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Cancer Epidemiology Biomarkers & Prevention

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Cancer Epidemiology Biomarkers & Prevention

The effects of blood levels of 25-hydroxyvitamin D (25-OHD) on the risk of total, low-, and high-grade prostate cancer were examined in the Selenium and Vitamin E Cancer Prevention Trial (SELECT) and the Prostate Cancer Prevention Trial (PCPT). In the SELECT study, plasma 25-OHD levels were associated with a linear decrease in prostate cancer risk for high-grade cancers in African American men and an apparent "U"-shaped effect in other men. The "U-shaped" curve may reflect detection bias. In the PCPT study, in which detection bias was minimized, serum 25-OHD levels were associated with a linear decrease in the risk of high-grade prostate cancers. The results from these large prevention trials support the hypothesis that circulating levels of 25-OHD decrease the risk of clinically relevant prostate cancers. Cancer Epidemiol Biomarkers Prev; 23(8); 1447–9. ©2014 AACR.

Melanoma incidence is increasing rapidly worldwide among white-skinned populations. Earlier diagnosis is the principal factor that can improve prognosis. Defining high-risk populations using risk prediction models may help targeted screening and early detection approaches. In this systematic review, we searched Medline, EMBASE, and the Cochrane Library for primary research studies reporting or validating models to predict risk of developing cutaneous melanoma. A total of 4,141 articles were identified from the literature search and six through citation searching. Twenty-five risk models were included. Between them, the models considered 144 possible risk factors, including 18 measures of number of nevi and 26 of sun/UV exposure. Those most frequently included in final risk models were number of nevi, presence of freckles, history of sunburn, hair color, and skin color. Despite the different factors included and different cutoff values for sensitivity and specificity, almost all models yielded sensitivities and specificities that fit along a summary ROC with area under the ROC (AUROC) of 0.755, suggesting that most models had similar discrimination. Only two models have been validated in separate populations and both also showed good discrimination with AUROC values of 0.79 (0.70–0.86) and 0.70 (0.64–0.77). Further research should focus on validating existing models rather than developing new ones. Cancer Epidemiol Biomarkers Prev; 23(8); 1450–63. ©2014 AACR.

Breast cancer imaging phenotype is diverse and may relate to molecular alterations driving cancer behavior. We systematically reviewed and meta-analyzed relations between breast cancer imaging features and human epidermal growth factor receptor type 2 (HER2) overexpression as a marker of breast cancer aggressiveness. MEDLINE and EMBASE were searched for mammography, breast ultrasound, magnetic resonance imaging (MRI), and/or [18F]fluorodeoxyglucose positron emission tomography studies through February 2013. Of 68 imaging features that could be pooled (85 articles, 23,255 cancers; random-effects meta-analysis), 11 significantly related to HER2 overexpression. Results based on five or more studies and robustness in subgroup analyses were as follows: the presence of microcalcifications on mammography [pooled odds ratio (pOR), 3.14; 95% confidence interval (CI), 2.46–4.00] or ultrasound (mass-associated pOR, 2.95; 95% CI, 2.34–3.71), branching or fine linear microcalcifications (pOR, 2.11; 95% CI, 1.07–4.14) or extremely dense breasts on mammography (pOR, 1.37; 95% CI, 1.07–1.76), and washout (pOR, 1.57; 95% CI, 1.11–2.21) or fast initial kinetics (pOR, 2.60; 95% CI, 1.43–4.73) on MRI all increased the chance of HER2 overexpression. Maximum [18F]fluorodeoxyglucose standardized uptake value (SUVmax) was higher upon HER2 overexpression (pooled mean difference, +0.76; 95% CI, 0.10–1.42). These results show that several imaging features relate to HER2 overexpression, lending credibility to the hypothesis that imaging phenotype reflects cancer behavior. This implies prognostic relevance, which is especially relevant as imaging is readily available during diagnostic work-up. Cancer Epidemiol Biomarkers Prev; 23(8); 1464–83. ©2014 AACR.

Background: Epidemiologic studies have reported inconsistent associations of vitamin D and prostate cancer risk; however, few have adequately controlled for detection bias related to prostate-specific antigen (PSA) screening, and the results of many studies may be affected by occult prostate cancers among controls.

Methods: Data for this nested case–control analysis (n = 1,695 cases/1,682 controls) are from the Prostate Cancer Prevention Trial. Baseline serum was analyzed for 25-hydroxyvitamin D [25(OH)D]. The presence or absence of cancer was subsequently determined by prostate biopsy. Polytomous logistic regression models were used to estimate associations of 25(OH)D with risk of total, Gleason 2–6, Gleason 7, and Gleason 8–10 prostate cancer. Results are presented for placebo and finasteride arms separately and combined.

Results: There were no associations of serum 25(OH)D with total prostate cancer risk. For Gleason 2–6 cancers, results were inconsistent across treatment arms with a suggestion of increased risk in the placebo arm only; however, there was no dose–response relationship. For Gleason 8–10 prostate cancers, 25(OH)D concentrations were associated with a linear decrease in risk among combined treatment arms [quartile 4 vs. 1: OR, 0.55; 95% confidence interval (CI), 0.32–0.94; Ptrend = 0.04]. These findings were somewhat stronger among men ≥65 versus 55–64 years at baseline (quartile 4 vs. 1: OR, 0.40; 95% CI, 0.18–0.88 vs. OR, 0.73; 95% CI, 0.35–1.52, respectively; Pinteraction = 0.52).

Conclusions: Higher serum 25(OH)D may modestly increase risk of Gleason 2–6 disease and more substantially reduce risk of Gleason 8–10 prostate cancer.

Impact: Vitamin D may have different effects for different stages of prostate cancers. Cancer Epidemiol Biomarkers Prev; 23(8); 1484–93. ©2014 AACR.

Background: In vitro, animal, and ecological studies suggest that inadequate vitamin D intake could increase prostate cancer risk, but results of biomarker-based longitudinal studies are inconsistent.

Methods: Data for this case (n = 1,731) and cohort (n = 3,203) analysis are from the Selenium and Vitamin E Cancer Prevention Trial. Cox proportional hazard models were used to test whether baseline plasma vitamin D (25-hydroxy) concentration, adjusted for season of blood collection, was associated with the risk of total and Gleason score 2–6, 7–10, and 8–10 prostate cancer.

Results: There were U-shaped associations of vitamin D with total cancer risk: compared with the first quintile, HRs were 0.83 [95% confidence interval (CI), 0.66–1.03; P = 0.092], 0.74 (95% CI, 0.59–0.92; P = 0.008), 0.86 (95% CI, 0.69–1.07; P = 0.181), and 0.98 (95% CI, 0.78–1.21; P = 0.823), for the second through fifth quintiles, respectively. For Gleason 7–10 cancer, corresponding HRs were 0.63 (95% CI, 0.45–0.90; P = 0.010), 0.66 (95% CI, 0.47–0.92; P = 0.016), 0.79 (95% CI, 0.56–1.10; P = 0.165), and 0.88 (95% CI, 0.63–1.22; P = 0.436). Among African American men (n = 250 cases), higher vitamin D was associated with reduced risk of Gleason 7–10 cancer only: in the a posteriori contrast of quintiles 1–2 versus 3–5, the HR was 0.55 (95% CI, 0.31–0.97; P = 0.037), with no evidence of dose–response or a U-shaped association.

Conclusions: Both low and high vitamin D concentrations were associated with increased risk of prostate cancer, and more strongly for high-grade disease.

Impact: The optimal range of circulating vitamin D for prostate cancer prevention may be narrow. Supplementation of men with adequate levels may be harmful. Cancer Epidemiol Biomarkers Prev; 23(8); 1494–504. ©2014 AACR.

Background: There is continuing controversy about prostate cancer testing and the recent American Urological Association guidelines. We hypothesize that the reduction and elimination of racial survival disparity among African American men (AAM; high-risk group) compared with European American men (EAM; intermediate-risk group) during the PSA testing era compared with the pre-PSA era strongly supports the use of PSA testing in AAM.

Methods: We used Surveillance, Epidemiology, and End Results (SEER) data to investigate relative survival disparities between AAM and EAM. To evaluate pre-PSA testing era, we selected malignant first primary prostate cancer in AAM and EAM, all stages, diagnosed during 1973–1994. To evaluate relative survival disparities in the current PSA testing era, we selected malignant first primary local, regional, and distant stage prostate cancers diagnosed during 1998–2005 to calculate 5-year relative survival rates.

Results: Age-adjusted 5-year relative survival of prostate cancer diagnosed during 1973–1994 in the national SEER data revealed significantly shorter survival for AAM compared with EAM (P < 0.0001). The SEER-based survival analysis from 1995 to 2005 indicated no statistical difference in relative survival rates between AAM and EAM by year of diagnosis of local, regional, or distant stage prostate cancer.

Conclusion: We conclude that the elimination of prostate cancer racial disparity of local, regional, and metastatic prostate cancer relative survival in the current PSA testing era compared with pre-PSA era as an endpoint to test PSA efficacy as a marker for prostate cancer diagnosis is evidence for aggressive testing of AAM.

Impact: Evidence for screening AAM. Cancer Epidemiol Biomarkers Prev; 23(8); 1505–11. ©2014 AACR.

Background: Although unopposed estrogen exposure is considered the main driver of endometrial carcinogenesis, factors associated with states of insulin resistance and hyperinsulinemia are independently associated with endometrial cancer risk. We used dietary insulin load and insulin index scores to represent the estimated insulin demand of overall diets and assessed their association with endometrial cancer risk in the prospective Nurses' Health Study.

Methods: We estimated incidence rate ratios (RR) and 95% confidence intervals (CI) for risk of invasive endometrial cancer using Cox proportional hazards models. Between the baseline dietary questionnaire (1980) and 2010, we identified a total of 798 incident-invasive epithelial endometrial adenocarcinomas over 1,417,167 person-years of follow-up.

Results: Dietary insulin scores were not associated with overall risk of endometrial cancer. Comparing women in the highest with the lowest quintile, the multivariable-adjusted RRs of endometrial cancer were 1.07 (95% CI, 0.84–1.35) for cumulative average dietary insulin load and 1.03 (95% CI, 0.82–1.31) for cumulative average dietary insulin index. Findings did not vary substantially by alcohol consumption, total dietary fiber intake, or body mass index and/or physical activity (Pheterogeneity ≥ 0.10).

Conclusions: Intake of a diet predicted to stimulate a high postprandial insulin response was not associated with endometrial cancer risk in this large prospective study. Considering the complex interplay of diet, lifestyle, and genetic factors contributing to the hyperinsulinemic state, dietary measures alone may not sufficiently capture absolute long-term insulin exposure.

Impact: This study is the first to investigate dietary insulin scores in relation to endometrial cancer risk. Cancer Epidemiol Biomarkers Prev; 23(8); 1512–20. ©2014 AACR.

Background: Little is known about how colorectal cancer screening test preferences operate together with test access and navigation to influence screening adherence in primary care.

Methods: We analyzed data from a randomized trial of 945 primary care patients to assess the independent effects of screening test preference for fecal immunochemical test (FIT) or colonoscopy, mailed access to FIT and colonoscopy, and telephone navigation for FIT and colonoscopy, on screening.

Results: Preference was not associated with overall screening, but individuals who preferred FIT were more likely to complete FIT screening (P = 0.005), whereas those who preferred colonoscopy were more likely to perform colonoscopy screening (P = 0.032). Mailed access to FIT and colonoscopy was associated with increased overall screening (OR = 2.6, P = 0.001), due to a 29-fold increase in FIT use. Telephone navigation was also associated with increased overall screening (OR = 2.1, P = 0.005), mainly due to a 3-fold increase in colonoscopy performance. We estimated that providing access and navigation for both screening tests may substantially increase screening compared with a preference-tailored approach, mainly due to increased performance of nonpreferred tests.

Conclusions: Preference influences the type of screening tests completed. Test access increases FIT and navigation mainly increases colonoscopy. Screening strategies providing access and navigation to both tests may be more effective than preference-tailored approaches.

Impact: Preference tailoring in colorectal cancer screening strategies should be avoided if the objective is to maximize screening rates, although other factors (e.g., costs, necessary follow-up) should also be considered. Cancer Epidemiol Biomarkers Prev; 23(8); 1521–8. ©2014 AACR.

Background: From 1958 to 1970, >100,000 people in northern Chile were exposed to a well-documented, distinct period of high drinking water arsenic concentrations. We previously reported ecological evidence suggesting that early-life exposure in this population resulted in increased mortality in adults from several outcomes, including lung and bladder cancer.

Methods: We have now completed the first study ever assessing incident cancer cases after early-life arsenic exposure, and the first study on this topic with individual participant exposure and confounding factor data. Subjects included 221 lung and 160 bladder cancer cases diagnosed in northern Chile from 2007 to 2010, and 508 age and gender-matched controls.

Results: ORs adjusted for age, sex, and smoking in those only exposed in early life to arsenic water concentrations of ≤110, 110 to 800, and >800 μg/L were 1.00, 1.88 [95% confidence interval (CI), 0.96–3.71], and 5.24 (3.05–9.00; Ptrend < 0.001) for lung cancer, and 1.00, 2.94 (1.29–6.70), and 8.11 (4.31–15.25; Ptrend < 0.001) for bladder cancer. ORs were lower in those not exposed until adulthood. The highest category (>800 μg/L) involved exposures that started 49 to 52 years before, and ended 37 to 40 years before the cancer cases were diagnosed.

Conclusion: Lung and bladder cancer incidence in adults was markedly increased following exposure to arsenic in early life, even up to 40 years after high exposures ceased. Such findings have not been identified before for any environmental exposure, and suggest that humans are extraordinarily susceptible to early-life arsenic exposure.

Impact: Policies aimed at reducing early-life exposure may help reduce the long-term risks of arsenic-related disease. Cancer Epidemiol Biomarkers Prev; 23(8); 1529–38. ©2014 AACR.

Background: UV radiation (UVR) exposure is the primary risk factor for basal cell carcinoma (BCC). Although prescription diuretics have photosensitizing properties, the relationship between diuretic use and BCC remains unclear.

Methods: Using data from the United States Radiologic Technologists Study, a large, nationwide prospective cohort, we assessed the relationship between diuretic use and first primary BCC while accounting for sun exposure history, constitutional characteristics, lifestyle factors, and anthropometric measurements for geographically dispersed individuals exposed to a wide range of ambient UVR.

Results: After adjustment for potential confounders, we found a significantly increased risk of BCC associated with diuretic use [HR, 1.22; 95% confidence interval (CI), 1.07–1.38]. This relationship was modified by body mass index (P = 0.019), such that BCC risk was increased with diuretic use in overweight (HR, 1.43; 95% CI, 1.16–1.76) and obese individuals (HR, 1.43; 95% CI, 1.09–1.88), but not in normal weight individuals (HR, 0.99; 95% CI, 0.81–1.21).

Conclusions: Increased risk of BCC associated with diuretic use in overweight and obese participants may be related to higher dosages, longer duration of medication use, reduced drug metabolism, or drug interactions.

Impact: Future cohort studies should obtain more detailed information on medication use, consider factors that affect drug metabolism, and measure intermediate endpoints such as photosensitivity reactions. Cancer Epidemiol Biomarkers Prev; 23(8); 1539–45. ©2014 AACR.

Background: Over the past several decades, advances in lung cancer research and practice have led to refinements of histologic diagnosis of lung cancer. The differential use and subsequent alterations of nonspecific morphology codes, however, may have caused artifactual fluctuations in the incidence rates for histologic subtypes, thus biasing temporal trends.

Methods: We developed a multiple imputation (MI) method to correct lung cancer incidence for nonspecific histology using data from the Surveillance, Epidemiology, and End Results Program during 1975 to 2010.

Results: For adenocarcinoma in men and squamous in both genders, the change to an increasing trend around 2005, after more than 10 years of decreasing incidence, is apparently an artifact of the changes in histopathology practice and coding system. After imputation, the rates remained decreasing for adenocarcinoma and squamous in men, and became constant for squamous in women.

Conclusions: As molecular features of distinct histologies are increasingly identified by new technologies, accurate histologic distinctions are becoming increasingly relevant to more effective "targeted" therapies, and therefore, are important to track in patients. However, without incorporating the coding changes, the incidence trends estimated for histologic subtypes could be misleading.

Impact: The MI approach provides a valuable tool for bridging the different histology definitions, thus permitting meaningful inferences about the long-term trends of lung cancer by histologic subtype. Cancer Epidemiol Biomarkers Prev; 23(8); 1546–58. ©2014 AACR.

Background: Circulating adipokines may be associated with breast cancer risk. Genetic variants governing adipokines and adipokine receptors may also predict risk, but their effect on breast adipokine concentrations is unknown.

Methods: We conducted a cross-sectional analysis of functional SNPs in 5 adipokine genes [adiponectin, leptin (LEP), and their receptors] among 85 cancer-free women who were undergoing reduction mammoplasty.

Results: In multivariable-adjusted regression models, compared with the common GG genotype, the AA genotype of the LEP A19G SNP was associated with 27% lower plasma adiponectin [ratio, 0.73; 95% confidence interval (CI), 0.54–0.98] and leptin (ratio, 0.73; 95% CI, 0.55–0.96). Women with the AG genotype of LEP A19G had 39% lower breast leptin (ratio, 0.61; 95% CI, 0.39–0.97) compared with those with the GG genotype. No associations were observed for SNPs in the remaining genes.

Conclusions: Genetic variation in LEP may alter endogenous adipokine concentrations in circulation and in breast tissues.

Impact: These preliminary findings may support the hypothesis that genetic variation in adipokine genes modifies circulating adipokine concentrations and possibly leptin concentrations in local breast tissues, which may be associated with breast cancer risk. Cancer Epidemiol Biomarkers Prev; 23(8); 1559–68. ©2014 AACR.

Background: Oral cavity squamous cell carcinoma (OSCC) is one of the most common cancers worldwide, and its incidence is still increasing. Approximately 50% of patients with OSCC die within 5 years after diagnosis, mostly ascribed to the fact that the majority of patients present advanced stages of OSCC at the time of diagnosis.

Methods: To discover salivary biomarkers for ameliorating the detection of OSCC, herein, we developed a multiplexed bead-based platform to simultaneously detect auto-antibodies (auto-Abs) in salivary samples.

Results: Compared with healthy individuals, the salivary levels of anti-p53, anti-survivin, anti-Hsp60, and anti-RPLP0 were significantly elevated in patients with OSCC. Noteworthily, the elevated levels of anti-p53, anti-survivin, and anti-Hsp60 were already observed in individuals with oral potentially malignant disorder. Moreover, the salivary levels of anti-p53, anti-survivin, anti-Hsp60, anti-RPLP0, and anti-CK8 were significantly elevated in patients with early-stage OSCC compared with those in healthy individuals. Most importantly, the use of a combined panel of salivary anti-p53, anti-survivin, anti-Hsp60, and anti-RPLP0 largely improves the detection of OSCC.

Conclusion: Collectively, our results reveal that the salivary auto-Abs are effective OSCC biomarkers and the four-auto-Ab panel provides a novel and practicable approach for OSCC screening.

Impact: This study provides the first evidence for the potential clinical application of salivary auto-Abs in OSCC diagnosis. Cancer Epidemiol Biomarkers Prev; 23(8); 1569–78. ©2014 AACR.

Background: Germline genetic variants in PLCE1 (10q23) have demonstrated consistent associations with risk of esophageal squamous cell carcinoma (ESCC) and gastric cancer among Chinese. We evaluated PLCE1 mRNA and protein expression in paired tumor-normal tissues, and their relationship with survival.

Methods: PLCE1 mRNA was profiled using three probes in the Affymetrix GeneChip U133 for paired tumor-normal tissues of ESCC (n = 132), gastric cardia adenocarcinoma (GCA, n = 62), and gastric noncardia adenocarcinoma (GNCA, n = 72). We used immunohistochemistry to detect PLCE1 protein on slides from tissue microarrays in paired tumor-normal tissues of ESCC (n = 303), and tumors of GCA (n = 298) and GNCA (n = 124).

Results: Compared with normal tissues, PLCE1 mRNA expression was significantly reduced in ESCC tumors (P = 0.03, probe_205112_at), as well as in GCA and GNCA tumors (P < 0.0001, each probe). Protein expression was nonsignificantly reduced in ESCC tumors (P = 0.51). Increased tumor-normal mRNA fold change (probe_205112_at) was associated with longer survival in ESCC (9.6 months for highest vs. lowest quartile; Ptrend = 0.02). Increased mRNA tumor-normal fold change (probe_205111_at) was associated with longer survival for GCA (10.7 months for highest quartile; Ptrend = 0.04), but not for GNCA cases (P = 0.72). Similar to mRNA, elevated tumor-normal fold change for protein in ESCC was also associated with improved survival (8.1 months for highest quartile; Ptrend = 0.04).

Conclusions: Dysregulated PLCE1 mRNA expression was observed for both ESCC (one probe only) and GCA tumors, and the altered PLCE1 expression seems to be associated with cancer prognosis.

Impact: A potential role for PLCE1 in the early detection and/or therapy of ESCC and GCA warrants further investigation. Cancer Epidemiol Biomarkers Prev; 23(8); 1579–88. ©2014 AACR.

Background: Research on the association between antihypertensive drug treatment (HTDT) and cancer is equivocal. We tested the hypothesis that large, rapid decreases in blood pressure following HTDT are associated with higher cancer mortality.

Methods: Data from the Systolic Hypertension in the Elderly Program (SHEP) with 15-year cause-specific follow-up for mortality were used. We used changes from baseline in seated and standing systolic blood pressure (SBP) measurements at 3, 6, 9, and 12 months after the initiation of HTDT. Hazard ratios adjusted for demographics, comorbidities, and competing risk of non–cancer-related deaths were estimated to determine the association between SBP change, as a continuous or time-dependent measure, and cancer-related death.

Results: SHEP participants taking antihypertensive medication who exhibited a decrease in seated SBP of 29 mm Hg or more (50th percentile and above) at 3 months were at a 58% greater risk of cancer-related death during a 15-year follow-up compared with those with no decrease in SBP (P = 0.007, 42% increased risk P = 0.02 for standing SBP). Those participants whose maximal seated SBP change occurred in the first 3 months of treatment had 2.6-times greater risk of cancer mortality compared with those whose maximal seated SBP change occurred at 12 months (P = 0.004).

Conclusions: Large SBP decreases early in HTDT were associated with an increased risk of cancer-related death during a 15-year follow-up. Further studies are needed to confirm and explore the potential mechanisms for this association.

Impact: Rapid decreases in blood pressure following HTDT may be a risk factor for cancer. Cancer Epidemiol Biomarkers Prev; 23(8); 1589–97. ©2014 AACR.

Background: With over 13 million cancer survivors in the United States today, second cancers are of rapidly growing importance. However, data on nontreatment risk factors for second cancers are sparse. We explored the feasibility of pooling data from cohort studies of cancer incidence to investigate second cancer etiology.

Methods: We combined data from five prospective studies including more than 800,000 individuals. We compared study designs and populations; evaluated availability of and ability to harmonize risk factor data; compared incidence and survival for common first primary malignancies and incidence of second primary malignancies; and estimated sample size requirements.

Results: Overall, 96,513 incident, first primary malignancies were diagnosed during 1985 to 2009. Incidence rates and survival following the first primary varied among the cohorts, but most of the heterogeneity could be explained by characteristics of the study populations (age, sex, smoking, and screening rates). A total of 7,890 second primary cancers (excluding original primary site) were identified, yielding sufficient statistical power (≥80%) for detecting modest associations with risk of all second cancers among survivors of common first primary malignancies (e.g., colorectal cancer); however, there were insufficient events for studying survivors of rarer cancers or identifying risk factors for specific second cancers.

Conclusions: Pooling data from cohort studies to investigate nontreatment risk factors for second primary cancers seems feasible but there are important methodologic issues—some of which are barriers to specific research questions—that require special attention.

Impact: Increased understanding of nontreatment risk factors for second cancers will provide valuable prevention and surveillance information. Cancer Epidemiol Biomarkers Prev; 23(8); 1598–608. ©2014 AACR.

Background: Chronic inflammation has been associated with colorectal cancer. Prediagnostic levels of C-reactive protein (CRP), a highly sensitive marker of inflammation, have been weakly associated with increased colorectal cancer incidence, but few data are available examining its relationship with colorectal cancer mortality.

Methods: In the Third National Health and Nutrition Examination Survey (NHANES III), 65% of the 15,924 adult participants had CRP levels ≤0.21 mg/dL. Using this as the reference group, we calculated hazard ratios (HR) for higher CRP categories and colorectal cancer mortality, and compared them with HRs for other mortality causes.

Results: Over a median follow-up period of 14.2 years, there were 92 deaths from colorectal cancer. Compared with the reference group, multivariable adjusted HRs for colorectal cancer mortality were 2.66 [95% confidence interval (CI), 1.36–5.20] for CRP levels 0.22–0.50 mg/dL; 3.40 (95% CI, 1.48–7.77) for levels 0.51–1.00 mg/dL; and 3.96 (95% CI, 1.64–9.52) for levels >1.00 mg/dL. Estimates for colorectal cancer mortality did not change appreciably after excluding deaths within the first 3 years or by limiting follow-up to 5 or 10 years.

Conclusions: In a large representative study of U.S. adults, we observed strong dose–response associations between CRP levels and colorectal cancer mortality.

Impact: Further evaluation of CRP may help identify high-risk groups for colorectal cancer screening and those who might benefit most from prophylactic anti-inflammatory therapy. Cancer Epidemiol Biomarkers Prev; 23(8); 1609–18. ©2014 AACR.

Background: We aimed to identify demographic and health-related predictors of declining physical activity levels over a four-year period among participants in the Childhood Cancer Survivor Study.

Methods: Analyses included 7,287 ≥5-year childhood cancer survivors and 2,107 siblings who completed multiple follow-up questionnaires. Participants were classified as active if they met the Centers for Disease Control and Prevention guidelines for physical activity. Generalized linear models were used to compare participants whose physical activity levels declined from active to inactive over the study to those who remained active. In addition, selected chronic conditions (CTCAE v4.03 Grade 3 and 4) were evaluated as risk factors in an analysis limited to survivors only.

Results: The median age at last follow-up among survivors and siblings was 36 (range, 21–58) and 38 (range, 21–62) years, respectively. The rate of decline did not accelerate over time among survivors when compared with siblings. Factors that predicted declining activity included body mass index ≥30 kg/m2 [RR = 1.32; 95% confidence interval (CI), 1.19–1.46, P < 0.01], not completing high school (RR = 1.31; 95% CI, 1.08–1.60, P < 0.01), and female sex (RR = 1.33; 95% CI, 1.22–1.44, P < 0.01). Declining physical activity levels were associated with the presence of chronic musculoskeletal conditions (P = 0.034), but not with the presence of cardiac (P = 0.10), respiratory (P = 0.92), or neurologic conditions (P = 0.21).

Conclusions: Interventions designed to maximize physical activity should target female, obese, and less educated survivors. Survivors with chronic musculoskeletal conditions should be monitored, counseled, and/or referred for physical therapy.

Impact: Clinicians should be aware of low activity levels among subpopulations of childhood cancer survivors, which may heighten their risk for chronic illness. Cancer Epidemiol Biomarkers Prev; 23(8); 1619–27. ©2014 AACR.

Background: Despite accumulating evidence for the preventive effect of vitamin D on colorectal carcinogenesis, its precise mechanisms remain unclear. We hypothesized that vitamin D was associated with a lower risk of colorectal cancer with high-level vitamin D receptor (VDR) expression, but not with risk of tumor with low-level VDR expression.

Methods: Among 140,418 participants followed from 1986 through 2008 in the Nurses' Health Study and the Health Professionals' Follow-up Study, we identified 1,059 incident colorectal cancer cases with tumor molecular data. The predicted 25-hydroxyvitamin D [25(OH)D] score was developed using the known determinants of plasma 25(OH)D. We estimated the HR for cancer subtypes using the duplication method Cox proportional hazards model.

Results: A higher predicted 25(OH)D score was associated with a lower risk of colorectal cancer irrespective of VDR expression level (Pheterogeneity for subtypes = 0.75). Multivariate HRs (95% confidence intervals) comparing the highest with the lowest quintile of predicted 25(OH)D scores were 0.48 (0.30–0.78) for VDR-negative tumor and 0.56 (0.42–0.75) for VDR-positive tumor. Similarly, the significant inverse associations of the predicted 25(OH)D score with colorectal cancer risk did not significantly differ by KRAS, BRAF, or PIK3CA status (Pheterogeneity for subtypes ≥ 0.22).

Conclusions: A higher predicted vitamin D score was significantly associated with a lower colorectal cancer risk, regardless of VDR status and other molecular features examined.

Impact: The preventive effect of vitamin D on colorectal carcinogenesis may not totally depend on tumor factors. Host factors (such as local and systemic immunity) may need to be considered. Cancer Epidemiol Biomarkers Prev; 23(8); 1628–37. ©2014 AACR.

Background: The Prostate Cancer Prevention Trial (PCPT) was a 7-year randomized, double-blind, placebo-controlled trial of the efficacy of finasteride for the prevention of prostate cancer with a primary outcome of histologically determined prevalence of prostate cancer at the end of 7 years.

Methods: A systematic modeling process using logistic regression identified factors available at year 6 that are associated with end-of-study (EOS) biopsy adherence at year 7, stratified by whether participants were ever prompted for a prostate biopsy by year 6. Final models were evaluated for discrimination. At year 6, 13,590 men were available for analysis.

Results: Participants were more likely to have the EOS biopsy if they were adherent to study visit schedules and procedures and/or were in good health (P < 0.01). Participants at larger sites and/or sites that received retention and adherence grants were also more likely to have the EOS biopsy (P < 0.05).

Conclusions: Our results show good adherence to study requirements 1 year before the EOS biopsy was associated with greater odds that a participant would comply with the invasive EOS requirement.

Impact: Monitoring adherence behaviors may identify participants at risk of nonadherence to more demanding study end points. Such information could help frame adherence intervention strategies in future trials. Cancer Epidemiol Biomarkers Prev; 23(8); 1638–48. ©2014 AACR.

Background: Most health surveys ask women whether they have had a recent mammogram, all of which report mammography use (past 2 years) at about 70% to 80% regardless of race or residence. We examined the potential extent of overreporting of mammography use in low income African-American and Latina women, and whether self-report inaccuracies might bias estimated associations between patient characteristics and mammography use.

Methods: Using venue-based sampling in two poor communities on the west side of Chicago, we asked eligible women living in two west side communities of Chicago to complete a survey about breast health (n = 2,200) and to provide consent to view their medical record. Of the 1,909 women who screened eligible for medical record review, 1,566 consented (82%). We obtained medical records of all women who provided both permission and a valid local mammography facility (n = 1,221). We compared the self-reported responses from the survey with the imaging reports found in the medical record (documented). To account for missing data, we conducted multiple imputations for key demographic variables and report standard measures of accuracy.

Results: Although 73% of women self-reported a mammogram in the last 2 years, only 44% of self-reports were documented. Overreporting of mammography use was observed for all three ethnic groups.

Conclusions: These results suggest considerable overestimation of prevalence of use in these vulnerable populations.

Impact: Relying on known faulty self-reported mammography data as a measure of mammography use provides an overly optimistic picture of utilization, a problem that may be exacerbated in vulnerable minority communities. Cancer Epidemiol Biomarkers Prev; 23(8); 1649–58. ©2014 AACR.

Background: Obesity is considered a risk factor for hepatocellular carcinoma (HCC). The relationship between adipocytokine and HCC in hepatitis B virus (HBV) carriers remains unclear. We prospectively investigated the association of adiponectin, leptin, and visfatin levels with HCC.

Methods: We conducted a nested case–control study in a community-based cohort with 187 incident HCC and 374 HCC-free HBV carriers. Unconditional logistic regression was conducted to estimate the ORs and 95% confidence intervals (CI).

Results: Adiponectin, but not leptin and visfatin, levels were associated with an increased risk of HCC after adjustment for other metabolic factors and HBV-related factors. The risk was increased [OR = 0.51; 95% CI, 0.12–2.11; OR = 4.88 (1.46–16.3); OR = 3.79 (1.10–13.0); OR = 4.13 (1.13–15.1) with each additional quintiles, respectively] with a significant dose–response trend (Ptrend = 0.003). HCC risk associated with higher adiponectin level was higher in HBV carriers with ultrasonographic fatty liver, genotype C infection, higher viral load, and with elevated alanine aminotransferase. Longitudinally, participants with higher adiponectin were less likely to achieve surface antigen of hepatitis B virus (HBsAg) seroclearance and more likely to have persistently higher HBV DNA. Eventually, they were more likely to develop liver cirrhosis [OR = 1.65 (0.62–4.39); OR = 3.85 (1.47–10.1); OR = 2.56 (0.96–6.84); OR = 3.76 (1.33–10.7) for the second, third, fourth, and fifth quintiles, respectively; Ptrend = 0.017] before HCC.

Conclusions: Elevated adiponectin levels were independently associated with an increased risk of HCC.

Impact: Adiponectin may play different roles in the virus-induced and metabolic-related liver diseases, but the underlying mechanism remains unknown. Cancer Epidemiol Biomarkers Prev; 23(8); 1659–71. ©2014 AACR.

Background: High fasting plasma proneurotensin concentration was associated with the development of breast cancer in the Malmö Diet and Cancer Study (MDCS). Here, we aimed at replicating the initial finding in an independent second cohort.

Methods: The Malmö Preventive Project (MPP) is a population study and comprised 18,240 subjects when examined in 2002–2006. Of women without history of breast cancer at examination, we included all who developed breast cancer during follow-up (n = 130) until December 31, 2010, and a random sample of women without breast cancer until the end of follow-up (n = 1,439) for baseline plasma proneurotensin assessment (mean age, 70.0 ± 4.4 years). Proneurotensin was measured in fasting plasma samples and was related to the risk of later breast cancer development using multivariate logistic regression.

Results: Proneurotensin [odds ratio (OR) per standard deviation (SD) increment of LN-transformed proneurotensin] was significantly related to incident breast cancer [OR, 2.09; 95% confidence interval (CI), 1.79–2.44; P < 0.001; adjusted for age, body mass index (BMI), smoking, and hormone replacement therapy]. The effect estimate in the MPP was larger than in the discovery cohort (MDCS), with the main difference between the two cohorts being that women of the MPP study were on the average about 10 years older and follow-up time was shorter than that of the MDCS.

Conclusion: As initially found in the MDCS, fasting plasma proneurotensin was significantly associated with the development of breast cancer in the MPP study as well.

Impact: Measurement of plasma proneurotensin warrants further investigation as a blood-based marker for early breast cancer detection. Cancer Epidemiol Biomarkers Prev; 23(8); 1672–6. ©2014 AACR.

Evaluation of prostate cancer prognosis after surgery is increasingly relying upon genomic analyses of tumor DNA. We assessed the ability of the biomarker panel Genomic Evaluators of Metastatic Prostate Cancer (GEMCaP) to predict biochemical recurrence in 33 European American and 28 African American prostate cancer cases using genome-wide copy number data from a previous study. "Biomarker positive" was defined as ≥20% of the 38 constituent copy number gain/loss GEMCaP loci affected in a given tumor; based on this threshold, the frequency of a positive biomarker was significantly lower in African Americans (n = 2; 7%) than European Americans (n = 11; 33%; P = 0.013). GEMCaP positivity was associated with risk of recurrence [hazard ratio (HR), 5.92; 95% confidence interval (CI), 2.32–15.11; P = 3 x 10–4] in the full sample and among European Americans (HR, 3.45; 95% CI, 1.13–10.51; P = 0.032) but was not estimable in African Americans due to the low rate of GEMCaP positivity. Overall, the GEMCaP recurrence positive predictive value (PPV) was 85%; in African Americans, PPV was 100%. When we expanded the definition of loss to include copy-neutral loss of heterozygosity (i.e., loss of one allele with concomitant duplication of the other), recurrence PPV was 83% for European American subjects. Under this definition, 5 African American subjects had a positive GEMCaP test value; 4 went on to develop biochemical recurrence (PPV = 80%). Our results suggest that the GEMCaP biomarker set could be an effective predictor for both European American and African American men diagnosed with localized prostate cancer who may benefit from immediate aggressive therapy after radical prostatectomy. Cancer Epidemiol Biomarkers Prev; 23(8); 1677–82. ©2014 AACR.

Understanding how interventions affect time to completion of colorectal cancer screening might assist in planning and delivering population-based screening interventions. The Systems of Support to Increase Colorectal Cancer Screening (SOS) study was conducted between 2008 and 2011 at 21 primary care medical centers in Western Washington. Participants in the study, ages 50 to 73 years, were eligible if they were enrolled in Group Health (Seattle, WA) and were due for colorectal cancer screening. Of note, 4,675 recruited participants were randomized to usual care or one of three interventions with incremental levels of systems of support for completion of colorectal cancer screening. We conducted time to screening analyses of the SOS data in years 1 and 2. We investigated whether these effects were time-varying. For year 1, the intervention effects on the time to completion of colorectal cancer screening were the strongest during the first two post-randomization months and then decreased, with no significant effect after the fifth month. For year 2, the intervention effects on the time to colorectal cancer screening increased from the first to the third month and then decreased, with no significant effect after the fifth month. Hence, each of the interventions to increase colorectal cancer screening had its greatest effect within the first 3 months after being offered to participants. Future studies should test whether booster interventions offered later could increase screening rate among those who remain unscreened. Additional research is needed to develop intervention strategies for colorectal cancer screening that focus on sustained behavior over time. Cancer Epidemiol Biomarkers Prev; 23(8); 1683–8. ©2014 AACR.

The recent release of version 2.0-8 of the BayesMendel package contains an updated BRCAPRO risk prediction model, which includes revised modeling of contralateral breast cancer (CBC) penetrance, provisions for pedigrees of mixed ethnicity and an adjustment for mastectomies among family members. We estimated penetrance functions for CBC by a combination of parametric survival modeling of literature data and deconvolution of SEER9 data. We then validated the resulting updated model of CBC in BRCAPRO by comparing it with the previous release (BayesMendel 2.0-7), using pedigrees from the Cancer Genetics Network (CGN) Model Validation Study. Version 2.0-8 of BRCAPRO discriminates BRCA1/BRCA2 carriers from noncarriers with similar accuracy compared with the previous version (increase in AUC, 0.0043), is slightly more precise in terms of the root-mean-square error (decrease in RMSE, 0.0108), and it significantly improves calibration (ratio of observed to expected events of 0.9765 in version 2.0-8, compared with 0.8910 in version 2.0-7). We recommend that the new version be used in clinical counseling, particularly in settings where families with CBC are common. Cancer Epidemiol Biomarkers Prev; 23(8); 1689–95. ©2014 AACR.

Background: The inverse association between physical activity and cancer risk may be mediated by higher melatonin levels. However, few studies have examined the effect of increased physical activity on melatonin levels.

Methods: The parent study was a randomized controlled trial that randomized 51 men and 49 women to a 12-month moderate-to-vigorous aerobic exercise intervention ("exercisers") and 51 men and 51 women to a stretching control ("controls"). Participants were of ages 40 to 75 years, and previously sedentary. Levels of the principal urinary metabolite of melatonin, 6-sulfatoxymelatonin (aMT6s), corrected for creatinine levels, were measured in spot morning urine samples by immunoassay at baseline and 12 months. Changes in levels between exercisers and controls were compared using generalized estimating equations for linear regression.

Results: We observed no statistically significant difference in the change in aMT6s levels from baseline to 12 months in exercisers compared with controls (change in aMT6s levels: exercisers, +6.5%; controls, +13%; P = 0.66). There was no evidence of effect modification by age, sex, or body mass index.

Conclusions: A 12-month moderate-intensity exercise intervention did not affect levels of aMT6s.

Impact: Further research needs to focus on other potential mechanisms through which physical activity may reduce the risk of cancer. Cancer Epidemiol Biomarkers Prev; 23(8); 1696–9. ©2014 AACR.

Background: Individuals with a family history of colorectal cancer in first-degree relatives have an elevated risk of developing colorectal cancer themselves, particularly colorectal cancer exhibiting high microsatellite instability (MSI-high). Given that MSI-high colorectal cancer is associated with a favorable prognosis, it is plausible that having a family history of colorectal cancer could, in turn, be favorably associated with colorectal cancer survival.

Methods: This study comprised N = 4,284 incident colorectal cancer cases enrolled in the Colon Cancer Family Registry via population-based cancer registries. Using Cox proportional hazards regression, we evaluated the association between family history and both overall and disease-specific survival, accounting for MSI status and tumor site via stratified analyses and statistical adjustment.

Results: There was no evidence of association between family history and overall [hazard ratio (HR), 0.92; 95% confidence interval (CI), 0.79–1.08] or disease-specific survival (HR, 1.03; 95% CI, 0.85–1.24) for all cases combined, after adjustment for MSI status or tumor site. Only for rectal cancer cases was colorectal cancer family history modestly associated with more favorable overall survival (HR, 0.75; 95% CI, 0.56–0.99).

Conclusions: Although individuals with a family history of colorectal cancer were more likely to have MSI-high tumors than those with nonfamilial disease, this did not translate to a survival benefit.

Impact: Overall, there is no evidence that family history of colorectal cancer is associated with colorectal cancer survival; however, specific mechanisms underlying family history may have prognostic impact and merit further study. Cancer Epidemiol Biomarkers Prev; 23(8); 1700–4. ©2014 AACR.