Showing papers in "Cancer Epidemiology, Biomarkers & Prevention in 2012"

Pathology of Breast and Ovarian Cancers among BRCA1 and BRCA2 Mutation Carriers: Results from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA).

Abstract: BACKGROUND: Previously, small studies have found that BRCA1 and BRCA2 breast tumors differ in their pathology. Analysis of larger datasets of mutation carriers should allow further tumor characterization.METHODS: We used data from 4,325 BRCA1 and 2,568 BRCA2 mutation carriers to analyze the pathology of invasive breast, ovarian, and contralateral breast cancers.RESULTS: There was strong evidence that the proportion of estrogen receptor (ER)-negative breast tumors decreased with age at diagnosis among BRCA1 (P-trend = 1.2 × 10(-5)), but increased with age at diagnosis among BRCA2, carriers (P-trend = 6.8 × 10(-6)). The proportion of triple-negative tumors decreased with age at diagnosis in BRCA1 carriers but increased with age at diagnosis of BRCA2 carriers. In both BRCA1 and BRCA2 carriers, ER-negative tumors were of higher histologic grade than ER-positive tumors (grade 3 vs. grade 1; P = 1.2 × 10(-13) for BRCA1 and P = 0.001 for BRCA2). ER and progesterone receptor (PR) expression were independently associated with mutation carrier status [ER-positive odds ratio (OR) for BRCA2 = 9.4, 95% CI: 7.0-12.6 and PR-positive OR = 1.7, 95% CI: 1.3-2.3, under joint analysis]. Lobular tumors were more likely to be BRCA2-related (OR for BRCA2 = 3.3, 95% CI: 2.4-4.4; P = 4.4 × 10(-14)), and medullary tumors BRCA1-related (OR for BRCA2 = 0.25, 95% CI: 0.18-0.35; P = 2.3 × 10(-15)). ER-status of the first breast cancer was predictive of ER-status of asynchronous contralateral breast cancer (P = 0.0004 for BRCA1; P = 0.002 for BRCA2). There were no significant differences in ovarian cancer morphology between BRCA1 and BRCA2 carriers (serous: 67%; mucinous: 1%; endometrioid: 12%; clear-cell: 2%).Conclusions/Impact: Pathologic characteristics of BRCA1 and BRCA2 tumors may be useful for improving risk-prediction algorithms and informing clinical strategies for screening and prophylaxis. Cancer Epidemiol Biomarkers Prev; 1-14. ©2011 AACR.

Mental and Physical Health–Related Quality of Life among U.S. Cancer Survivors: Population Estimates from the 2010 National Health Interview Survey

Abstract: Background: Despite extensive data on health-related quality of life (HRQOL) among cancer survivors, we do not yet have an estimate of the percentage of survivors with poor mental and physical HRQOL compared with population norms. HRQOL population means for adult-onset cancer survivors of all ages and across the survivorship trajectory also have not been published. Methods: Survivors ( N = 1,822) and adults with no cancer history ( N = 24,804) were identified from the 2010 National Health Interview Survey. The PROMIS® Global Health Scale was used to assess HRQOL. Poor HRQOL was defined as 1 SD or more below the PROMIS® population norm. Results: Poor physical and mental HRQOL were reported by 24.5% and 10.1% of survivors, respectively, compared with 10.2% and 5.9% of adults without cancer (both P < 0.0001). This represents a population of approximately 3.3 million and 1.4 million U.S. survivors with poor physical and mental HRQOL. Adjusted mean mental and physical HRQOL scores were similar for breast, prostate, and melanoma survivors compared with adults without cancer. Survivors of cervical, colorectal, hematologic, short-survival, and other cancers had worse physical HRQOL; cervical and short-survival cancer survivors reported worse mental HRQOL. Conclusion: These data elucidate the burden of cancer diagnosis and treatment among U.S. survivors and can be used to monitor the impact of national efforts to improve survivorship care and outcomes. Impact: We present novel data on the number of U.S. survivors with poor HRQOL. Interventions for high-risk groups that can be easily implemented are needed to improve survivor health at a population level. Cancer Epidemiol Biomarkers Prev; 21(11); 2108–17. ©2012 AACR .

The TMPRSS2:ERG Rearrangement, ERG Expression, and Prostate Cancer Outcomes: a Cohort Study and Meta-analysis

Abstract: Background: Whether the genomic rearrangement TMPRSS2:ERG has prognostic value in prostate cancer is unclear. Methods: Among men with prostate cancer in the prospective Physicians' Health and Health Professionals Follow-Up Studies, we identified rearrangement status by immunohistochemical assessment of ERG protein expression. We used Cox models to examine associations of ERG overexpression with biochemical recurrence and lethal disease (distant metastases or cancer-specific mortality). In a meta-analysis including 47 additional studies, we used random effects models to estimate associations between rearrangement status and outcomes. Results: The cohort consisted of 1,052 men treated with radical prostatectomy between 1982 and 2005. During a median follow-up of 12.5 years, 245 men experienced recurrence, and 95 men developed lethal disease. We found no significant association between ERG overexpression and biochemical recurrence (HR: 0.93; 95% CI: 0.72-1.19) or lethal disease (HR: 0.81; 95% CI: 0.54-1.21). The meta-analysis of prostatectomy series included 4,946 men followed for biochemical recurrence (1,602 events), and 1,921 men followed for lethal disease (141 events). TMPRSS2:ERG was associated with stage at diagnosis (RR≥T3 vs. T2: 1.22; 95% CI: 1.15-1.29) but not with biochemical recurrence (RR: 1.00; 95% CI: 0.86-1.17) or lethal disease (RR: 0.93; 95% CI: 0.43-1.99). Conclusions: These results suggest that TMPRSS2:ERG , or ERG overexpression, is associated with tumor stage but does not strongly predict recurrence or mortality among men treated with radical prostatectomy. Impact: This is the largest prospective cohort study to examine associations of ERG overexpression and lethal prostate cancer among men treated with radical prostatectomy.

The Role of Obesity in Cancer Survival and Recurrence

Abstract: Obesity and components of energy imbalance, that is, excessive energy intake and suboptimal levels of physical activity, are established risk factors for cancer incidence. Accumulating evidence suggests that these factors also may be important after the diagnosis of cancer and influence the course of disease, as well as overall health, well-being, and survival. Lifestyle and medical interventions that effectively modify these factors could potentially be harnessed as a means of cancer control. However, for such interventions to be maximally effective and sustainable, broad sweeping scientific discoveries ranging from molecular and cellular advances, to developments in delivering interventions on both individual and societal levels are needed. This review summarizes key discussion topics that were addressed in a recent Institute of Medicine Workshop entitled, “The Role of Obesity in Cancer Survival and Recurrence”; discussions included (i) mechanisms associated with obesity and energy balance that influence cancer progression; (ii) complexities of studying and interpreting energy balance in relation to cancer recurrence and survival; (iii) associations between obesity and cancer risk, recurrence, and mortality; (iv) interventions that promote weight loss, increased physical activity, and negative energy balance as a means of cancer control; and (v) future directions. Cancer Epidemiol Biomarkers Prev; 1–16. ©2012 AACR .

The Oncogenic Role of miR-155 in Breast Cancer

Abstract: miR-155 is an oncogenic miRNA with well described roles in leukemia. However, additional roles of miR-155 in breast cancer progression have recently been described. A thorough literature search was conducted to review all published data to date, examining the role of miR-155 in breast cancer. Data on all validated miR-155 target genes was collated to identify biologic pathways relevant to miR-155 and breast cancer progression. Publications describing the clinical relevance, functional characterization, and regulation of expression of miR-155 in the context of breast cancer are reviewed. A total of 147 validated miR-155 target genes were identified from the literature. Pathway analysis of these genes identified likely roles in apoptosis, differentiation, angiogenesis, proliferation, and epithelial–mesenchymal transition. The large number of validated miR-155 targets presented here provide many avenues of interest as to the clinical potential of miR-155. Further investigation of these target genes will be required to elucidate the specific mechanisms and functions of miR-155 in breast cancer. This is the first review examining the role of miR-155 in breast cancer progression. The collated data of target genes and biologic pathways of miR-155 identified in this review suggest new avenues of research for this oncogenic miRNA. Cancer Epidemiol Biomarkers Prev; 21(8); 1236–43. ©2012 AACR .

Effectiveness of hepatocellular carcinoma surveillance in patients with cirrhosis.

Abstract: Background: Surveillance for hepatocellular carcinoma (HCC) is recommended in patients with cirrhosis, but the effectiveness of a surveillance program in clinical practice has yet to be established. Aims: To evaluate the effectiveness of a surveillance program with ultrasound and alpha-fetoprotein (AFP) to detect early HCCs. Methods: Four hundred and forty-six patients with Child A/B cirrhosis were prospectively enrolled between January 2004 and September 2006 and followed until July 2010. HCC surveillance using ultrasound and AFP was conducted per the treating hepatologist, although the standard was every 6 to 12 months. HCC was diagnosed using American Association for the Study of Liver Disease (AASLD) guidelines and early HCC defined by Barcelona Clinic Liver Cancer (BCLC) staging. Performance characteristics were determined for surveillance using AFP, ultrasound, or the combination. Results: After a median follow-up of 3.5 years, 41 patients developed HCCs, of whom 30 (73.2%) had early HCCs. The annual incidence of HCC was 2.8%, with cumulative 3- and 5-year incidence rates of 5.7% and 9.1%, respectively. Surveillance ultrasound and AFP had sensitivities of 44% and 66% and specificities of 92% and 91%, respectively, for the detection of HCCs. Sensitivity significantly improved to 90%, with minimal loss in specificity (83%) when these tests were used in combination. Conclusions: When used as a surveillance program in a real-world clinical setting, combination of ultrasound and AFP is the most effective strategy to detect HCC at an early stage. Impact: Our results differ from the guidelines of the AASLD. Cancer Epidemiol Biomarkers Prev; 1–7. ©2012 AACR .

Exercise Effects on Depressive Symptoms in Cancer Survivors: A Systematic Review and Meta-analysis

Abstract: Background: Depression is a distressing side effect of cancer and its treatment. In the general population, exercise is an effective antidepressant. Objective: We conducted a systematic review and meta-analysis to determine the antidepressant effect of exercise in cancer survivors. Data Sources: In May 2011, we searched MEDLINE, PsycInfo, EMBASE, CINAHL, CDSR, CENTRAL, AMED, Biosis Previews, and Sport Discus and citations from relevant articles and reviews. Study Eligibility Criteria: We included randomized controlled trials (RCT) comparing exercise interventions with usual care in cancer survivors, using a self-report inventory or clinician rating to assess depressive symptoms, and reporting symptoms pre- and postintervention. Study Appraisal: Around 7,042 study titles were identified and screened, with 15 RCTs included. Synthesis Methods: Effect sizes (ES) were reported as mean change scores. The Q test was conducted to evaluate heterogeneity of ES. Potential moderator variables were evaluated with examination of scatter plots and Wilcoxon rank-sum or Kruskal–Wallis tests. Results: The overall ES, under a random-effects model, was −0.22 (confidence interval, −0.43 to −0.09; P = 0.04). Significant moderating variables ( ps < 0.05) were exercise location, exercise supervision, and exercise duration. Limitations: Only one study identified depression as the primary endpoint. Conclusions: Exercise has modest positive effects on depressive symptoms with larger effects for programs that were supervised or partially supervised, not conducted at home, and at least 30 minutes in duration. Impact: Our results complement other studies showing that exercise is associated with reduced pain and fatigue and with improvements in quality of life among cancer survivors. Cancer Epidemiol Biomarkers Prev; 21(1); 3–19. ©2011 AACR .

Risk factors for oral HPV infection among a high prevalence population of HIV-positive and at-risk HIV-negative adults

Abstract: Background:Human papillomavirus (HPV) is an important risk factor for oropharyngeal cancer. Individuals with human immunodeficiency virus (HIV) have higher oral HPV prevalence but the risk factors for oral HPV infection are not well understood for either HIV-positive or HIV-negative individuals. Methods:This study was nested within the MACS (men) and WIHS (women) cohorts. Exfoliated oral epithelial cells were collected from 379 HIV-positive and 266 at-risk HIV-negative individuals using a rinse and gargle with ScopeTM mouthwash. Samples were tested for 36 types of HPV DNA using PGMY09/11 consensus primers and reverse line blot hybridization. Risk factors for oral HPV infection were explored using logistic regression with generalized estimating equations (GEE) in this cross-sectional analysis. Results:Prevalent oral HPV infection was common (34%), including HPV16 infection in 5.7% of participants. HIV-positive individuals had increased odds of prevalent oral HPV infection compared to HIV-negative individuals (aOR=2.1, 95%CI=1.6-2.8). Risk factors for prevalent oral HPV differed in HIV-positive and HIV-negative participants. Among HIV-negative individuals, higher number of recent oral sex or rimming partners were strong risk factors for prevalent oral HPV infection (each p-trend<0.01). In contrast, among HIV-positive individuals lower CD4 T-cell count (p-trend<0.001) and higher number of lifetime sexual partners (p-trend=0.03) were strong risk factors. Conclusions:Oral HPV prevalence was elevated in HIV-positive individuals after controlling for differences in cigarette smoking and sexual behavior, supporting the possibility that HIV may affect the natural history of oral HPV. Impact:Immunosuppression may contribute to increased persistence or progression of oral HPV infection.

Trends in Colorectal Cancer Incidence Rates in the United States by Tumor Location and Stage, 1992–2008

Abstract: Background: Results from case–control studies outside the United States have been conflicted about the efficacy of colonoscopy for reducing cancer risk in the right colon. To contribute to this discourse from an alternative perspective, we analyzed high-quality surveillance data to report on recent trends in population-based colorectal cancer incidence rates by tumor location in the United States. Methods: Data from cancer registries in the Surveillance, Epidemiology, and End Results Program were analyzed to examine colorectal cancer incidence trends from 1992 through 2008 among individuals aged ≥50 years ( n = 267,072). Joinpoint regression analysis was used to quantify annual percent change in age-standardized rates by tumor location and disease stage. Results: Incidence rates for right-sided colon tumors decreased annually by 2.6% (95% CI: 2.0–3.2) since 1999 in men and 2.3% (CI: 1.6–3.0) since 2000 in women, after remaining stable during the previous seven/eight years. Incidence rates for left-sided tumors were generally decreasing from 1992 to 2008 in both sexes. Beginning in 1999/2000, substantial, almost identical annual declines occurred for late-stage disease in both the right and left colon: 3.9% (CI: 3.1–4.8) and 4.2% (CI: 3.5–4.9), respectively, in men; and 3.3% (CI: 2.5–4.1) and 3.3% (CI: 2.8–3.8) in women. Conclusion: Large declines in the incidence of right-sided colon tumors among individuals 50 years and older began around 2000. Impact: Increased colonoscopy utilization during the past decade may have contributed to a reduction in risk for cancers in both the right and left colorectum in the United States. Cancer Epidemiol Biomarkers Prev; 21(3); 411–6. ©2012 AACR . This article is featured in Highlights of This Issue, [p. 389][1] [1]: /lookup/volpage/21/389?iss=3

Impact of Breast Cancer Subtypes and Treatment on Survival: An Analysis Spanning Two Decades

Abstract: Background: We investigated the impact of breast cancer molecular subtypes and treatment on survival in a cohort of medically insured women followed for more than 20 years. Methods: We examined 934 female members of an integrated health care delivery system newly diagnosed with invasive breast cancer between 1988 and 1995 and followed them through 2008. Tumors were classified into four molecular subtypes on the basis of their expression profile: luminal A; luminal B; basal-like; and HER2-enriched. We followed women from the surgery date to death, health plan disenrollment, or study's end. HR and 95% confidence intervals (CI) were fit using Cox proportional hazards models adjusting for cancer treatments and tumor characteristics. Results: A total of 223 (23.9%) women died because of breast cancer during the 21-year study period. Compared with women with luminal A tumors, women with HER2-enriched (HR 2.56, 95% CI 1.53–4.29) and luminal B tumors (HR 1.96, 95% CI: 1.08–3.54) had roughly a two-fold increased adjusted risk of breast cancer mortality. In addition, the survival curves suggest that risk of late mortality persists in women with luminal A tumors. Conclusion: Among women with health care coverage, molecular subtypes were important predictors of breast cancer mortality. Women with HER2-enriched tumors and luminal B subtypes had the poorest survival despite adjusting for important covariates. Impact: In a cohort followed for more than 20 years, women with HER2-enriched tumors had worse survival, but interestingly, the survival curve for women with luminal A tumors continued to steadily decline after 10 years of follow-up. Cancer Epidemiol Biomarkers Prev; 1–8. ©2012 AACR .

Sex Hormones, Hormonal Interventions, and Gastric Cancer Risk: A Meta-analysis

Abstract: Estrogens may influence gastric cancer risk but published studies are inconclusive. We therefore performed a meta-analysis addressing the associations of gastric cancer in women with menstrual and reproductive factors, and with use of estrogen- and antiestrogen-related therapies. Searches of PubMed up to June, 2011 and review of citations yielded a total of 28 independent studies including at least one exposure of interest. Random effects pooled estimates of relative risk (RR) and corresponding 95% confidence intervals (CI) were calculated for eight exposures reported in at least five studies, including: age at menarche, age at menopause, years of fertility, parity, age at first birth, oral contraceptive use, hormone replacement therapy (HRT), and tamoxifen treatment. Longer years of fertility (RR= 0.74; 95% CI= 0.63 to 0.86) and HRT (RR= 0.77, 95% CI= 0.64 to 0.92) were each associated with decreased gastric cancer risk. Conversely, tamoxifen treatment was associated with increased risk (RR= 1.82, 95% CI= 1.39 to 2.38). The other five exposures were not significantly associated. Our analysis supports the hypothesis that longer exposure to estrogen effects of either ovarian or exogenous origin may decrease risk of gastric cancer. Additional studies are warranted to extend this finding and to identify the underlying mechanisms.

Patterns of Colorectal Cancer Test Use, Including CT Colonography, in the 2010 National Health Interview Survey

Abstract: Background: Recommended colorectal cancer (CRC) screening tests for adults ages 50 to 75 years include home fecal occult blood tests (FOBT), sigmoidoscopy with FOBT, and colonoscopy. A newer test, computed tomographic (CT) colonography, has been recommended by some, but not all, national organizations. Methods: We analyzed 2010 National Health Interview Survey data, including new CT colonography questions, from respondents ages 50 to 75 years ( N = 8,952). We (i) assessed prevalence of CRC test use overall, by test type, and by sociodemographic and health care access factors and (ii) assessed reported reasons for not having a CRC test. Results: The age-standardized percentage of respondents reporting FOBT, sigmoidoscopy, or colonoscopy within recommended time intervals was 58.3% [95% confidence interval (CI), 57.0–59.6]. Colonoscopy was the most commonly reported test [within past 10 years: 54.6% (95% CI, 53.2–55.9)]. Home FOBT and sigmoidoscopy with FOBT were less frequently used [FOBT within past year: 8.8% (95% CI, 8.1–9.6); sigmoidoscopy within past 5 years with FOBT within past 3 years: 1.3% (95% CI, 1.0–1.6)]. CT colonography was rare: 1.3% (95% CI, 1.0–1.7). Increasing age, education, income, having health care insurance, and having a usual source of health care were associated with higher CRC test use. Test use within recommended time intervals was particularly low among individuals ages 50 to 64 years without health care insurance [21.2% (95% CI, 18.3–24.4)]. The most common reason for nonuse was “no reason or never thought about it.” Conclusions: About 40% of Americans ages 50 to 75 years do not meet the recommendations for having CRC screening tests. Impact: Expanded health care coverage and greater awareness of CRC screening are needed to further decrease CRC mortality. Cancer Epidemiol Biomarkers Prev; 21(6); 895–904. ©2012 AACR . This article is featured in Highlights of This Issue, [p. 873][1] [1]: /lookup/volpage/21/873?iss=6

Contribution of screening and survival differences to racial disparities in colorectal cancer rates

Abstract: Background: Considerable disparities exist in colorectal cancer (CRC) incidence and mortality rates between blacks and whites in the United States. We estimated how much of these disparities could be explained by differences in CRC screening and stage-specific relative CRC survival. Methods: We used the MISCAN-Colon microsimulation model to estimate CRC incidence and mortality rates in blacks, aged 50 years and older, from 1975 to 2007 assuming they had: (i) the same trends in screening rates as whites instead of observed screening rates (incidence and mortality); (ii) the same trends in stage-specific relative CRC survival rates as whites instead of observed (mortality only); and (iii) a combination of both. The racial disparities in CRC incidence and mortality rates attributable to differences in screening and/or stage-specific relative CRC survival were then calculated by comparing rates from these scenarios to the observed black rates. Results: Differences in screening accounted for 42% of disparity in CRC incidence and 19% of disparity in CRC mortality between blacks and whites. Thirty-six percent of the disparity in CRC mortality could be attributed to differences in stage-specific relative CRC survival. Together screening and survival explained a little more than 50% of the disparity in CRC mortality between blacks and whites. Conclusion: Differences in screening and relative CRC survival are responsible for a considerable proportion of the observed disparities in CRC incidence and mortality rates between blacks and whites. Impact: Enabling blacks to achieve equal access to care as whites could substantially reduce the racial disparities in CRC burden. Cancer Epidemiol Biomarkers Prev; 1–9. ©2012 AACR .

The Origin, Evolution, and Principles of Patient Navigation

Abstract: This issue of CEBP focuses on patient navigation with specific emphasis on the findings of the National Cancer institute (NCI) Patient Navigation Research Program (PNRP). This research program was designed to develop interventions to reduce the time to diagnosis and treatment of cancer after

Prevalidation of Salivary Biomarkers for Oral Cancer Detection

Abstract: Background: Oral cancer is the sixth most common cancer with a 5-year survival rate of approximately 60%. Presently, there are no scientifically credible early detection techniques beyond conventional clinical oral examination. The goal of this study is to validate whether the seven mRNAs and three proteins previously reported as biomarkers are capable of discriminating patients with oral squamous cell carcinomas (OSCC) from healthy subjects in independent cohorts and by a National Cancer Institute (NCI)-Early Detection Research Network (EDRN)-Biomarker Reference Laboratory (BRL). Methods: Three hundred and ninety-five subjects from five independent cohorts based on case controlled design were investigated by two independent laboratories, University of California, Los Angeles (Los Angeles, CA) discovery laboratory and NCI-EDRN-BRL. Results: Expression of all seven mRNA and three protein markers was increased in OSCC versus controls in all five cohorts. With respect to individual marker performance across the five cohorts, the increase in interleukin (IL)-8 and subcutaneous adipose tissue (SAT) was statistically significant and they remained top performers across different cohorts in terms of sensitivity and specificity. A previously identified multiple marker model showed an area under the receiver operating characteristic (ROC) curve for prediction of OSCC status ranging from 0.74 to 0.86 across the cohorts. Conclusions: The validation of these biomarkers showed their feasibility in the discrimination of OSCCs from healthy controls. Established assay technologies are robust enough to perform independently. Individual cutoff values for each of these markers and for the combined predictive model need to be further defined in large clinical studies. Impact: Salivary proteomic and transcriptomic biomarkers can discriminate oral cancer from control subjects. Cancer Epidemiol Biomarkers Prev; 21(4); 664–72. ©2012 AACR .

Human Papillomavirus DNA Methylation as a Potential Biomarker for Cervical Cancer

Abstract: Sexually transmitted carcinogenic human papillomavirus (HPV) infections are extraordinarily prevalent worldwide. However, most incident HPV infections clear within a few years, whereas a small minority persists to invasive cancer. Recent studies indicate that detection of methylated viral DNA may distinguish women with cervical intraepithelial neoplasia grade 2+ (CIN2+) from those with a carcinogenic HPV-type infection that shows no evidence of CIN2+. Several studies have reported a positive association between methylation of CpG sites in the L1 gene and CIN2+, although there are inconclusive results about methylation of CpG sites in the upstream regulatory region (URR). In this review, we summarize the current state of knowledge on HPV DNA methylation in cervical carcinogenesis, and discuss the merits of different methods used to measure HPV DNA methylation. To follow the promising leads, we suggest future studies to validate the use of methylated carcinogenic HPV DNA as a predictive and/or diagnostic biomarker for risk of cervical cancer among HPV-positive women.

Smoking Behavior and Exposure to Tobacco Toxicants during 6 Months of Smoking Progressively Reduced Nicotine Content Cigarettes

Abstract: Background: Recent federal legislation gives the U.S. Food and Drug Administration authority to regulate the nicotine content of cigarettes. A nationwide strategy for progressive reduction of the nicotine content of cigarettes is a potential way to reduce the addictiveness of cigarettes, to prevent new smokers from becoming addicted, and to facilitate quitting in established smokers. We conducted a trial of progressive nicotine content tapering over 6 months to determine the effects on smoking behaviors and biomarkers of tobacco smoke exposure and cardiovascular effects. Methods: One hundred and thirty-five healthy smokers were randomly assigned to one of two groups. A research group smoked their usual brand of cigarettes followed by five types of research cigarettes with progressively lower nicotine content, each smoked for one month. A control group smoked their own brand of cigarettes for the same period of time. Results: Nicotine intake, as indicated by plasma cotinine concentration, declined progressively as the nicotine content of cigarettes was reduced. Cigarette consumption and markers of exposure to carbon monoxide and polycyclic aromatic hydrocarbons, as well as cardiovascular biomarkers remained stable, whereas urinary 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) excretion decreased. No significant changes in biomarkers of exposure or cardiovascular effects were observed in controls. Conclusions: Our data support the proposition that the intake of nicotine from cigarettes of smokers can be substantially lowered without increasing exposure to other tobacco smoke toxins. Impact: These findings support the feasibility and safety of gradual reduction of the nicotine content in cigarettes. Cancer Epidemiol Biomarkers Prev; 21(5); 761–9. ©2012 AACR .

Circadian disruption, sleep loss, and prostate cancer risk: A systematic review of epidemiologic studies

Abstract: Disruption of the circadian system has been hypothesized to increase cancer risk, either due to direct disruption of the molecular machinery generating circadian rhythms or due to disruption of parameters controlled by the clock such as melatonin levels or sleep duration. This hypothesis has been studied in hormone-dependent cancers among women, but data are sparse regarding potential effects of circadian disruption on the risk of prostate cancer. This review systematically examines available data evaluating the effects of light at night, sleep patterns, and night shift work on prostate cancer risk.

Patient navigation improves cancer diagnostic resolution: an individually randomized clinical trial in an underserved population

Abstract: Background: Barriers to timely resolution of abnormal cancer screening tests add to cancer health disparities among low-income, uninsured, and minority populations. We conducted a randomized trial to evaluate the impact of lay patient navigators on time to resolution and completion of follow-up testing among patients with abnormal screening tests in a medically underserved patient population. Methods: Denver Health, the safety-net health care system serving Denver, is one of 10 performance sites participating in the Patient Navigation Research Program. Of 993 eligible subjects with abnormal screening tests randomized to navigation and no-navigation (control) arms and analyzed, 628 had abnormal breast screens (66 abnormal clinical breast examinations, 304 BIRADS 0, 200 BIRADS 3, 58 BIRADS 4 or 5) whereas 235 had abnormal colorectal and 130 had abnormal prostate screens. Results: Time to resolution was significantly shorter in the navigated group (stratified log rank test, P < 0.001). Patient navigation improved diagnostic resolution for patients presenting with mammographic BIRADS 3 ( P = 0.0003) and BIRADS 0 ( P = 0.09), but not BIRADS 4/5 or abnormal breast examinations. Navigation shortened the time for both colorectal ( P = 0.0017) and prostate screening resolution ( P = 0.06). Participant demographics included 72% minority, 49% with annual household income less than $10,000, and 36% uninsured. Conclusions: Patient navigation positively impacts time to resolution of abnormal screening tests for breast, colorectal, and prostate cancers in a medically underserved population. Impact: By shortening the time to and increasing the proportion of patients with diagnostic resolution patient navigation could reduce disparities in stage at diagnosis and improve cancer outcomes. Cancer Epidemiol Biomarkers Prev; 21(10); 1629–38. ©2012 AACR .

Boston Patient Navigation Research Program: The Impact of Navigation on Time to Diagnostic Resolution after Abnormal Cancer Screening

Abstract: Background: There is a need for controlled studies to assess the impact of patient navigation in vulnerable cancer populations. Methods: Boston Patient Navigation Research Program conducted a quasi-experimental patient navigation intervention across six federally qualified inner-city community health centers, three assigned to a breast cancer navigation intervention and three assigned to a cervical cancer navigation intervention; each group then served as the control for the other. Eligible women had an abnormal breast or cervical cancer screening test conducted at one of the participating health centers during a baseline (2004–2005) or intervention period (2007–2008). Kaplan–Meier survival curves and proportional hazards regression examined the effect of patient navigation on time to definitive diagnosis, adjusting for covariates, clustering by clinic and differences between the baseline and intervention period. Results: We enrolled 997 subjects in the baseline period and 3,041 subjects during the intervention period, of whom 1,497 were in the navigated arm, and 1,544 in the control arm. There was a significant decrease in time to diagnosis for subjects in the navigated group compared with controls among those with a cervical screening abnormality [aHR 1.46; 95% confidence interval (CI), 1.1–1.9]; and among those with a breast cancer screening abnormality that resolved after 60 days (aHR 1.40; 95% CI, 1.1–1.9), with no differences before 60 days. Conclusions: This study documents a benefit of patient navigation on time to diagnosis among a racially/ethnically diverse inner city population. Impact: Patient navigation may address cancer health disparities by reducing time to diagnosis following an abnormal cancer-screening event. Cancer Epidemiol Biomarkers Prev; 21(10); 1645–54. ©2012 AACR .

Prediagnostic 25-Hydroxyvitamin D, VDR and CASR Polymorphisms, and Survival in Patients with Colorectal Cancer in Western European Populations

Abstract: Background: Individuals with higher blood 25-hydroxyvitamin D [25(OH)D] levels have a lower risk of developing colorectal cancer (CRC), but the influence of 25(OH)D on mortality after CRC diagnosis ...

Night Shift Work and Hormone Levels in Women

Abstract: Background: Night shift work may disrupt the normal nocturnal rise in melatonin, resulting in increased breast cancer risk, possibly through increased reproductive hormone levels We investigated whether night shift work is associated with decreased levels of urinary 6-sulfatoxymelatonin, the primary metabolite of melatonin, and increased urinary reproductive hormone levels Methods: Participants were 172 night shift and 151 day shift–working nurses, aged 20–49 years, with regular menstrual cycles Urine samples were collected throughout work and sleep periods and assayed for 6-sulfatoxymelatonin, luteinizing hormone (LH), follicle–stimulating hormone (FSH), and estrone conjugate (E1C) Results: 6-Sulfatoxymelatonin levels were 62% lower and FSH and LH were 62% and 58% higher, respectively, in night shift–working women during daytime sleep than in day shift–working women during nighttime sleep ( P ≤ 00001) Nighttime sleep on off-nights was associated with 42% lower 6-sulfatoxymelatonin levels among the night shift workers, relative to the day shift workers ( P < 00001); no significant differences in LH or FSH were observed 6-Sulfatoxymelatonin levels during night work were approximately 69% lower and FSH and LH were 35% and 38% higher, compared with day shift workers during nighttime sleep No differences in E1C levels between night and day shift workers were observed Within night shift workers, 6-sulfatoxymelatonin levels were lower and reproductive hormone levels were higher during daytime sleep and nighttime work, relative to nighttime sleep ( P < 005) Conclusions: These results indicate that night shift workers have substantially reduced 6-sulfatoxymelatonin levels during night work and daytime sleep and that levels remain low even when a night shift worker sleeps at night Impact: Shift work could be an important risk factor for many other cancers in addition to breast cancer MeSH Subject Headings: breast cancer, shift work, circadian rhythm, environmental carcinogens, estrogen, melatonin, 6-sulfatoxymelatonin, pineal Cancer Epidemiol Biomarkers Prev; ©2012 AACR

Weight Change and Survival after Breast Cancer in the After Breast Cancer Pooling Project

Abstract: Background: Weight change after a breast cancer diagnosis has been linked to lower survival. To further understand effects of postdiagnostic weight variation on survival, we examined the relationship by comorbid status and initial body mass index (BMI). Methods: The current analysis included 12,915 patients with breast cancer diagnosed between 1990 and 2006 with stage I–III tumors from four prospective cohorts in the United States and China. HRs and 95% confidence intervals (CI) representing the associations of five weight change categories [within <5% (reference); 5%–<10% and ≥10% loss and gain] with mortality were estimated using Cox proportional hazards models. Results: Mean weight change was 1.6 kg. About 14.7% women lost and 34.7% gained weight. Weight stability in the early years postdiagnosis was associated with the lowest overall mortality risk. Weight loss ≥10% was related to a 40% increased risk of death (HR, 1.41; 95% CI, 1.14–1.75) in the United States and over three times the risk of death (HR, 3.25; 95% CI: 2.24, 4.73) in Shanghai. This association varied by prediagnosis BMI, and in the United States, lower survival was seen for women who lost weight and had comorbid conditions. Weight gain ≥10% was associated with a nonsignificant increased risk of death. Conclusions: Prevention of excessive weight gain is a valid public health goal for breast cancer survivors. Although intentionality of weight loss could not be determined, women with comorbid conditions may be particularly at risk of weight loss and mortality. Impact: Weight control strategies for breast cancer survivors should be personalized to the individual's medical history. Cancer Epidemiol Biomarkers Prev; 21(8); 1260–71. ©2012 AACR . This article is featured in Highlights of This Issue, [p. 1227][1] [1]: /lookup/volpage/21/1227?iss=8

BRAF Mutation Status and Survival after Colorectal Cancer Diagnosis According to Patient and Tumor Characteristics

Abstract: Background: BRAF mutations in colorectal cancer (CRC) are disproportionately observed in tumors exhibiting microsatellite instability (MSI) and are associated with other prognostic factors. The independent association between BRAF mutation status and CRC survival, however, remains unclear. Methods: We evaluated the association between the BRAF c.1799T>A (p.V600E) mutation and survival in individuals with incident invasive CRC diagnosed between 1997 and 2007 in Western Washington State. Tumor specimens were tested for this BRAF mutation and MSI status. We used Cox regression to estimate HRs and 95% confidence intervals (CI) for the association between BRAF mutation status and disease-specific and overall survival. Stratified analyses were conducted by age, sex, tumor site, stage, and MSI status. Results: Among 1,980 cases tested, 12% were BRAF c.1799T>A (p.V600E) mutation–positive ( n = 247). BRAF -mutated CRC was associated with poorer disease-specific survival adjusting for age, sex, time from diagnosis to enrollment, stage, and MSI status (HR, 1.43; 95% CI, 1.05–1.95). This association was limited to cases diagnosed at ages <50 (HR, 3.06; 95% CI, 1.70–5.52) and was not evident in cases with MSI-high tumors (HR, 0.94; 95% CI, 0.44–2.03). Associations with overall survival were similar. Conclusions: Our results show that the prevalence of BRAF mutations in CRC differs by patient and tumor characteristics and suggest that the association between BRAF status and CRC survival may differ by some of these factors. Impact: The presence of a BRAF c.1799T>A (p.V600E) mutation is associated with significantly poorer prognosis after CRC diagnosis among subgroups of patients. Cancer Epidemiol Biomarkers Prev; 21(10); 1792–8. ©2012 AACR .

Associations between arsenic exposure and global posttranslational histone modifications among adults in Bangladesh.

Abstract: Background: Exposure to arsenic (As) is associated with an increased risk of several cancers as well as cardiovascular disease, and childhood neuro-developmental deficits. Arsenic compounds are weakly mutagenic, alter gene expression and posttranslational histone modifications (PTHMs) in vitro. Methods: Water and urinary As concentrations as well as global levels of histone 3 lysine 9 di-methylation and acetylation (H3K9me2 and H3K9ac), histone 3 lysine 27 tri-methylation and acetylation (H3K27me3 and H3K27ac), histone 3 lysine 18 acetylation (H3K18ac), and histone 3 lysine 4 trimethylation (H3K4me3) were measured in peripheral blood mononuclear cells (PBMC) from a subset of participants ( N = 40) of a folate clinical trial in Bangladesh (FACT study). Results: Total urinary As (uAs) was positively correlated with H3K9me2 ( r = 0.36, P = 0.02) and inversely with H3K9ac ( r = −0.47, P = 0.002). The associations between As and other PTHMs differed in a gender-dependent manner. Water As (wAs) was positively correlated with H3K4me3 ( r = 0.45, P = 0.05) and H3K27me3 ( r = 0.50, P = 0.03) among females and negatively correlated among males (H3K4me3: r = −0.44, P = 0.05; H3K27me3: r = −0.34, P = 0.14). Conversely, wAs was inversely associated with H3K27ac among females ( r = −0.44, P = 0.05) and positively associated among males ( r = 0.29, P = 0.21). A similar pattern was observed for H3K18ac (females: r = −0.22, P = 0.36; males: r = 0.27, P = 0.24). Conclusion: Exposure to As is associated with alterations of global PTHMs; gender-specific patterns of association were observed between As exposure and several histone marks. Impact: These findings contribute to the growing body of evidence linking As exposure to epigenetic dysregulation, which may play a role in the pathogenesis of As toxicity. Cancer Epidemiol Biomarkers Prev; 21(12); 2252–60. ©2012 AACR .

Plasma 25-Hydroxyvitamin D and Risk of Pancreatic Cancer

Abstract: Background: Laboratory studies suggest that vitamin D may inhibit pancreatic cancer cell growth. However, epidemiologic studies of vitamin D and pancreatic cancer risk have been conflicting. Methods: To determine whether prediagnostic levels of plasma 25-hydroxyvitamin D (25[OH]D; IDS Inc.; enzyme immunoassay) were associated with risk of pancreatic cancer, we conducted a pooled analysis of nested case–control studies with 451 cases and 1,167 controls from five cohorts through 2008. Median follow-up among controls was 14.1 years in Health Professionals Follow-Up Study (HPFS), 18.3 years in Nurses' Health Study (NHS), 25.3 years in Physicians' Health Study (PHS), 12.2 years in Women's Health Initiative-Observational Study (WHI), and 14.4 years in Women's Health Study (WHS). Logistic regression was used to compare the odds of pancreatic cancer by plasma level of 25(OH)D. Results: Mean plasma 25(OH)D was lower in cases versus controls (61.3 vs. 64.5 nmol/L, P = 0.005). In logistic regression models, plasma 25(OH)D was inversely associated with odds of pancreatic cancer. Participants in quintiles two through five had multivariable-adjusted ORs (95% confidence intervals) of 0.79 (0.56–1.10), 0.75 (0.53–1.06), 0.68 (0.48–0.97), and 0.67 (0.46–0.97; P trend = 0.03), respectively, compared with the bottom quintile. Compared with those with insufficient levels [25[OH]D, <50 nmol/L], ORs were 0.75 (0.58–0.98) for subjects with relative insufficiency [25[OH]D, 50 to <75 nmol/L] and 0.71 (0.52–0.97) for those with sufficient levels [25[OH]D, ≥75 nmol/L]. No increased risk was noted in subjects with 25(OH)D ≥100 nmol/L, as suggested in a prior study. In subgroup analyses, ORs for the top versus bottom quartile of 25(OH)D were 0.72 (0.48–1.08) for women, 0.73 (0.40–1.31) for men, and 0.73 (0.51–1.03) for Whites. Conclusions: Among participants in five large prospective cohorts, higher plasma levels of 25(OH)D were associated with a lower risk for pancreatic cancer. Impact: Low circulating 25(OH)D may predispose individuals to the development of pancreatic cancer. Cancer Epidemiol Biomarkers Prev; 21(1); 82–91. ©2011 AACR . This article is featured in Highlights of This Issue, [p. 1][1] [1]: /lookup/volpage/21/1?iss=1

Common Breast Cancer Susceptibility Variants in LSP1 and RAD51L1 Are Associated with Mammographic Density Measures that Predict Breast Cancer Risk

Abstract: BACKGROUND: Mammographic density adjusted for age and body mass index (BMI) is a heritable marker of breast cancer susceptibility. Little is known about the biologic mechanisms underlying the association between mammographic density and breast cancer risk. We examined whether common low-penetrance breast cancer susceptibility variants contribute to interindividual differences in mammographic density measures. METHODS: We established an international consortium (DENSNP) of 19 studies from 10 countries, comprising 16,895 Caucasian women, to conduct a pooled cross-sectional analysis of common breast cancer susceptibility variants in 14 independent loci and mammographic density measures. Dense and nondense areas, and percent density, were measured using interactive-thresholding techniques. Mixed linear models were used to assess the association between genetic variants and the square roots of mammographic density measures adjusted for study, age, case status, BMI, and menopausal status. RESULTS: Consistent with their breast cancer associations, the C-allele of rs3817198 in LSP1 was positively associated with both adjusted dense area (P = 0.00005) and adjusted percent density (P = 0.001), whereas the A-allele of rs10483813 in RAD51L1 was inversely associated with adjusted percent density (P = 0.003), but not with adjusted dense area (P = 0.07). CONCLUSION: We identified two common breast cancer susceptibility variants associated with mammographic measures of radiodense tissue in the breast gland. IMPACT: We examined the association of 14 established breast cancer susceptibility loci with mammographic density phenotypes within a large genetic consortium and identified two breast cancer susceptibility variants, LSP1-rs3817198 and RAD51L1-rs10483813, associated with mammographic measures and in the same direction as the breast cancer association.

Peripheral Blood Immune Cell Methylation Profiles Are Associated with Nonhematopoietic Cancers

Abstract: Background: Blood leukocytes from patients with solid tumors exhibit complex and distinct cancer-associated patterns of DNA methylation. However, the biologic mechanisms underlying these patterns remain poorly understood. Because epigenetic biomarkers offer significant clinical potential for cancer detection, we sought to address a mechanistic gap in recently published works, hypothesizing that blood-based epigenetic variation may be due to shifts in leukocyte populations. Methods: We identified differentially methylated regions (DMR) among leukocyte subtypes using epigenome-wide DNA methylation profiling of purified peripheral blood leukocyte subtypes from healthy donors. These leukocyte-tagging DMRs were then evaluated using epigenome-wide blood methylation data from three independent case-control studies of different cancers. Results: A substantial proportion of the top 50 leukocyte DMRs were significantly differentially methylated among head and neck squamous cell carcinoma (HNSCC) cases and ovarian cancer cases compared with cancer-free controls (48 and 47 of 50, respectively). Methylation classes derived from leukocyte DMRs were significantly associated cancer case status ( P < 0.001, P < 0.03, and P < 0.001) for all three cancer types: HNSCC, bladder cancer, and ovarian cancer, respectively and predicted cancer status with a high degree of accuracy (area under the curve [AUC] = 0.82, 0.83, and 0.67). Conclusions: These results suggest that shifts in leukocyte subpopulations may account for a considerable proportion of variability in peripheral blood DNA methylation patterns of solid tumors. Impact: This illustrates the potential use of DNA methylation profiles for identifying shifts in leukocyte populations representative of disease, and that such profiles may represent powerful new diagnostic tools, applicable to a range of solid tumors. Cancer Epidemiol Biomarkers Prev; 21(8); 1293–302. ©2012 AACR . This article is featured in Highlights of This Issue, [p. 1227][1] [1]: /lookup/volpage/21/1227?iss=8

The Communications Revolution and Health Inequalities in the 21st Century: Implications for Cancer Control

Abstract: The radical and transformative developments in information and communication technologies (ICT) offer unprecedented opportunities to promote cancer control and enhance population and individual health. However, the current context in which these technologies are being deployed—where cancer incidence and mortality and communication are characterized by inequalities among different racial/ethnic and socioeconomic status groups—raises important questions for cancer communication research, policy, and practice. Drawing on illustrative data, this essay characterizes the communications revolution and elucidates its implications for cancer control, with a particular focus on communication inequalities and cancer disparities. Cancer Epidemiol Biomarkers Prev; 21(10); 1701–8. ©2012 AACR .

Residential Radon Exposure, Histologic Types, and Lung Cancer Risk. A Case–Control Study in Galicia, Spain

Abstract: Background: Lung cancer is an important public health problem, and tobacco is the main risk factor followed by residential radon exposure. Recommended exposure levels have been progressively lowered. Galicia, the study area, has high residential radon concentrations. We aim (i) to assess the risk of lung cancer linked to airborne residential radon exposure, (ii) to ascertain whether tobacco modifies radon risk, and (iii) to know whether there is a lung cancer histologic type more susceptible to radon. Methods: A hospital-based case–control design was conducted in two Spanish hospitals. Consecutive cases with histologic diagnosis of lung cancer and controls undergoing trivial surgery not tobacco-related were included. Residential radon was measured using standard procedures. Results were obtained using logistic regression. Results: Three hundred and forty-nine cases and 513 controls were included. Radon exposure posed a risk even with a low exposure, with those exposed to 50 to 100 Bq/m 3 having an OR of 1.87 [95% confidence interval (CI), 1.21–2.88] and of 2.21 (95% CI, 1.33–3.69) for those exposed to 148 Bq/m 3 or more. Tobacco increased appreciably the risk posed by radon, with an OR of 73 (95% CI, 19.88–268.14) for heavy smokers exposed to more than 147 Bq/m 3 . Less frequent histologic types (including large cell carcinomas), followed by small cell lung cancer, had the highest risk associated with radon exposure. Conclusions: The presence of airborne radon even at low concentrations poses a risk of developing lung cancer, with tobacco habit increasing considerably this risk. Impact: Public health initiatives should address the higher risk of lung cancer for smokers exposed to radon. Cancer Epidemiol Biomarkers Prev; 21(6); 951–8. ©2012 AACR .