, with values >8.46 significantly associated with gastric cancer (OR, 3.93). Three ranges of mtDNA values were identified: interval I, <2.0; interval II, 2.0–20; and interval III, >20. Interval I included mainly NAG cases, and few gastric cancer samples and interval III corresponded almost exclusively to patients with gastric cancer. All controls fell in interval II, together with some NAG and gastric cancer cases. IL8 levels were significantly higher in patients with gastric cancer (P < 0.05), with levels >50 pg/mL observed exclusively in patients with gastric cancer, allowing to distinguish them within interval II. We validated mtDNA results in a second cohort of patients, confirming that mtDNA was significantly higher in gastric cancer than in patients with preneoplasia.

Conclusions: Circulating levels of mtDNA and IL8 constitute a potential biomarker for the early detection of gastric cancer.

Impact: Our findings lead us to propose a new noninvasive method to detect patients with gastric cancer risk. Cancer Epidemiol Biomarkers Prev; 23(11); 2430–8. ©2014 AACR.


Background: Shorter telomere length (TL) has been reported to be associated with increased risk of early death in elder individuals. Telomere shortening has been also related to chromosomal instability, which may possibly contribute to the development of several types of digestive or urogenital system cancers and smoking-related tumors. Therefore, we investigated the impact of TL on bladder cancer survival.

Methods: TL was measured in leukocyte DNA from whole peripheral blood using quantitative real-time PCR in 463 patients with bladder cancer from a total 726 cases who were followed for up to 18 years.

Results: Patients with muscle-invasive tumor/any grade had shorter telomere than patients with non–muscle-invasive tumor/high-grade and with non–muscle-invasive tumor/non–high-grade (TL reference 0.7 ± 0.2; vs. respectively, 0.8 ± 0.2, P = 3.4 x 10–2 and 0.8 ± 0.2, P = 3.6 x 10–2). Moreover, patients in the lowest quartiles of TL were associated with decreased survival after diagnosis (log-rank test, P = 3.9 x 10–4). A Cox regression adjusted by age, cancer aggressiveness, Bacillus Calmette-Guérin, radical cystectomy, radiotherapy, and chemotherapy showed an independent effect of TL on bladder cancer survival (HR, 3.9; 95% confidence interval, 1.7–9.1; P = 1.2 x 10–3).

Conclusions: Our results suggest that leukocyte TL is only partly related to tumor aggressiveness and that shorter telomeres act as independent prognostic predictor of survival in patients with bladder cancer. TL information may allow to better select therapeutic approaches in patients with the same stage and grade.

Impact: Blood leukocyte TL levels could provide an additional noninvasive prognostic marker to better predict survival and personalize therapies in patients with bladder cancer. Cancer Epidemiol Biomarkers Prev; 23(11); 2439–46. ©2014 AACR.


Background: Several studies have examined leukocyte telomere length (LTL) as a possible predictor for cancer at various organ sites. The hypothesis originally motivating many of these studies was that shorter telomeres would be associated with an increase in cancer risk; the results of epidemiologic studies have been inconsistent, however, and suggested positive, negative, or null associations. Two studies have addressed the association of LTL in relation to pancreatic cancer risk and the results are contrasting.

Methods: We measured LTL in a prospective study of 331 pancreatic cancer cases and 331 controls in the context of the European Prospective Investigation into Cancer and Nutrition (EPIC).

Results: We observed that the mean LTL was higher in cases (0.59 ± 0.20) than in controls (0.57 ± 0.17), although this difference was not statistically significant (P = 0.07), and a basic logistic regression model showed no association of LTL with pancreas cancer risk. When adjusting for levels of HbA1c and C-peptide, however, there was a weakly positive association between longer LTL and pancreatic cancer risk [OR, 1.13; 95% confidence interval (CI), 1.01–1.27]. Additional analyses by cubic spline regression suggested a possible nonlinear relationship between LTL and pancreatic cancer risk (P = 0.022), with a statistically nonsignificant increase in risk at very low LTL, as well as a significant increase at high LTL.

Conclusion: Taken together, the results from our study do not support LTL as a uniform and strong predictor of pancreatic cancer.

Impact: The results of this article can provide insights into telomere dynamics and highlight the complex relationship between LTL and pancreatic cancer risk. Cancer Epidemiol Biomarkers Prev; 23(11); 2447–54. ©2014 AACR.


Background: We assessed human papillomavirus (HPV) seroconversion following anal and penile HPV infection in HIV-negative and HIV-infected men who have sex with men (MSM).

Methods: MSM aged ≥18 years were recruited in Amsterdam, the Netherlands (2010–2011), and followed up semiannually. Antibodies against 7 high-risk HPV types in baseline and 12-month serum samples were tested using a multiplex immunoassay. Baseline, 6-, and 12-month anal and penile samples were tested for HPV DNA using the SPF10-PCR DEIA/LiPA25 system. Statistical analyses were performed using logistic regression with generalized estimating equations.

Results: Of 644 MSM included in the analysis, 245 (38%) were HIV-infected. Median age was 38 years for HIV-negative and 47 years for HIV-infected MSM (P < 0.001). Seroconversion against ≥1 of the 7 HPV types was observed in 74 of 396 (19%) HIV-negative and 52 of 223 (23%) HIV-infected MSM at risk (P = 0.2). Incident [adjusted OR (aOR) 2.0; 95% confidence interval (CI), 1.1–3.4] and persistent (aOR 3.7; 95% CI, 1.5–9.5) anal HPV infections were independently associated with type-specific seroconversion in HIV-negative MSM. In HIV-infected MSM, there was a nonsignificant positive association between penile HPV infection at any time point and seroconversion (aOR 1.7; 95% CI, 0.9–3.2).

Conclusions: Incident or persistent anal HPV infection was an independent determinant of seroconversion in HIV-negative MSM.

Impact: Our data support that seroresponse may vary per anatomic site and that persistent HPV infections are more likely to elicit a detectable humoral immune response. Cancer Epidemiol Biomarkers Prev; 23(11); 2455–61. ©2014 AACR.


Background: There is an urgent need to improve lung cancer outcome by identifying and validating markers of risk. We previously reported that the cytokinesis-blocked micronucleus assay (CBMN) is a strong predictor of lung cancer risk. Here, we validate our findings in an independent external lung cancer population and test discriminatory power improvement of the Spitz risk prediction model upon extension with this biomarker.

Methods: A total of 1,506 participants were stratified into a test set of 995 (527 cases/468 controls) from MD Anderson Cancer Center (Houston, TX) and a validation set of 511 (239 cases/272 controls) from Massachusetts General Hospital (Boston, MA). An epidemiologic questionnaire was administered and genetic instability was assessed using the CBMN assay.

Results: Excellent concordance was observed between the two populations in levels and distribution of CBMN endpoints [binucleated-micronuclei (BN-MN), binucleated-nucleoplasmic bridges (BN-NPB)] with significantly higher mean BN-MN and BN-NPB values among cases (P < 0.0001). Extension of the Spitz model led to an overall improvement in the AUC (95% confidence intervals) from 0.61 (55.5–65.7) with epidemiologic variables to 0.92 (89.4–94.2) with addition of the BN-MN endpoint. The most dramatic improvement was observed with the never-smokers extended model followed by the former and current smokers.

Conclusions: The CBMN assay is a sensitive and specific predictor of lung cancer risk, and extension of the Spitz risk prediction model led to an AUC that may prove useful in population screening programs to identify the "true" high-risk individuals.

Impact: Identifying high-risk subgroups that would benefit from screening surveillance has immense public health significance. Cancer Epidemiol Biomarkers Prev; 23(11); 2462–70. ©2014 AACR.


Background: miRNAs have been implicated in the regulation of key metabolic, inflammatory, and malignant pathways; hence, they might be considered both predictors and players of cancer development.

Methods: Using a case–control study design nested in the ORDET prospective cohort study, we addressed the possibility that specific mRNAs can serve as early predictors of breast cancer incidence in postmenopausal women. We compared leukocyte miRNA profiles of 133 incident postmenopausal breast cancer cases and profiles of 133 women who remained healthy over a follow-up period of 20 years.

Results: The analysis identified 20 differentially expressed miRNAs, 15 of which were downregulated. Of the 20 miRNAs, miR145-5p and miR145-3p, each derived from another arm of the respective pre-miRNA, were consistently and significantly downregulated in all the databases that we surveyed. For example, analysis of more than 1,500 patients (the UK Metabric cohort) indicated that high abundance of miR145-3p and miR145-5p was associated with longer, and for miR145-3p also statistically significant, survival. The experimental data attributed different roles to the identified miRNAs: Although the 5p isoform was associated with invasion and metastasis, the other isoform seems related to cell proliferation.

Conclusions: These observations and the prospective design of our study lend support to the hypothesis that downregulation of specific miRNAs constitutes an early event in cancer development. This finding might be used for breast cancer prevention.

Impact: The identification of the miRNAs as long-term biomarkers of breast cancer may have an impact on breast cancer prevention and early detection. Cancer Epidemiol Biomarkers Prev; 23(11); 2471–81. ©2014 AACR.


Background: We aimed to quantify previously observed relatively high cancer risks in BRCA2 mutation carriers (BRCA2 carriers) older than 60 in the Northern Netherlands, and to analyze whether these could be explained by mutation spectrum or population background risk.

Methods: This consecutive cohort study included all known pathogenic BRCA1/2 carriers in the Northern Netherlands (N = 1,050). Carrier and general reference populations were: BRCA1/2 carriers in the rest of the Netherlands (N = 2,013) and the general population in both regions. Regional differences were assessed with HRs and ORs. HRs were adjusted for birth year and mutation spectrum.

Results: All BRCA1 carriers and BRCA2 carriers younger than 60 had a significantly lower breast cancer risk in the Northern Netherlands; HRs were 0.66 and 0.64, respectively. Above age 60, the breast cancer risk in BRCA2 carriers in the Northern Netherlands was higher than in the rest of the Netherlands [HR, 3.99; 95% confidence interval (CI), 1.11–14.35]. Adjustment for mutational spectrum changed the HRs for BRCA1, BRCA2 <60, and BRCA2 ≥60 years by –3%, +32%, and +11% to 0.75, 0.50, and 2.61, respectively. There was no difference in background breast cancer incidence between the two regions (OR, 1.03; 95% CI, 0.97–1.09).

Conclusions: Differences in mutation spectrum only partly explain the regional differences in breast cancer risk in BRCA2 carriers, and for an even smaller part in BRCA1 carriers.

Impact: The increased risk in BRCA2 carriers older than 60 may warrant extension of intensive breast screening beyond age 60. Cancer Epidemiol Biomarkers Prev; 23(11); 2482–91. ©2014 AACR.


Background: Autoantibodies are of growing interest in cancer research as potential biomarkers; yet, the determinants of autoimmunity are not well understood. Antinuclear antibodies (ANA) are common in the general population and are more prevalent in women and older adults. Here, we examined the relationship of ANA with reproductive and hormonal factors in a representative sample of U.S. women.

Methods: We analyzed data on reproductive history and exogenous hormone use in relation to serum ANA in 2,037 females ages 12 years and older from the National Health and Nutrition Examination Survey (NHANES; 1999–2004). Estimated ANA prevalences were adjusted for sampling weights. Prevalence ORs (POR) and 95% confidence intervals (CI) were adjusted for age, race, and poverty–income ratio, and models were stratified by menopause status.

Results: In premenopausal women ages 20 years and older, ANA prevalence was associated with parity (P < 0.001; parous vs. nulliparous POR = 2.0; 95% CI, 1.2–3.4), but in parous women, ANA did not vary by number of births, age at first birth, years since last birth, or breastfeeding. In postmenopausal women, ANA prevalence was associated with an older age at menarche (P = 0.019; age 16–20 vs. 10–12 years POR = 3.0; 95% CI, 1.6–5.9), but not with parity. Oral contraceptives and estrogen therapy were not associated with a higher ANA prevalence.

Conclusions: Childbearing (having had one or more births) may explain age-associated elevations in ANA prevalence seen in premenopausal women.

Impact: These findings highlight the importance of considering reproductive history in studies of autoimmunity and cancer in women. Cancer Epidemiol Biomarkers Prev; 23(11); 2492–502. ©2014 AACR.


Background: MicroRNAs (miRNA) play important roles in the regulation of eukaryotic gene expression and are involved in human carcinogenesis. Single-nucleotide polymorphisms (SNP) in miRNA sequence may alter miRNA functions in gene regulation, which, in turn, may affect cancer risk and disease progression.

Methods: We conducted an analysis of associations of 142 miRNA SNPs with non–small cell lung cancer (NSCLC) survival using data from a genome-wide association study (GWAS) in a Caucasian population from the Massachusetts General Hospital (Boston, MA) including 452 early-stage and 526 late-stage NSCLC cases. Replication analyses were further performed in two external populations, one Caucasian cohort from The University of Texas MD Anderson Cancer Center (Houston, TX) and one Han Chinese cohort from Nanjing, China.

Results: We identified seven significant SNPs in the discovery set. Results from the independent Caucasian cohort demonstrated that the C allele of rs2042253 (hsa-miRNA-5197) was significantly associated with decreased risk for death among the patients with late-stage NSCLC (discovery set: HR, 0.80; P = 0.007; validation set: HR, 0.86; P = 0.035; combined analysis: HR, 0.87; P = 0.007).

Conclusions: These findings provide evidence that some miRNA SNPs are associated with NSCLC survival and can be used as predictive biomarkers.

Impact: This study provided an estimate of outcome probability for survival experience of patients with NSCLC, which demonstrates that genetic factors, as well as classic nongenetic factors, may be used to predict individual outcome. Cancer Epidemiol Biomarkers Prev; 23(11); 2503–11. ©2014 AACR.


Background: Although cancer research has advanced at a rapid pace, a gap remains between what is known about how to improve cancer prevention and control (CPC) and what is implemented as best practices within health care systems and communities. The Cancer Prevention and Control Research Network (CPCRN), with more than 10 years of dissemination and implementation research experience, aims to accelerate the uptake and use of evidence-based CPC interventions.

Methods: The collective work of the CPCRN has facilitated the analysis and categorization of research and implementation efforts according to the Interactive Systems Framework for Dissemination and Implementation (ISF), providing a useful heuristic for bridging the gap between prevention research and practice. The ISF authors have called for examples of its application as input to help refine the model.

Results: We provide examples of how the collaborative activities supported by the CPCRN, using community-engaged processes, accelerated the synthesis and translation of evidence, built both general and innovation-specific capacity, and worked with delivery systems to advance cancer control research and practice.

Conclusions: The work of the CPCRN has provided real-world examples of the application of the ISF and demonstrated that synthesizing and translating evidence can increase the potential that evidence-based CPC programs will be used and that capacity building for both the support system and the delivery system is crucial for the successful implementation and maintenance of evidence-based cancer control.

Impact: Adoption and implementation of CPC can be enhanced by better understanding ISF systems and intervening to improve them. Cancer Epidemiol Biomarkers Prev; 23(11); 2512–21. ©2014 AACR.


Background: Physical activity has been associated with reduced risk of breast cancer. Evidence on the association in African Americans is limited.

Methods: With prospective data from the Black Women's Health Study, we assessed vigorous exercise and walking in relation to incidence of invasive breast cancer overall (n = 1,364), estrogen receptor–positive (ER+, n = 688) cancer, and estrogen receptor–negative (ER, n = 405) cancer, based on 307,672 person-years of follow-up of 44,708 African-American women ages 30 years or older at enrollment. Cox proportional hazards models estimated incidence rate ratios (IRR) and 95% confidence intervals (CI).

Results: Vigorous exercise at baseline was inversely associated with overall breast cancer incidence (Ptrend = 0.05): the IRR for ≥7 h/wk relative to <1 h/wk was 0.74 (95% CI, 0.57–0.96). The association did not differ by ER status. Brisk walking for ≥7 h/wk was associated with a reduction similar to that for vigorous exercise. Vigorous exercise at the age of 30 years, 21 years, or in high school was not associated with breast cancer incidence. Sitting for long periods at work or watching TV was not significantly associated with breast cancer incidence.

Conclusion: High levels of vigorous exercise or brisk walking may be associated with a reduction in incidence of breast cancer in African-American women.

Impact: These results provide informative data on a potential modifiable risk factor, exercise, for breast cancer in African-American women. Cancer Epidemiol Biomarkers Prev; 23(11); 2522–31. ©2014 AACR.


Background: Experimental and epidemiologic data suggest that higher circulating prolactin is associated with breast cancer risk; however, how various risk factors for breast cancer influence prolactin levels in healthy women is not clear.

Methods: We analyzed cross-sectional associations between several suggested reproductive and lifestyle risk factors for breast cancer and circulating prolactin among pre- and postmenopausal women, taking into account the use of current postmenopausal hormone therapy, among 2,560 controls from a breast cancer nested case–control study within the EPIC cohort.

Results: Adjusted geometric mean prolactin levels were significantly higher among premenopausal women, and among postmenopausal women using hormone therapy compared with nonusers (8.2, 7.0, and 6.3 ng/mL, respectively; Pcat = <0.0001). Furthermore, prolactin levels were significantly higher among users of combined estrogen–progestin hormone therapy compared with users of estrogen-alone hormone therapy (6.66 vs. 5.90 ng/mL; Pcat = 0.001). Prolactin levels were lower among parous women compared with nulliparous women (8.61 vs. 10.95 ng/mL; Pcat = 0.0002, premenopausal women); the magnitude of this difference depended on the number of full-term pregnancies (22.1% lower, ≥3 vs. 1 pregnancy, Ptrend = 0.01). Results for parity were similar but lower in magnitude among postmenopausal women. Prolactin did not vary by other studied factors, with the exception of lower levels among postmenopausal smokers compared with never smokers.

Conclusions: Our study shows that current hormone therapy use, especially the use of combined hormone therapy, is associated with higher circulating prolactin levels in postmenopausal women, and confirms prior findings of lower circulating prolactin in parous women.

Impact: Our study extends the knowledge linking various breast cancer risk factors with circulating prolactin. Cancer Epidemiol Biomarkers Prev; 23(11); 2532–42. ©2014 AACR.


Background: Quantifying the risk of colorectal cancer for individuals is likely to be useful for health service provision. Our aim was to develop and externally validate a prediction model to predict 5-year colorectal cancer risk.

Methods: We used proportional hazards regression to develop the model based on established personal and lifestyle colorectal cancer risk factors using data from 197,874 individuals from the 45 and Up Study, Australia. We subsequently validated the model using 24,233 participants from the Melbourne Collaborative Cohort Study (MCCS).

Results: A total of 1,103 and 224 cases of colorectal cancer were diagnosed in the development and validation sample, respectively. Our model, which includes age, sex, BMI, prevalent diabetes, ever having undergone colorectal cancer screening, smoking, and alcohol intake, exhibited a discriminatory accuracy of 0.73 [95% confidence interval (CI), 0.72–0.75] and 0.70 (95% CI, 0.66–0.73) using the development and validation sample, respectively. Calibration was good for both study samples. Stratified models according to colorectal cancer screening history, that additionally included family history, showed discriminatory accuracies of 0.75 (0.73–0.76) and 0.70 (0.67–0.72) for unscreened and screened individuals of the development sample, respectively. In the validation sample, discrimination was 0.68 (0.64–0.73) and 0.72 (0.67–0.76), respectively.

Conclusion: Our model exhibited adequate predictive performance that was maintained in the external population.

Impact: The model may be useful to design more powerful cancer prevention trials. In the group of unscreened individuals, the model may be useful as a preselection tool for population-based screening programs. Cancer Epidemiol Biomarkers Prev; 23(11); 2543–52. ©2014 AACR.


Background: DNA integrity analysis could represent an alternative approach to the early detection of colorectal cancer. Previously, fluorescence long DNA (FL-DNA) in stools was extracted using a manual approach and analyzed by capillary electrophoresis assay (CE FL-DNA). We aimed to improve diagnostic accuracy using a simpler and more standardized method [Real Time PCR FL-DNA (RT FL-DNA)] for the detection of early malignant lesions in a population undergoing colorectal cancer screening.

Methods: From 241 stool samples, DNA was extracted using manual and semiautomatic extraction systems and analyzed using FL-DNA tests by CE and RT assays. The RT FL-DNA approach showed slightly higher sensitivity and specificity compared with the CE FL-DNA method. Furthermore, we compared the RT FL-DNA approach with the iFOBT report.

Results: Nonparametric ranking statistics were used to analyze the relationship between the median values of RT FL-DNA and the clinicohistopathologic characteristics. The median values of both variables were significantly higher in patients with cancer than in patients with noncancerous lesions. According to the Fagan nomogram results, the iFOBT and FL-DNA methods provided more accurate diagnostic information and were able to identify subgroups at varying risks of cancer.

Conclusions: The combination of the semiautomatic extraction system and RT FL-DNA analysis improved the quality of DNA extracted from stool samples.

Impact: RT FL-DNA shows great potential for colorectal cancer diagnosis as it is a reliable and relatively easy analysis to perform on routinely processed stool samples in combination with iFOBT. Cancer Epidemiol Biomarkers Prev; 23(11); 2553–60. ©2014 AACR.


Background: TH1 cytokines, such as IFN and TNFα, and potentially innate cytokines, such as IL6, can potentiate the immune response to tumor. Cytokines, such as IL1β, IL8, and IL10, may suppress anticancer immunity. Thus, we prospectively evaluated the association between peripheral-cytokine concentrations and prostate cancer.

Methods: We conducted an age-race matched case–control study (268 pairs) of incident prostate cancer in CLUE-II. We measured plasma IFN, IL10, IL12p70, IL1β, IL6, IL8, and TNFα concentrations using an ultrasensitive multiplex kit. ORs and 95% confidence intervals (CI) were calculated using conditional logistic regression.

Results: The OR of prostate cancer decreased across quartiles of IFN (highest vs. lowest quartiles: OR, 0.49; 95% CI, 0.30–0.81; Ptrend = 0.006), TNFα (OR, 0.56; 95% CI, 0.33–0.96; Ptrend = 0.01), and IL6 (OR, 0.46; 95% CI, 0.26–0.79; Ptrend = 0.007). Higher TNFα (OR, 0.28; 95% CI, 0.09–0.85; Ptrend = 0.01) and IL6 (OR, 0.20; 95% CI, 0.06–0.67; Ptrend = 0.003) concentrations were associated with lower Gleason sum ≥7 disease risk. Other cytokines were not as clearly associated with risk.

Conclusions: Men with a prediagnostic circulating TH1 profile and higher IL6 may have a lower risk of prostate cancer, including aggressive disease. Whether this profile reflects (i) an intraprostatic immune environment in benign tissue that protects against prostate cancer, (ii) the immune milieu in response to a prostate adenocarcinoma that inhibits tumor growth and detectability, and/or (iii) a systemic immune profile that mediates the influence of modifiable factors on risk, warrants additional study.

Impact: Identifying specific inflammatory cytokines associated with prostate cancer may lead to improved prevention and treatment strategies. Cancer Epidemiol Biomarkers Prev; 23(11); 2561–7. ©2014 AACR.


Background: Multiple primary cancers account for approximately 16% of all incident cancers in the United States. Although genome-wide association studies (GWAS) have identified many common genetic variants associated with various cancer sites, no study has examined the association of these genetic variants with risk of multiple primary cancers (MPC).

Methods: As part of the National Human Genome Research Institute (NHGRI) Population Architecture using Genomics and Epidemiology (PAGE) study, we used data from the Multiethnic Cohort (MEC) and Women's Health Initiative (WHI). Incident MPC (IMPC) cases (n = 1,385) were defined as participants diagnosed with more than one incident cancer after cohort entry. Participants diagnosed with only one incident cancer after cohort entry with follow-up equal to or longer than IMPC cases served as controls (single-index cancer controls; n = 9,626). Fixed-effects meta-analyses of unconditional logistic regression analyses were used to evaluate the associations between 188 cancer risk variants and IMPC risk. To account for multiple comparisons, we used the false-positive report probability (FPRP) to determine statistical significance.

Results: A nicotine dependence–associated and lung cancer variant, CHRNA3 rs578776 [OR, 1.16; 95% confidence interval (CI), 1.05–1.26; P = 0.004], and two breast cancer variants, EMBP1 rs11249433 and TOX3 rs3803662 (OR, 1.16; 95% CI, 1.04–1.28; P = 0.005 and OR, 1.13; 95% CI, 1.03–1.23; P = 0.006), were significantly associated with risk of IMPC. The associations for rs578776 and rs11249433 remained (P < 0.05) after removing subjects who had lung or breast cancers, respectively (P ≤ 0.046). These associations did not show significant heterogeneity by smoking status (Pheterogeneity ≥ 0.53).

Conclusions: Our study has identified rs578776 and rs11249433 as risk variants for IMPC.

Impact: These findings may help to identify genetic regions associated with IMPC risk. Cancer Epidemiol Biomarkers Prev; 23(11); 2568–78. ©2014 AACR.


Background: Some studies suggest smoking may result in poorer clinical outcomes in head and neck cancer, but the evidence is heterogeneous and some of it is poor quality. In a large, population-based, study we investigated: (i) whether smoking at diagnosis is an independent prognostic factor for cancer-specific survival in head and neck cancer; and (ii) whether the association varies by site and treatment.

Methods: Head and neck cancers (ICD10 C01-C14, and C30–32) diagnosed from 1994 to 2009 were abstracted from the National Cancer Registry Ireland, and classified by smoking status at diagnosis. Follow-up was for 5 years or until December 31, 2010. Multivariate Cox proportional hazards models were used to compare cancer-specific death rates in current, ex-, and never smokers. Subgroup analyses by site and treatment were conducted.

Results: In total, 5,652 head and neck cancers were included. At diagnosis, 24% were never smokers, 20% ex-smokers, and 56% current smokers. Compared with never smokers, current smokers had a significantly raised death rate from cancer [multivariate HR, 1.36; 95% confidence interval (CI), 1.21–1.53]. The association was similar after restriction to squamous cell tumors. A significantly increased cancer-related death rate was seen for current smokers with oral cavity, pharyngeal, and laryngeal cancers. The association was stronger in surgically treated patients [HR, 1.49; 95% CI, 1.25–1.79; P(interaction) = 0.01]. Neither radiotherapy nor chemotherapy modified the effect of smoking.

Conclusions: Patients with head and neck cancer who smoke at diagnosis have a significantly increased cancer death rate.

Impact: Greater efforts are needed to encourage and support smoking cessation in those at risk of, and diagnosed with, head and neck cancer. Cancer Epidemiol Biomarkers Prev; 23(11); 2579–90. ©2014 AACR.


John Cunningham virus (JCV) is a common polyomavirus classified as a possible carcinogen by the International Agency for Research on Cancer. JCV may play a role in colorectal carcinogenesis, although we previously reported no association between JCV capsid antibodies and colorectal cancer. No studies have examined the role of seroreactivity to JCV T-antigen (T-Ag) oncoprotein in colorectal cancer. A case–control study nested within a community-based prospective cohort (CLUE II) was conducted. In 1989, 25,080 residents of Washington County, Maryland, were enrolled in CLUE II, completing baseline questionnaires and providing blood samples. At follow-up, 257 incident colorectal cancer cases were identified by linkage to population-based cancer registries through 2006 and matched to controls on age, sex, race, and date of blood draw. One hundred and twenty-three colorectal adenoma cases were identified through self-report during follow-up and matched to controls on age, sex, race, date of blood draw, and colorectal cancer screening. Baseline serum samples were tested for seroreactivity to JCV T-Ag. Associations between JCV T-Ag seroreactivity and colorectal cancer/adenomas were evaluated using conditional logistic regression models. Overall, seroreactivity to JCV T-Ag was not statistically significantly associated with the risk of either colorectal cancer [OR, 1.34; 95% confidence interval (CI), 0.89–2.01] or adenoma (OR, 1.30; 95% CI, 0.70–2.42), while a borderline association with colorectal cancer was observed among women (OR, 1.82; 95% CI, 1.00–3.31). Our past evaluation of JCV capsid seropositivity, combined with current findings, does not support a notable etiologic role for JCV infection in colorectal cancer. Cancer Epidemiol Biomarkers Prev; 23(11); 2591–6. ©2014 AACR.


Despite considerable research, the pathogenesis of prostate cancer remains poorly understood. Meanwhile, PSA testing has shifted prostate cancer case populations for study to include a greater proportion of asymptomatic and indolent disease. Thus, efforts to identify prostate cancer biomarkers—particularly for aggressive disease—are required to elucidate pathogenesis and aid screening efficacy. Current evidence suggests that decreased circulating concentrations of the testis-derived, TGFβ family peptide hormone—anti-Müllerian hormone (AMH)—may be associated with prostate cancer pathogenesis. To test this hypothesis, we measured AMH concentrations in prediagnostic (cohort baseline) sera using the Beckman Coulter AMH Gen II ELISA in 1,000 cases and 1,000 controls nested within the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial. Controls were frequency matched to cases on age at entry, enrollment year, and years of follow-up. Unconditional logistic regression models, adjusted for age at randomization, were used to estimate odds ratios (ORs) and 95% confidence intervals (95% CI). We found that prediagnostic serologic AMH concentrations were not significantly associated with total (ORQ4 vs. Q1 = 1.15; 95% CI, 0.89–1.48; Ptrend = 0.13), aggressive (ORQ4 vs. Q1 = 1.14; 95% CI, 0.80–1.63; Ptrend = 0.51), or nonaggressive (ORQ4 vs. Q1 = 1.22; 95% CI, 0.91–1.63; Ptrend = 0.07) prostate cancer risks. Different definitions of aggressive disease did not meaningfully alter these results. Despite in vitro studies linking AMH to prostate cancer, this first analysis of prediagnostic, circulating AMH concentrations in men provides no evidence for an association with prostate cancer risk. Cancer Epidemiol Biomarkers Prev; 23(11); 2597–602. ©2014 AACR.


Background: Telomeres are essential for the maintenance of chromosomal integrity. Telomere shortening leads to genomic instability, which is hypothesized to play a role in cancer development and prognosis. No studies to date have evaluated the prognostic significance of telomere length for ovarian cancer.

Methods: We examined whether relative telomere length in peripheral blood leukocytes was associated with survival following a diagnosis of ovarian cancer. We analyzed data from a large population-based study of incident ovarian cancer conducted in Ontario between 1995 and 2004. Telomere length was measured using the quantitative PCR–based relative telomere length assay and vital status was determined by computerized record linkage and by chart review (n = 1,042). Proportional hazard models were used to estimate ovarian cancer–specific survival HRs and 95% confidence intervals (CI) associated with quartiles of telomere length z score.

Results: We found no significant relationship between telomere length and ovarian cancer–specific mortality (P log-rank test = 0.55). Compared with women in the lowest quartile of telomere length z score, the HR for women in the highest three quartiles of telomere length z score combined was 0.88 (95% CI, 0.77–1.10). The corresponding estimates for serous and nonserous tumors were 0.68 (95% CI, 0.66–1.13) and 1.13 (95% CI, 0.71–1.79), respectively.

Conclusions: Our data provide preliminary evidence that telomere length likely does not predict outcome after a diagnosis of ovarian cancer.

Impact: This represents the first study to suggest no prognostic role of telomere length for ovarian cancer. Cancer Epidemiol Biomarkers Prev; 23(11); 2603–6. ©2014 AACR.







The International Agency for Research on Cancer estimates that over half of the new cancer cases and almost two-thirds of the cancer deaths in 2012 occurred in low and middle income countries. To discuss the challenges and opportunities to reducing the burden of cancer worldwide, the Molecular Epidemiology and the Environment and the International Issues in Cancer Special Interest Groups joined forces to hold a session during the 38th Annual Meeting of the American Society of Preventive Oncology (March 2014, Arlington, Virginia). The session highlighted three topics of particular interest to molecular cancer prevention researchers working internationally, specifically: 1) biomarkers in cancer research; 2) environmental exposures and cancer; and 3) molecular pathological epidemiology. A major factor for successful collaboration illuminated during the discussion was the need for strong, committed, and reliable international partners. A key element of establishing such relationships is to thoroughly involve individual international collaborators in the development of the research question; engaged international collaborators are particularly motivated to champion and shepherd the project through all necessary steps, including issues relating to institutional review boards, political sensitivity, laboratory-based assays, and tumor subtyping. Also essential is allotting time for the building, maintaining, and investing in such relationships so that successful international collaborations may take root and bloom. While there are many challenges inherent to international molecular cancer research, the opportunities for furthering the science and prevention of cancer worldwide are great, particularly at this time of increasing cancer incidence and prevalence in low and middle income countries. Cancer Epidemiol Biomarkers Prev; 23(11); 2613–7. ©2014 AACR.