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Cancer Epidemiology Biomarkers & Prevention

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Cancer Epidemiology Biomarkers & Prevention

Consideration is given to the idea that the nutritional epidemiology of cancer is dead, as some in the media have claimed. The basis for the claim does not lie in science nor has anyone with relevant knowledge made such a statement—although that, too, has been claimed. Evidence is adduced for the importance of past achievements of nutritional epidemiology. Attention is similarly drawn to recent contributions. In particular, I note the state of play of cancer and plant foods, fat and breast cancer, meat and cancer, vegetarians, intervention studies, migrant studies, and westernization of diet and lifestyle. Some next steps and some currently important questions are outlined. Cancer Epidemiol Biomarkers Prev; 24(2); 323–30. ©2014 AACR.

Background: The reduction of the nicotine content of cigarettes to nonaddicting levels is a potential federal regulatory intervention to reduce the prevalence of cigarette smoking and related disease. Many clinical trials on the effects and safety of nicotine reduction are ongoing. An important methodologic concern is noncompliance with reduced nicotine content cigarettes in the context of freely available conventional cigarettes. We propose two approaches using biomarkers to estimate noncompliance in smokers of very low nicotine content (VLNC) cigarettes in a clinical trial.

Methods: Data from 50 subjects in a study of gradual nicotine reduction were analyzed. Using plasma cotinine concentrations measured at baseline and while smoking VLNC cigarettes, we compared within-subject ratios of plasma cotinine comparing usual brand to VLNC in relation to nicotine content of these cigarettes. In another approach, we used nicotine pharmacokinetic data to estimate absolute plasma cotinine/cigarettes per day (CPD) threshold values for compliance based on the nicotine content of VLNC.

Results: The two approaches showed concordance, indicating at least 60% noncompliance with smoking VLNC. In a sensitivity analysis assuming extreme compensation and extreme values for nicotine metabolic parameters, noncompliance was still at least 40%, much higher than self-reported noncompliance.

Conclusion: Biomarker analysis demonstrates a high degree of noncompliance with smoking VLNC cigarettes, indicating that smokers are supplementing these with conventional cigarettes.

Impact: We propose a practical approach to assessing compliance with smoking VLNC in clinical trials of nicotine reduction. Cancer Epidemiol Biomarkers Prev; 24(2); 331–5. ©2014 AACR.

Background: Depression is associated with an increased risk of mortality in patients with cancer; it has been hypothesized that depression-associated alterations in cell aging mechanisms, in particular, the telomere/telomerase maintenance system, may underlie this increased risk. We evaluated the association of depressive symptoms and telomere length to mortality and recurrence/progression in 464 patients with bladder cancer.

Methods: We used the Center for Epidemiologic Studies Depression Scale (CES-D) and Structured Clinical Interview for DSM-IV Disorder (SCID) to assess current depressive symptoms and lifetime major depressive disorder (MDD), respectively, and telomere length was assessed from peripheral blood lymphocytes. Multivariate Cox regression was used to assess the association of depression and telomere length to outcomes and the joint effect of both. Kaplan–Meier plots and log-rank tests were used to compare survival time of subgroups by depression variables and telomere length.

Results: Patients with depressive symptoms (CES-D ≥ 16) had a 1.83-fold [95% confidence interval (CI), 1.08–3.08; P = 0.024] increased risk of mortality compared with patients without depressive symptoms (CES-D < 16) and shorter disease-free survival time (P = 0.004). Patients with both depressive symptoms and lifetime history of MDD were at 4.88-fold (95% CI, 1.40–16.99; P = 0.013) increased risk compared with patients with neither condition. Compared to patients without depressive symptoms and long telomere length, patients with depressive symptoms and short telomeres exhibited a 4-fold increased risk of mortality (HR, 3.96; 95% CI, 1.86–8.41; P = 0.0003) and significantly shorter disease-free survival time (P < 0.001).

Conclusion: Short telomere length and depressive symptoms are associated with bladder cancer mortality individually and jointly.

Impact: Further investigation of interventions that impact depression and telomere length may be warranted in patients with cancer. Cancer Epidemiol Biomarkers Prev; 24(2); 336–43. ©2014 AACR.

Background: We previously demonstrated disparate acute myelogenous leukemia (AML) survival for black and Hispanic patients; these differences persisted despite younger ages and higher prevalence of favorable cytogenetics in these groups. This study determined: (i) whether there are differences in treatment delivered to minorities, and (ii) how these differences affect outcomes in AML. We hypothesize that differences in treatment explain some proportion of survival disparities.

Methods: We used California Cancer Registry data linked to hospital discharge abstracts for patients with AML (1998–2008). Logistic regression models estimated odds of treatment (chemotherapy and/or hematopoietic stem cell transplant) by race/ethnicity. Cox proportional hazard models estimated mortality by race after adjustment for treatment.

Results: We analyzed 11,084 records. Black race was associated with lower odds of chemotherapy [OR, 0.74; 95% confidence interval (CI), 0.61–0.91]. Black and Hispanic patients had decreased odds of transplant [(OR, 0.64; 95% CI, 0.46–0.87); (OR, 0.74; 95% CI, 0.62–0.89), respectively]. Black patients had increased hazard of mortality (HR, 1.14; 95% CI, 1.04–1.25) compared with whites. Adjustment for receipt of any treatment resulted in decreased mortality (HR, 1.09; 95% CI, 1.00–1.20) for black patients.

Conclusions: AML treatment differences for black patients explain some proportion of the disparity. Future AML disparities studies should investigate socioeconomic and other characteristics.

Impact: Study findings may better elucidate drivers of disparities in AML. Cancer Epidemiol Biomarkers Prev; 24(2); 344–9. ©2015 AACR.

Background: Serum biomarkers for diagnosis and risk stratification of childhood solid tumors would improve the accuracy/timeliness of diagnosis and reduce the need for invasive biopsies. We hypothesized that differential expression and/or release of microRNAs (miRNAs) by such tumors may be detected as altered serum miRNA profiles.

Methods: We undertook global quantitative reverse transcription PCR (qRT-PCR) miRNA profiling (n = 741) on RNA from 53 serum samples, representing 33 diagnostic cases of common childhood cancers plus 20 controls. Technical confirmation was performed in a subset of 21 cases, plus four independent samples.

Results: We incorporated robust quality control steps for RNA extraction, qRT-PCR efficiency and hemolysis quantification. We evaluated multiple methods to normalize global profiling data and identified the ‘global mean’ approach as optimal. We generated a panel of six miRNAs that were most stable in pediatric serum samples and therefore most suitable for normalization of targeted miRNA qRT-PCR data. Tumor-specific serum miRNA profiles were identified for each tumor type and selected miRNAs underwent confirmatory testing. We identified a panel of miRNAs (miR-124-3p/miR-9-3p/miR-218-5p/miR-490-5p/miR-1538) of potential importance in the clinical management of neuroblastoma, as they were consistently highly overexpressed in MYCN-amplified high-risk cases (MYCN-NB). We also derived candidate miRNA panels for noninvasive differential diagnosis of a liver mass (hepatoblastoma vs. combined MYCN-NB/NB), an abdominal mass (Wilms tumor vs. combined MYCN-NB/NB), and sarcoma subtypes.

Conclusions: This study describes a pipeline for robust diagnostic serum miRNA profiling in childhood solid tumors, and has identified candidate miRNA profiles for prospective testing.

Impact: We propose a new noninvasive method with the potential to diagnose childhood solid tumors. Cancer Epidemiol Biomarkers Prev; 24(2); 350–60. ©2014 AACR.

Background: The role of comorbidities in survival of patients with breast cancer has not been well studied, particularly in non-white populations.

Methods: We investigated the association of specific comorbidities with mortality in a multiethnic cohort of 8,952 breast cancer cases within the California Breast Cancer Survivorship Consortium (CBCSC), which pooled questionnaire and cancer registry data from five California-based studies. In total, 2,187 deaths (1,122 from breast cancer) were observed through December 31, 2010. Using multivariable Cox proportional hazards regression, we estimated HRs and 95% confidence intervals (CI) for overall and breast cancer–specific mortality associated with previous cancer, diabetes, high blood pressure (HBP), and myocardial infarction.

Results: Risk of breast cancer–specific mortality increased among breast cancer cases with a history of diabetes (HR, 1.48; 95% CI, 1.18–1.87) or myocardial infarction (HR, 1.94; 95% CI, 1.27–2.97). Risk patterns were similar across race/ethnicity (non-Latina white, Latina, African American, and Asian American), body size, menopausal status, and stage at diagnosis. In subgroup analyses, risk of breast cancer–specific mortality was significantly elevated among cases with diabetes who received neither radiotherapy nor chemotherapy (HR, 2.11; 95% CI, 1.32–3.36); no increased risk was observed among those who received both treatments (HR, 1.13; 95% CI, 0.70–1.84; Pinteraction = 0.03). A similar pattern was found for myocardial infarction by radiotherapy and chemotherapy (Pinteraction = 0.09).

Conclusion: These results may inform future treatment guidelines for patients with breast cancer with a history of diabetes or myocardial infarction.

Impact: Given the growing number of breast cancer survivors worldwide, we need to better understand how comorbidities may adversely affect treatment decisions and ultimately outcome. Cancer Epidemiol Biomarkers Prev; 24(2); 361–8. ©2014 AACR.

Background: Breast density is a strong risk factor for breast cancer and reflects epithelial and stromal content. Breast tissue is particularly sensitive to hormonal stimuli before it fully differentiates following the first full-term pregnancy. Few studies have examined associations between sex hormones and breast density among young women.

Methods: We conducted a cross-sectional study among 180 women ages 25 to 29 years old who participated in the Dietary Intervention Study in Children 2006 Follow-up Study. Eighty-five percent of participants attended a clinic visit during their luteal phase of menstrual cycle. Magnetic resonance imaging measured the percentage of dense breast volume (%DBV), absolute dense breast volume (ADBV), and absolute nondense breast volume (ANDBV). Multiple-linear mixed-effect regression models were used to evaluate the association of sex hormones and sex hormone–binding globulin (SHBG) with %DBV, ADBV, and ANDBV.

Results: Testosterone was significantly positively associated with %DBV and ADBV. The multivariable geometric mean of %DBV and ADBV across testosterone quartiles increased from 16.5% to 20.3% and from 68.6 to 82.3 cm3, respectively (Ptrend ≤ 0.03). There was no association of %DBV or ADBV with estrogens, progesterone, non–SHBG-bound testosterone, or SHBG (Ptrend ≥ 0.27). Neither sex hormones nor SHBG was associated with ANDBV except progesterone; however, the progesterone result was nonsignificant in analysis restricted to women in the luteal phase.

Conclusions: These findings suggest a modest positive association between testosterone and breast density in young women.

Impact: Hormonal influences at critical periods may contribute to morphologic differences in the breast associated with breast cancer risk later in life. Cancer Epidemiol Biomarkers Prev; 24(2); 369–78. ©2014 AACR.

Background: Although many Latinos in the United States smoke, they receive assistance to quit less often than non-Latinos. To address this disparity, we recruited Latino couples into a randomized controlled trial and provided a smoking cessation program during a teachable moment, when men's partners were pregnant.

Methods: We compared two interventions: (i) written materials plus nicotine replacement therapy (NRT) to (ii) materials, NRT, and couple-based counseling that addressed smoking cessation and couples communication. We recruited 348 expectant fathers who smoked via their pregnant partners from county health departments. Our primary outcome was 7-day point prevalence smoking abstinence and was collected from November 2010 through April 2013 and analyzed in February 2014.

Results: We found high rates of cessation but no arm differences in smoking rates at the end of pregnancy (0.31 vs. 0.30, materials only vs. counseling, respectively) and 12 months after randomization (postpartum: 0.39 vs. 0.38). We found high quit rates among nondaily smokers but no arm differences (0.43 vs. 0.46 in pregnancy and 0.52 vs. 0.48 postpartum). Among daily smokers, we found lower quit rates with no arm differences but effects favoring the intervention arm (0.13 vs. 0.16 in pregnancy and 0.17 vs. 0.24 postpartum).

Conclusions: A less intensive intervention promoted cessation equal to more intensive counseling. Postpartum might be a more powerful time to promote cessation among Latino men.

Impact: Less intensive interventions when delivered during teachable moments for Latino men could result in a high smoking cessation rate and could reduce disparities. Cancer Epidemiol Biomarkers Prev; 24(2); 379–85. ©2014 AACR.

Background: C-reactive protein (CRP) is a marker of systemic inflammation that has been associated with the incidence and prognosis for a number of different cancers. Recent data suggest that CRP may be a prognostic factor for liver cancer and cirrhosis. However, few long-term studies are available.

Methods: We prospectively examined associations between serum CRP and subsequent risk of liver cancer incidence or chronic liver disease mortality in a nested case–control study performed in the Linxian Nutrition Intervention Trials cohort. Baseline serum CRP was measured for 220 incident liver cancer cases, 276 participants who died of chronic liver disease, and 1,018 age-, sex-, and trial-matched controls. Unconditional logistical regression models were used to estimate ORs and 95% confidence intervals (CI).

Results: Compared with the lowest quartile, subjects in the fourth quartile of serum CRP had a higher risk of liver cancer incidence (OR, 1.63; 95% CI, 1.06–2.51), with a significant Ptrend across quartiles (P = 0.01). The association with liver cancer was only significant among men (Q4 vs. Q1; OR, 2.00; 1.10–3.62), but not among women (Q4 vs. Q1; OR, 1.15; 0.60–2.22). For chronic liver disease deaths, the corresponding risk estimate in men and women was 2.95 (1.90–4.57), with a monotonic trend (P < 0.001).

Conclusions: Higher serum CRP concentrations at baseline were associated with subsequent incidence of liver cancer and death from chronic liver disease.

Impact: Our findings suggest that levels of systemic inflammation may serve as a long-term marker of liver cancer and liver disease. Cancer Epidemiol Biomarkers Prev; 24(2); 386–92. ©2015 AACR.

Background: Two currently available vaccines targeting human papillomavirus (HPV) types 16 and 18 could prevent 70% of cervical cancers and 50% of high-grade cervical lesions. Next-generation vaccines against additional types, such as a candidate 9-valent vaccine against HPV6/11/16/18/31/33/45/52/58, could further reduce HPV-associated disease burden.

Methods: HPV was typed in archived tissues from women ages 21 to 39 years residing in five catchment areas in the United States with cervical intraepithelial neoplasia 2/3 and adenocarcinoma in situ (CIN2+) using L1 consensus PCR and type-specific hybridization. Type attribution was estimated using weights to account for lesions with multiple types detected.

Results: From 2008 to 2011, 5,498 of 6,306 (87.2%) specimens obtained from 8,469 women with CIN2+ had valid typing results; HPV DNA was detected in 97.3%. Overall, 50.1% of lesions were attributable to HPV16/18, ranging from 50.3% to 52.4% among those ages 21 to 34 years, and significantly declined in 35 to 39 year-olds (43.5%). HPV16/18 attribution was higher in non-Hispanic whites (56.4%) versus racial/ethnic minorities (range, 41.8%–45.9%; P < 0.001). HPV31/33/45/52/58 attribution was 25.0% overall and increased with age (P < 0.001). A higher proportion of CIN2+ was attributable to HPV31/33/45/52/58 in non-Hispanic black (29.9%), Hispanic (29.2%), and Asian (33.1%) women compared with non-Hispanic whites (22.8%; P < 0.001).

Conclusions: Overall, 75% of lesions were attributable to 7 oncogenic HPV types: 50% to HPV16/18 and 25% to HPV31/33/45/52/58. HPV16/18 had the largest attributable fraction in CIN2+ across all subpopulations, although to a lesser extent in older women and racial/ethnic minorities.

Impact: Vaccines targeting additional oncogenic HPV types could prevent more high-grade cervical lesions, especially among racial/ethnic minorities. Cancer Epidemiol Biomarkers Prev; 24(2); 393–9. ©2014 AACR.

Background: Cancer fear has been associated with higher and lower screening uptake across different studies, possibly because different aspects of cancer fear have different effects on intentions versus behavior. The present study examined associations of three aspects of cancer fear with intention and uptake of endoscopic screening for colorectal cancer.

Methods: A subsample of UK Flexible Sigmoidoscopy (FS) Trial participants received a baseline questionnaire that included three cancer fear items from a standard measure asking if: (i) cancer was feared more than other diseases, (ii) cancer worry was experienced frequently, and (iii) thoughts about cancer caused discomfort. Screening intention was assessed by asking participants whether, if invited, they would accept an invitation for FS screening. Positive responders were randomized to be invited or not in a 1:2 ratio. The behavioral outcome was clinic-recorded uptake. Control variables were age, gender, ethnicity, education, and marital status.

Results: The questionnaire return rate was 60% (7,971/13,351). The majority (82%) intended to attend screening; 1,920 were randomized to receive an invitation, and 71% attended. Fearing cancer more than other diseases (OR = 2.32, P < 0.01) and worrying a lot about cancer (OR = 2.34, P < 0.01) increased intentions to attend screening, but not uptake. Finding thoughts about cancer uncomfortable did not influence intention, but predicted lower uptake (OR = 0.72, P < 0.01).

Conclusions: Different aspects of cancer fear have different effects on the decision and action processes leading to screening participation.

Impact: Knowledge of the different behavioral effects of cancer fear may aid the design of effective public health messages. Cancer Epidemiol Biomarkers Prev; 24(2); 400–5. ©2015 AACR.

Introduction: Overall survival of early-stage breast cancer patients is similar for those who undergo breast-conserving therapy (BCT) and mastectomy; however, 10% to 15% of women undergoing BCT suffer ipsilateral breast tumor recurrence. The risk of recurrence may vary with breast cancer subtype. Understanding the gene expression of the cancer-adjacent tissue and the stromal response to specific tumor subtypes is important for developing clinical strategies to reduce recurrence risk.

Methods: We utilized two independent datasets to study gene expression data in cancer-adjacent tissue from invasive breast cancer patients. Complementary in vitro cocultures were used to study cell–cell communication between fibroblasts and specific breast cancer subtypes.

Results: Our results suggest that intrinsic tumor subtypes are reflected in histologically normal cancer-adjacent tissue. Gene expression of cancer-adjacent tissues shows that triple-negative (Claudin-low or basal-like) tumors exhibit increased expression of genes involved in inflammation and immune response. Although such changes could reflect distinct immune populations present in the microenvironment, altered immune response gene expression was also observed in cocultures in the absence of immune cell infiltrates, emphasizing that these inflammatory mediators are secreted by breast-specific cells. In addition, although triple-negative breast cancers are associated with upregulated immune response genes, luminal breast cancers are more commonly associated with estrogen-response pathways in adjacent tissues.

Conclusions: Specific characteristics of breast cancers are reflected in the surrounding histologically normal tissue. This commonality between tumor and cancer-adjacent tissue may underlie second primaries and local recurrences.

Impact: Biomarkers derived from cancer-adjacent tissue may be helpful in defining personalized surgical strategies or in predicting recurrence risk. Cancer Epidemiol Biomarkers Prev; 24(2); 406–14. ©2014 AACR.

Background: Prevention and early detection measures for melanoma, such as sun avoidance and skin examinations, are important, but are practiced inconsistently. In this replication of the Project SCAPE trial, we sought to determine whether tailored print materials were more effective at improving adherence than generic print materials for patients at increased risk of skin cancer.

Methods: Participants were randomized to receive personalized mailed communications about their skin cancer risk and recommended sun protection, or generic mailings. Participants were Caucasian adults, at moderate or high risk for skin cancer, recruited in outpatient primary care. The main outcomes were overall sun protection behaviors and specific protective behaviors including use of sunscreen, shirt, hat, sunglasses, shade, and sun avoidance; recent sunburns; and skin self-examination and provider skin examination.

Results: One hundred ninety-two (93.2%) subjects completed the study. Six outcome variables showed significant intervention condition effects in mixed effects models: overall sun protection behavior (P = 0.025); sunscreen use (P = 0.026); use of sunglasses (P = 0.011); sunburns in the past three months (P = 0.033); recency of last skin self-exam (P = 0.017); and frequency of skin exams by health care provider (P = 0.016).

Conclusions: Relative to generic communications, tailored risk communications resulted in improved adherence to six skin cancer protective behaviors, including a composite sun protection behavior measure, sunburns, and health care provider skin examinations.

Impact: Tailored interventions can be more effective in improving patient prevention behaviors than nontailored, generic information for patients at moderate to high risk of skin cancer. Cancer Epidemiol Biomarkers Prev; 24(2); 415–21. ©2014 AACR.

Background: This study assessed the contribution of organizational structures and processes identified from facility surveys to follow-up for positive fecal occult blood tests [FOBT-positive (FOBT+)].

Methods: We identified 74,104 patients with FOBT+ results from 98 Veterans Health Administration (VHA) facilities between August 16, 2009 and March 20, 2011, and followed them until September 30, 2011, for completion of colonoscopy. We identified patient characteristics from VHA administrative records, and organizational factors from facility surveys completed by primary care and gastroenterology chiefs. We estimated predictors of colonoscopy completion within 60 days and six months using hierarchical logistic regression models.

Results: Thirty percent of patients with FOBT+ results received colonoscopy within 60 days and 49% within six months. Having gastroenterology or laboratory staff notify gastroenterology providers directly about FOBT+ cases was a significant predictor of 60-day [odds ratio (OR), 1.85; P = 0.01] and six-month follow-up (OR, 1.25; P = 0.008). Additional predictors of 60-day follow-up included adequacy of colonoscopy appointment availability (OR, 1.43; P = 0.01) and frequent individual feedback to primary care providers about FOBT+ referral timeliness (OR, 1.79; P = 0.04). Additional predictors of six-month follow-up included using guideline-concordant surveillance intervals for low-risk adenomas (OR, 1.57; P = 0.01) and using group appointments and combined verbal–written methods for colonoscopy preparation instruction (OR, 1.48; P = 0.0001).

Conclusion: Directly notifying gastroenterology providers about FOBT+ results, using guideline-concordant adenoma surveillance intervals, and using colonoscopy preparations instruction methods that provide both verbal and written information may increase overall follow-up rates. Enhancing follow-up within 60 days may require increased colonoscopy capacity and feedback to primary care providers.

Impact: These findings may inform organizational-level interventions to improve FOBT+ follow-up. Cancer Epidemiol Biomarkers Prev; 24(2); 422–34. ©2014 AACR.

Background: Many circulating biomarkers have been reported for the diagnosis of breast cancer, but few, if any, have undergone rigorous credentialing using prospective cohorts and blinded evaluation.

Methods: The NCI Early Detection Research Network (EDRN) has created a prospective, multicenter collection of plasma and serum samples from 832 subjects designed to evaluate circulating biomarkers for the detection and diagnosis of breast cancer. These samples are available to investigators who wish to evaluate their biomarkers using a set of blinded samples. The breast cancer reference set is composed of blood samples collected using a standard operating procedure at four U.S. medical centers from 2008 to 2010 from women undergoing either tissue diagnosis for breast cancer or routine screening mammography. The reference set contains samples from women with incident invasive cancer (n = 190), carcinoma in situ (n = 55), benign pathology with atypia (n = 63), benign disease with no atypia (n = 231), and women with no evidence of breast disease by screening mammography (BI-RADS 1 or 2, n = 276). Using a subset of plasma samples (n = 505) from the reference set, we analyzed 90 proteins by multiplexed immunoassays for their potential utility as diagnostic markers.

Results: We found that none of these markers is useful for distinguishing cancer from benign controls. However, elevated CA-125 does appear to be a candidate marker for estrogen receptor–negative cancers.

Conclusions: Markers that can distinguish benign breast conditions from invasive cancer have not yet been found.

Impact: Availability of prospectively collected samples should improve future validation efforts. Cancer Epidemiol Biomarkers Prev; 24(2); 435–41. ©2014 AACR.

Background: Genome-wide association studies have identified polymorphisms associated with breast cancer subtypes and across multiple population subgroups; however, few studies to date have applied linkage analysis to other population groups.

Methods: We performed the first genome-wide breast cancer linkage analysis in 106 African American families (comprising 179 affected and 79 unaffected members) not known to be segregating BRCA mutations to search for novel breast cancer loci. We performed regression-based model-free multipoint linkage analyses of the sibling pairs using SIBPAL, and two-level Haseman–Elston linkage analyses of affected relative pairs using RELPAL.

Results: We identified –log10 P values that exceed 4 on chromosomes 3q and 12q, as well as a region near BRCA1 on chromosome 17 (–log10 P values in the range of 3.0–3.2) using both sibling-based and relative-based methods; the latter observation may suggest that undetected BRCA1 mutations or other mutations nearby such as HOXB13 may be segregating in our sample.

Conclusions: In summary, these results suggest novel putative regions harboring risk alleles in African Americans that deserve further study.

Impact: We hope that our study will spur further family-based investigation into specific mechanisms for breast cancer disparities. Cancer Epidemiol Biomarkers Prev; 24(2); 442–7. ©2014 AACR.

Background: Blacks have a higher incidence of colorectal cancer and a younger age at diagnosis compared with whites. Few studies have investigated racial differences in risk of metachronous adenomas and serrated polyps and whether this risk differs by polyp characteristics or age of patient.

Methods: We analyzed data pooled from three placebo-controlled adenoma chemoprevention trials to explore racial differences in the risk of large bowel polyps in patients ≤50 and >50 years of age. Using generalized linear regression, we estimated risk ratios (RR) and 95% confidence intervals (CI) as measures of the association between race and risk of one or more adenomas or serrated polyps after randomization.

Results: Among the 2,605 subjects who completed at least one follow-up exam, blacks ≤50 years of age had a higher risk of any conventional adenoma (RR, 1.70; 95% CI, 0.99–2.92) and advanced neoplasms (RR, 4.05; 95% CI, 1.43–11.46) and a nonsignificantly lower risk of serrated polyps (RR, 0.75; 95% CI, 0.34–1.62) compared with whites. Among patients >50 years, there was no racial difference in risk of adenomas (RR, 1.08; 95% CI, 0.92–1.27) or advanced neoplasms (RR, 1.05; 95% CI, 0.71- 1.56). However, blacks had a significantly lower risk of serrated polyps (RR, 0.65; 95% CI, 0.49–0.87) than whites.

Conclusions: Our results demonstrate a higher risk of metachronous adenomas in blacks compared with whites at younger ages.

Impact: Our results suggest that the racial disparity in colorectal cancer incidence may be due to an excess of neoplasia in younger blacks. Cancer Epidemiol Biomarkers Prev; 24(2); 448–53. ©2014 AACR.

Background: Children with Down syndrome have unique immune profiles and increased leukemia susceptibility.

Methods: Mothers of 158 children with Down syndrome diagnosed with acute leukemia at 0 to 19 years in 1997 to 2002 and 173 children with Down syndrome but no leukemia were interviewed. Associations were evaluated via multivariable unconditional logistic regression.

Results: No associations were detected for asthma, eczema, allergies, or hypothyroidism. Diabetes mellitus associated with leukemia (OR = 9.23; 95% confidence interval 2.33–36.59); however, most instances occurred concurrent with or after the leukemia diagnosis.

Conclusions and Impact: Children with Down syndrome who develop leukemia have increased diabetes risk, likely due to treatment and underlying susceptibility factors. Cancer Epidemiol Biomarkers Prev; 24(2); 454–8. ©2014 AACR.

Background: C-reactive protein (CRP) has been associated with cancer risk in some prospective studies. However, the associations have not been entirely consistent and have not been evaluated in Chinese females. We conducted a large population-based cohort study to investigate whether elevated levels of CRP at baseline are associated with an increased risk of cancer among Chinese females.

Methods: A total of 19,437 women from the Chinese Kailuan Female Cohort were enrolled in the study in July 2006. Levels of high-sensitivity CRP (hsCRP) were tested at baseline for all subjects. Multivariable Cox proportional hazards regression models were used to evaluate the association between levels of hsCRP and risk of all cancers, including breast cancer, lung cancer, colorectal cancer, and other cancers.

Results: By December 31, 2011, a total of 322 incident cancer cases accrued. Compared with women with lower hsCRP levels (<1 mg/L), women with higher hsCRP (>3 mg/L) had a significantly increased risk of all incident cancers [HR, 1.62; 95% confidence intervals (CI), 1.23–2.14; Ptrend = 0.001] and breast cancer (HR, 1.74; 95% CI, 1.01–2.97; Ptrend = 0.047). The significant association between hsCRP levels and breast cancer risk was apparent among younger women (<50 years; HR, 2.76; 95% CI, 1.18–6.48).

Conclusion: Elevated levels of hsCRP at baseline may be associated with an increased risk of cancer, especially breast cancer, and particularly in younger Chinese women.

Impact: Our findings provide additional evidence for a role of inflammation in carcinogenesis and suggest that CRP may be a potentially useful biomarker of cancer risk in this population. Cancer Epidemiol Biomarkers Prev; 24(2); 459–65. ©2014 AACR.

Data on the role of dietary factors in endometrial cancer development are limited and inconsistent. We applied a "nutrient-wide association study" approach to systematically evaluate dietary risk associations for endometrial cancer while controlling for multiple hypothesis tests using the false discovery rate (FDR) and validating the results in an independent cohort. We evaluated endometrial cancer risk associations for dietary intake of 84 foods and nutrients based on dietary questionnaires in three prospective studies, the European Prospective Investigation into Cancer and Nutrition (EPIC; N = 1,303 cases) followed by validation of nine foods/nutrients (FDR ≤ 0.10) in the Nurses' Health Studies (NHS/NHSII; N = 1,531 cases). Cox regression models were used to estimate HRs and 95% confidence intervals (CI). In multivariate adjusted comparisons of the extreme categories of intake at baseline, coffee was inversely associated with endometrial cancer risk (EPIC, median intake 750 g/day vs. 8.6; HR, 0.81; 95% CI, 0.68–0.97, Ptrend = 0.09; NHS/NHSII, median intake 1067 g/day vs. none; HR, 0.82; 95% CI, 0.70–0.96, Ptrend = 0.04). Eight other dietary factors that were associated with endometrial cancer risk in the EPIC study (total fat, monounsaturated fat, carbohydrates, phosphorus, butter, yogurt, cheese, and potatoes) were not confirmed in the NHS/NHSII. Our findings suggest that coffee intake may be inversely associated with endometrial cancer risk. Further data are needed to confirm these findings and to examine the mechanisms linking coffee intake to endometrial cancer risk to develop improved prevention strategies. Cancer Epidemiol Biomarkers Prev; 24(2); 466–71. ©2015 AACR.

Reducing the addictiveness of cigarettes by reducing their nicotine content can potentially have a profound impact on public health. Two different approaches to nicotine reduction have been proposed: gradual and immediate. To determine if either of these approaches results in significant compensatory smoking behavior, which might lead to safety concerns, we performed a secondary analysis of data from studies that have utilized these two approaches. The number of cigarettes smoked per day, carbon monoxide exposure, and cotinine levels in plasma or urine were assessed while participants smoked reduced nicotine content cigarettes and compared with when they smoked their usual brand cigarettes. The results showed that in general, these two approaches led to minimal compensatory smoking and reduced levels of cotinine over the course of the experimental period, suggesting that neither of these approaches poses a major safety concern. Cancer Epidemiol Biomarkers Prev; 24(2); 472–6. ©2014 AACR.

Background: Three human polyomaviruses have been classified as probable (Merkel cell polyomavirus) or possible (BK and JC polyomaviruses) carcinogens, but few epidemiologic studies have examined associations between this growing class of viruses and risk of non-Hodgkin lymphoma (NHL).

Methods: Associations between polyomavirus antibodies and NHL incidence were examined using data from the American Cancer Society Cancer Prevention Study-II. This nested case–control study included 279 NHL cases and 557 controls. Prediagnostic antibodies to the major capsid protein of polyomaviruses BKV, JCV, MCV, TSV, WUV, KIV, HPy6, and HPy7 were measured by fluorescent bead-based multiplex serology, and associations with NHL were estimated using conditional logistic regression (NHL overall) and unconditional polytomous logistic regression (NHL subtypes).

Results: Although an inverse trend was suggested for TSV antibody levels and NHL risk, the HRs were not statistically significant. There were no other observed associations between polyomaviruses and NHL risk. For NHL subtypes, TSV antibody level above the median was associated with a lower risk of CLL/SLL; however, this association was based on 19 cases in the high antibody group and may be due to chance.

Conclusions: Our results do not support associations of polyomaviruses BKV, JCV, WUV, KIV, HPyV6, HPyv7, MCV, or TSV with risk of NHL.

Impact: Human polyomavirus antibody levels do not appear to predict a higher NHL risk in immunocompetent individuals. Cancer Epidemiol Biomarkers Prev; 24(2); 477–80. ©2014 AACR.