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Cancer Epidemiology Biomarkers & Prevention

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Cancer Epidemiology Biomarkers & Prevention

In 2016, the Netherlands will switch, as first European country, from cytology-based to HPV-based cervical cancer screening, with cytology triage for those with a positive HPV test. The new Dutch program includes sending self-sampling devices to women who do not respond to an invitation to have a cervical sample taken by their general practitioner. The cost-effectiveness of this additional strategy will depend on its capacity to recruit nonscreened women and in particular those at increased risk of cervical (pre)cancer, the possible switch of previous responders to self-sampling, the accuracy and cost of the HPV assay–self-sampler combination, and the compliance of women being self-sample HPV-positive with further follow-up. Validated PCR-based assays, detecting high-risk HPV DNA, are as accurate on self-samples as on clinician-collected samples. On the contrary, HPV assays, based on signal amplification, are less sensitive and specific on self-samples. The introduction of self-sampling strategies should be carefully prepared and evaluated in pilot studies integrated in well-organized settings before general rollout. Opt-in procedures involving a request for a self-sampler may reduce response rates. Therefore, an affordable device that can be included with the invitation to all nonattendees may yield a stronger effect on participation. Cancer Epidemiol Biomarkers Prev; 24(5); 769–72. ©2015 AACR.

See related article by Rozemeijer et al., p. 773

Background: Human papillomavirus (HPV) self-sampling might be a promising tool to increase effectiveness of primary HPV screening programs when offered to non-attendees. However, effectiveness could decrease if regular attendees "switch" to self-sampling, because self-sampling test characteristics may be inferior. We examined under which conditions the harms would outweigh the benefits.

Methods: The MISCAN-cervix model was used to estimate quality-adjusted life years (QALY) gained and costs of offering HPV self-sampling to non-attendees. We varied the relative CIN2+ sensitivity and specificity (self-sampling vs. regular sampling), extra attendance, risk of extra attendees, and the switching percentage.

Results: Without switching, offering self-sampling is (cost-)effective under every studied condition. If the attendance due to self-sampling increases by ≥6 percentage points, higher primary background risk women (unscreened women who will never attend regular screening) attend and the relative CIN2+ sensitivity and specificity are ≥0.95; it is (cost-)effective to offer self-sampling to non-attendees, even if all regular attendees switch. If the relative sensitivity decreases to 0.90 combined with either a 3 percentage points extra attendance or the absence of higher primary background risk women, QALYs are lost when more than 30% to 20% of the regular attendees switch.

Conclusions: Offering self-sampling will gain health effects if the relative CIN2+ sensitivity is ≥0.95, unscreened attendees are recruited, and the total attendance increases by ≥6 percentage points. Otherwise, switching of regular attendees may decrease the total effectiveness of the program.

Impact: Self-sampling needs to be implemented with great care and advantages of office-based sampling need to be emphasized to prevent switching. Cancer Epidemiol Biomarkers Prev; 24(5); 773–82. ©2014 AACR.

See related commentary by Arbyn and Castle, p. 769

Background: A novel line of research has emerged, suggesting that daily feeding–fasting schedules that are synchronized with sleep-wake cycles have metabolic implications that are highly relevant to breast cancer. We examined associations of nighttime fasting duration with biomarkers of breast cancer risk among women in the 2009–2010 U.S. National Health and Nutrition Examination Survey.

Methods: Dietary, anthropometric, and HbA1c data were available for 2,212 women, and 2-hour postprandial glucose concentrations were available for 1,066 women. Nighttime fasting duration was calculated using 24-hour food records. Separate linear regression models examined associations of nighttime fasting with HbA1c and 2-hour glucose concentrations. Logistic regression modeled associations of nighttime fasting with elevated HbA1c (HbA1c ≥ 39 mmol/mol or 5.7%) and elevated 2-hour glucose (glucose ≥ 140 mg/dL). All models adjusted for age, education, race/ethnicity, body mass index, total kcal intake, evening kcal intake, and the number of eating episodes per day.

Results: Each 3-hour increase in nighttime fasting (roughly 1 SD) was associated with a 4% lower 2-hour glucose measurement [β, 0.96; 95% confidence interval (CI), 0.93–1.00; P < 0.05], and a nonstatistically significant decrease in HbA1c. Logistic regression models indicate that each 3-hour increase in nighttime fasting duration was associated with roughly a 20% reduced odds of elevated HbA1c (OR, 0.81; 95% CI, 0.68–0.97; P < 0.05) and nonsignificantly reduced odds of elevated 2-hour glucose.

Conclusions: A longer nighttime duration was significantly associated with improved glycemic regulation.

Impact: Randomized trials are needed to confirm whether prolonged nighttime fasting could improve biomarkers of glucose control, thereby reducing breast cancer risk. Cancer Epidemiol Biomarkers Prev; 24(5); 783–9. ©2015 AACR.

Background: Results from prospective studies suggest that nonsteroidal anti-inflammatory drugs (NSAID) may decrease lung cancer risk; however, any protective effect appears to be most evident in men.

Methods: We evaluated the associations between NSAID use and lung cancer incidence in postmenopausal women in the Women's Health Initiative (WHI) adjusting for female-specific potential confounders such as hormone therapy in addition to smoking histories and other potential confounders. We identified 143,841 women from ages 50 to 79 and 1,902 centrally confirmed lung cancer cases were included in the analysis. We used Cox regression models to estimate HRs and their 95% confidence intervals (CI).

Results: Compared with nonuse, regular NSAID use was not associated with overall lung cancer incidence (NSAID use >10 years HR 0.87; 95% CI, 0.71–1.08, Ptrend = 0.13). No statistically significant associations were found when examined by histologic subtypes and although there was a trend of decreased risk with longer duration of NSAID use in the adenocarcinoma subtype, this was not statistically significant (NSAID use >10 years HR 0.80; 95% CI, 0.58–1.10; Ptrend = 0.07).

Conclusion: Our study did not show that NSAID use is associated with lung cancer risk in women even after adjusting for female-specific confounders. There was a trend of decreased risk in the adenocarcinoma subtype; however, this was not statistically significant.

Impact: Future studies will need to take in account the various molecular subtypes of non–small cell lung cancer to further elucidate the role of NSAIDs in lung cancer, especially for the adenocarcinoma subtype. Cancer Epidemiol Biomarkers Prev; 24(5); 790–7. ©2015 AACR.

Background: Mammographic density (MD) is a strong breast cancer risk factor. We previously reported associations of percent mammographic density (PMD) with larger and node-positive tumors across all ages, and estrogen receptor (ER)–negative status among women ages <55 years. To provide insight into these associations, we examined the components of PMD [dense area (DA) and nondense area (NDA)] with breast cancer subtypes.

Methods: Data were pooled from six studies including 4,095 breast cancers and 8,558 controls. DA and NDA were assessed from digitized film-screen mammograms and standardized across studies. Breast cancer odds by density phenotypes and age according to histopathologic characteristics and receptor status were calculated using polytomous logistic regression.

Results: DA was associated with increased breast cancer risk [OR for quartiles: 0.65, 1.00 (Ref), 1.22, 1.55; Ptrend <0.001] and NDA was associated with decreased risk [ORs for quartiles: 1.39, 1.00 (Ref), 0.88, 0.72; Ptrend <0.001] across all ages and invasive tumor characteristics. There were significant trends in the magnitude of associations of both DA and NDA with breast cancer by increasing tumor size (Ptrend < 0.001) but no differences by nodal status. Among women <55 years, DA was more strongly associated with increased risk of ER+ versus ER tumors (Phet = 0.02), while NDA was more strongly associated with decreased risk of ER versus ER+ tumors (Phet = 0.03).

Conclusions: DA and NDA have differential associations with ER+ versus ER tumors that vary by age.

Impact: DA and NDA are important to consider when developing age- and subtype-specific risk models. Cancer Epidemiol Biomarkers Prev; 24(5); 798–809. ©2015 AACR.

Background: Although glioma etiology is poorly understood in general, growing evidence indicates a genetic component. Four large genome-wide association studies (GWAS) have linked common genetic variants with an increased glioma risk. However, to date, these studies are based largely on a case–control design, where cases have been recruited at the time of or after diagnosis. They may therefore suffer from a degree of survival bias, introduced when rapidly fatal cases are not included.

Methods: To confirm glioma risk variants in a prospective setting, we have analyzed 11 previously identified risk variants in a set of prediagnostic serum samples with 598 cases and 595 matched controls. Serum samples were acquired from The Janus Serum Bank, a Norwegian population-based biobank reserved for cancer research.

Results: We confirmed the association with glioma risk for variants within five genomic regions: 8q24.21 (CCDC26), 9p21.3 (CDKN2B-AS1), 11q23.3 (PHLDB1), 17p13.1 (TP53), and 20q13.33 (RTEL1). However, previously identified risk variants within the 7p11.2 (EGFR) region were not confirmed by this study.

Conclusions: Our results indicate that the risk variants that were confirmed by this study are truly associated with glioma risk and may, consequently, affect gliomagenesis. Though the lack of positive confirmation of EGFR risk variants may be attributable to relatively limited statistical power, it nevertheless raises the question whether they truly are risk variants or markers for glioma prognosis.

Impact: Our findings indicate the need for further studies to clarify the role of glioma risk loci with respect to prolonged survival versus etiology. Cancer Epidemiol Biomarkers Prev; 24(5); 810–6. ©2015 AACR.

Background: We report the development of a cutaneous melanoma risk algorithm based upon seven factors; hair color, skin type, family history, freckling, nevus count, number of large nevi, and history of sunburn, intended to form the basis of a self-assessment Web tool for the general public.

Methods: Predicted odds of melanoma were estimated by analyzing a pooled dataset from 16 case–control studies using logistic random coefficients models. Risk categories were defined based on the distribution of the predicted odds in the controls from these studies. Imputation was used to estimate missing data in the pooled datasets. The 30th, 60th, and 90th centiles were used to distribute individuals into four risk groups for their age, sex, and geographic location. Cross-validation was used to test the robustness of the thresholds for each group by leaving out each study one by one. Performance of the model was assessed in an independent UK case–control study dataset.

Results: Cross-validation confirmed the robustness of the threshold estimates. Cases and controls were well discriminated in the independent dataset [area under the curve, 0.75; 95% confidence interval (CI), 0.73–0.78]. Twenty-nine percent of cases were in the highest risk group compared with 7% of controls, and 43% of controls were in the lowest risk group compared with 13% of cases.

Conclusion: We have identified a composite score representing an estimate of relative risk and successfully validated this score in an independent dataset.

Impact: This score may be a useful tool to inform members of the public about their melanoma risk. Cancer Epidemiol Biomarkers Prev; 24(5); 817–24. ©2015 AACR.

Background: Regular aspirin use may decrease cancer risk by reducing chronic inflammation. However, associations between aspirin use and circulating markers of inflammation have not been well studied.

Methods: Serum levels of 78 inflammatory markers were measured in 1,819 55- to 74-year-old men and women in the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial. Data were combined from three completed case–control studies and reweighted to the PLCO screening arm. Self-reported aspirin and ibuprofen use (number of tablets taken per day/week/month) over the previous 12 months was collected at baseline. Associations between (i) nonregular (<4 tablets/month), (ii) low (1–4 tablets/week), (iii) moderate (1 tablet/day), or (iv) high (2+ tablets/day) regular aspirin or ibuprofen use and marker levels were assessed with weighted logistic regression.

Results: Aspirin use was nominally associated with (Ptrend across categories ≤ 0.05) decreased levels of chemokine C-C motif ligand 15 [CCL15; OR, 0.5; 95% confidence intervals (CI), 0.3–0.8; moderate versus nonregular use]; soluble vascular endothelial growth factor receptor 2 (sVEGFR2; OR, 0.7; 95% CI, 0.4–1.0); soluble tumor necrosis factor receptor 1 (sTNFR1; OR, 0.6; 95% CI, 0.4–0.9) and increased levels of CCL13 (OR, 1.3; 95% CI, 0.8–2.1); CCL17 (OR, 1.1; 95% CI, 0.7–1.9) and interleukin 4 (IL4; OR, 1.6; 95% CI, 0.9–2.8). Trends were not statistically significant following correction for multiple comparisons. Likewise, no statistically significant associations were observed between ibuprofen use and marker levels.

Conclusions: No significant associations were observed between regular aspirin use and the inflammatory markers assessed.

Impact: Additional studies are needed to better understand the relationship between aspirin use, chronic inflammation, and cancer risk. Cancer Epidemiol Biomarkers Prev; 24(5); 825–32. ©2015 AACR.

Background: Preclinical evidence from lung cancer cell lines and animal models suggest that statins could have anticancer properties. We investigated whether statin users had reduced risk of cancer-specific mortality in a population-based cohort of lung cancer patients.

Methods: Newly diagnosed lung cancer patients, from 1998 to 2009, were identified from English cancer registry data and linked to the UK Clinical Practice Research Datalink, providing prescription records, and to Office of National Statistics mortality data up to 2012. Cox regression models were used to calculate HRs for cancer-specific mortality and 95% confidence intervals (CI) by statin use before and after diagnosis, and to adjust these HRs for potential confounders.

Results: In 3,638 lung cancer patients, there was some evidence that statin use after diagnosis was associated with reduced lung cancer–specific mortality (adjusted HR, 0.89; 95% CI, 0.78–1.02; P = 0.09). Associations were more marked after 12 prescriptions (adjusted HR, 0.81; 95% CI, 0.67–0.98; P = 0.03) and when lipophilic statins were investigated (adjusted HR, 0.81; 95% CI, 0.70–0.94; P = 0.01), but were attenuated in some sensitivity analyses. Furthermore, in 11,051 lung cancer patients, statin use before diagnosis was associated with reduced lung cancer–specific mortality (adjusted HR, 0.88; 95% CI, 0.83–0.93; P < 0.001).

Conclusions: There was some evidence that lung cancer patients who used statins, and particularly simvastatin, had reduced rates of cancer-specific mortality.

Impact: These findings should first be confirmed in observational studies, but provide some support for conducting randomized controlled trials of simvastatin as adjuvant cancer therapy in lung cancer patients. Cancer Epidemiol Biomarkers Prev; 24(5); 833–41. ©2015 AACR.

Background: The third British National Survey of Sexual Attitudes and Lifestyles (Natsal-3) provides an opportunity to explore high-risk human papillomavirus (HR-HPV) and uptake of cervical screening and HPV vaccination in the general population.

Methods: Natsal-3, a probability sample survey of men and women ages 16 to 74, resident in Britain, interviewed 8,869 women in 2010 to 2012. We explored risk factors for HR-HPV (in urine from 2,569 sexually experienced women ages 16 to 44), nonattendance for cervical screening in the past 5 years, and noncompletion of HPV catch-up vaccination.

Results: HR-HPV was associated with increasing numbers of lifetime partners, younger age, increasing area-level deprivation, and smoking. Screening nonattendance was associated with younger and older age, increasing area-level deprivation (age-adjusted OR 1.91, 95% confidence interval, 1.48–2.47 for living in most vs. least deprived two quintiles), Asian/Asian British ethnicity (1.96, 1.32–2.90), smoking (1.97, 1.57–2.47), and reporting no partner in the past 5 years (2.45, 1.67–3.61 vs. 1 partner) but not with HR-HPV (1.35, 0.79–2.31). Lower uptake of HPV catch-up vaccination was associated with increasing area-level deprivation, non-white ethnicity, smoking, and increasing lifetime partners.

Conclusions: Socioeconomic markers and smoking were associated with HR-HPV positivity, nonattendance for cervical screening, and noncompletion of catch-up HPV vaccination.

Impact: The cervical screening program needs to engage those missing HPV catch-up vaccination to avoid a potential widening of cervical cancer disparities in these cohorts. As some screening nonattenders are at low risk for HR-HPV, tailored approaches may be appropriate to increase screening among higher-risk women. Cancer Epidemiol Biomarkers Prev; 24(5); 842–53. ©2015 AACR.

Background: Night shift work has been associated with an increased risk for breast and prostate cancer. The effect of circadian disruption on sex steroid production is a possible underlying mechanism, underinvestigated in humans. We have assessed daily rhythms of sex hormones and melatonin in night and day shift workers of both sexes.

Methods: We recruited 75 night and 42 day workers, ages 22 to 64 years, in different working settings. Participants collected urine samples from all voids over 24 hours on a working day. Urinary concentrations of 16 sex steroid hormones and metabolites (estrogens, progestagens, and androgens) and 6-sulfatoxymelatonin were measured in all samples. Mean levels and peak time of total and individual metabolite production were compared between night and day workers.

Results: Night workers had higher levels of total progestagens [geometric mean ratio (GMR) 1.65; 95% confidence intervals (CI), 1.17–2.32] and androgens (GMR: 1.44; 95% CI, 1.03–2.00), compared with day workers, after adjusting for potential confounders. The increased sex hormone levels among night shift workers were not related to the observed suppression of 6-sulfatoxymelatonin. Peak time of androgens was significantly later among night workers, compared with day workers (testosterone: 12:14 hours; 10:06-14:48 vs. 08:35 hours; 06:52-10:46).

Conclusions: We found increased levels of progestagens and androgens as well as delayed peak androgen production in night shift workers compared with day workers.

Impact: The increase and mistiming of sex hormone production may explain part of the increased risk for hormone-related cancers observed in night shift workers. Cancer Epidemiol Biomarkers Prev; 24(5); 854–63. ©2015 AACR.

Background: Fanconi anemia is a rare genetic disorder resulting in a loss of function of the Fanconi anemia–related DNA repair pathway. Individuals with Fanconi anemia are predisposed to some cancers, including oropharyngeal and gynecologic cancers, with known associations with human papillomavirus (HPV) in the general population. As individuals with Fanconi anemia respond poorly to chemotherapy and radiation, prevention of cancer is critical.

Methods: To determine whether individuals with Fanconi anemia are particularly susceptible to oral HPV infection, we analyzed survey-based risk factor data and tested DNA isolated from oral rinses from 126 individuals with Fanconi anemia and 162 unaffected first-degree family members for 37 HPV types.

Results: Fourteen individuals (11.1%) with Fanconi anemia tested positive, significantly more (P = 0.003) than family members (2.5%). While HPV prevalence was even higher for sexually active individuals with Fanconi anemia (17.7% vs. 2.4% in family; P = 0.003), HPV positivity also tended to be higher in the sexually inactive (8.7% in Fanconi anemia vs. 2.9% in siblings). Indeed, having Fanconi anemia increased HPV positivity 4.9-fold (95% CI, 1.6–15.4) considering age and sexual experience, but did not differ by other potential risk factors.

Conclusion: Our studies suggest that oral HPV is more common in individuals with Fanconi anemia. It will be essential to continue to explore associations between risk factors and immune dysfunction on HPV incidence and persistence over time.

Impact: HPV vaccination should be emphasized in those with Fanconi anemia as a first step to prevent oropharyngeal cancers, although additional studies are needed to determine whether the level of protection it offers in this population is adequate. Cancer Epidemiol Biomarkers Prev; 24(5); 864–72. ©2015 AACR.

Research regarding the association between physical activity and the risk of non-Hodgkin lymphoma (NHL) is limited and inconsistent, and few studies have investigated whether the intensity and timing of physical activity influence the association. A case–control study of NHL was conducted in British Columbia, Canada, in 2000 to 2004. Data were collected on various NHL risk factors, including moderate-intensity and vigorous-intensity physical activity performed over the lifetime. Logistic regression was used to estimate the association between physical activity and the risk of NHL. This analysis included 818 controls and 749 cases. Lifetime vigorous-intensity physical activity was inversely associated with NHL risk. Participants in the second, third, and fourth quartiles of lifetime vigorous-intensity physical activity had an approximately 25% to 30% lower risk of NHL than those in the lowest quartile [adjusted odds ratios, 0.69 (95% confidence interval [CI], 0.52–0.93); 0.68 (95% CI, 0.50–0.92); and 0.75 (95% CI, 0.55–1.01), respectively]. No consistent associations were observed for total or moderate-intensity physical activity. There were no apparent age periods in which physical activity appeared to confer a greater risk reduction. In this study, we found that lifetime vigorous-intensity physical activity was associated with a significantly reduced risk of NHL. Given this finding, more research on physical activity intensity and timing in relation to NHL risk is warranted. Cancer Epidemiol Biomarkers Prev; 24(5); 873–7. ©2015 AACR.

A workshop entitled "Building a funded research program in cancer health disparities" was held at the 38th Annual American Society of Preventive Oncology (ASPO) Meeting. Organized by the Junior Members Interest Group, the session addressed topics relevant to career development for cancer disparities investigators. Such considerations include the development of research programs on a backdrop of existing multi- and transdisciplinary teams, recognizing opportunities for advancing their research, given the growth of consortia-related research, and development of effective community-based partnerships. Key strategies for developing a sustainable career in cancer health disparities in the current environment include the need to effectively engage with communities, appreciate the value of team science and develop cross-discipline collaborations, and navigate the use and utility of consortia for disparities research. Academic considerations related to earning tenure and promotion that may be faced by the junior investigator in cancer health disparities were also discussed. This report may serve to both educate and provide lessons for early-stage investigators who wish to tackle complex scientific questions while developing their careers in cancer health disparities. Cancer Epidemiol Biomarkers Prev; 24(5); 882–5. ©2015 AACR.