Aspirin Metabolites and Mammographic Breast Density in Premenopausal Women.

BACKGROUND: Studies investigating the associations of self-reported aspirin use and mammographic breast density (MBD) have reported conflicting results. We, therefore, investigated the associations of aspirin metabolites, with MBD in premenopausal women. METHODS: We performed this study on 705 premenopausal women who had fasting blood draw for metabolomic profiling. We performed covariate-adjusted linear regression models to calculate the least squares means of volumetric measures of MBD (volumetric percent density (VPD), dense volume (DV), and non-dense volume (NDV)) by quartiles of aspirin metabolites (salicyluric glucuronide, 2-hydroxyhippurate (salicylurate), salicylate, and 2,6-dihydroxybenzoic acid). RESULTS: Approximately 13% of participants reported taking aspirin in the past 12 months. Aspirin users had higher levels of 2-hydroxyhippurate (salicylurate), salicylate, and salicyluric glucuronide (peak area) than non-users, but only mean peak area of salicyluric glucuronide increased by both dose (1-2 tabs per day=1,140,663.7, and ≥3 tabs per day=1,380,476.0) and frequency (days per week: 1 day=888,129.3, 2-3 days=1,199,897.9 and ≥4 days=1,654,637.0). Aspirin metabolites were not monotonically associated with VPD, DV, or NDV. CONCLUSIONS: Given the null results, additional research investigating the associations of aspirin metabolites in breast tissue and MBD is necessary. IMPACT: Elucidating the determinants of MBD, a strong risk factor for breast cancer, can play an important role in breast cancer prevention. Future studies should determine the associations of non-aspirin non-steroidal anti-inflammatory drug metabolites with MBD.

Aspirin use and head and neck cancer survival and recurrence.

BACKGROUND: Head and neck cancer (HNC) has low 5-year survival, and evidence-based recommendations for tertiary prevention are lacking. Aspirin improves outcomes for cancers at other sites, but its role in HNC tertiary prevention remains understudied. METHODS: HNC patients were recruited in the University of Michigan Head and Neck Cancer Specialized Program of Research Excellence (SPORE) from 2003 to 2014. Aspirin data were collected through medical record review; outcomes (overall mortality, HNC-specific mortality, and recurrence) were collected through medical record review, Social Security Death Index, or LexisNexis. Cox proportional hazards models were used to evaluate the associations between aspirin use at diagnosis (yes/no) and HNC outcomes. RESULTS: We observed no statistically significant associations between aspirin and cancer outcome in our HNC patient cohort (n = 1161) (HNC-specific mortality: HR = 0.91, 95% CI = 0.68-1.21; recurrence: HR = 0.94, 95% CI = 0.73-1.19). In analyses stratified by anatomic site, HPV status, and disease stage, we observed no association in any strata examined with the possible exception of a lower risk of recurrence in oropharynx patients (HR = 0.60, 95% CI 0.35-1.04). CONCLUSIONS: Our findings do not support a protective association between aspirin use and cancer-specific death or recurrence in HNC patients, with the possible exception of a lower risk of recurrence in oropharynx patients.

Associations of Vitamins and Related Cofactor Metabolites with Mammographic Breast Density in Premenopausal Women.

BACKGROUND: Identifying biological drivers of mammographic breast density (MBD), a strong risk factor for breast cancer, could provide insight into breast cancer etiology and prevention. Studies on dietary factors and MBD have yielded conflicting results. There are, however, very limited data on the associations of dietary biomarkers and MBD. OBJECTIVE: We aimed to investigate the associations of vitamins and related cofactor metabolites with MBD in premenopausal women. METHODS: We measured 37 vitamins and related cofactor metabolites in fasting plasma samples of 705 premenopausal women recruited during their annual screening mammogram at the Washington University School of Medicine, St. Louis, MO. Volpara was used to assess volumetric percent density (VPD), dense volume (DV), and nondense volume (NDV). We estimated the least square means of VPD, DV, and NDV across quartiles of each metabolite, as well as the regression coefficient of a metabolite in continuous scale from multiple covariate-adjusted linear regression. We corrected for multiple testing using the Benjamini-Hochberg procedure to control the false discover rate (FDR) at a 5% level. RESULTS: Participants' mean VPD was 10.5%. Two vitamin A metabolites (ß-cryptoxanthin and carotene diol 2) were positively associated, and one vitamin E metabolite (γ-tocopherol) was inversely associated with VPD. The mean VPD increased across quartiles of ß-cryptoxanthin (Q1 = 7.2%, Q2 = 7.7%, Q3 = 8.4%%, Q4 = 9.2%; P-trend = 1.77E-05, FDR P value = 1.18E-03). There was a decrease in the mean VPD across quartiles of γ-tocopherol (Q1 = 9.4%, Q2 = 8.1%, Q3 = 8.0%, Q4 = 7.8%; P -trend = 4.01E-03, FDR P value = 0.04). Seven metabolites were associated with NDV: 3 vitamin E (γ-CEHC glucuronide, δ-CEHC, and γ-tocopherol) and 1 vitamin C (gulonate) were positively associated, whereas 2 vitamin A (carotene diol 2 and ß-cryptoxanthin) and 1 vitamin C (threonate) were inversely associated with NDV. No metabolite was significantly associated with DV. CONCLUSION: We report novel associations of vitamins and related cofactor metabolites with MBD in premenopausal women.

Lipidome of mammographic breast density in premenopausal women.

BACKGROUND: High mammographic breast density (MBD) is a strong risk factor for breast cancer development, but the biological mechanisms underlying MBD are unclear. Lipids play important roles in cell differentiation, and perturbations in lipid metabolism are implicated in cancer development. Nevertheless, no study has applied untargeted lipidomics to profile the lipidome of MBD. Through this study, our goal is to characterize the lipidome of MBD in premenopausal women. METHODS: Premenopausal women were recruited during their annual screening mammogram at the Washington University School of Medicine in St. Louis, MO. Untargeted lipidomic profiling for 982 lipid species was performed at Metabolon (Durham, NC®), and volumetric measures of MBD (volumetric percent density (VPD), dense volume (DV), and non-dense volume (NDV)) was assessed using Volpara 1.5 (Volpara Health®). We performed multivariable linear regression models to investigate the associations of lipid species with MBD and calculated the covariate-adjusted least square mean of MBD by quartiles of lipid species. MBD measures were log10 transformed, and lipid species were standardized. Linear coefficients of MBD were back-transformed and considered significant if the Bonferroni corrected p-value was < 0.05. RESULTS: Of the 705 premenopausal women, 72% were non-Hispanic white, and 23% were non-Hispanic black. Mean age, and BMI were 46 years and 30 kg/m2, respectively. Fifty-six lipid species were significantly associated with VPD (52 inversely and 4 positively). The lipid species with positive associations were phosphatidylcholine (PC)(18:1/18:1), lysophosphatidylcholine (LPC)(18:1), lactosylceramide (LCER)(14:0), and phosphatidylinositol (PI)(18:1/18:1). VPD increased across quartiles of PI(18:1/18:1): (Q1 = 7.5%, Q2 = 7.7%, Q3 = 8.4%, Q4 = 9.4%, Bonferroni p-trend = 0.02). The lipid species that were inversely associated with VPD were mostly from the triacylglycerol (N = 43) and diacylglycerol (N = 7) sub-pathways. Lipid species explained some of the variation in VPD. The inclusion of lipid species increased the adjusted R2 from 0.45, for a model that includes known determinants of VPD, to 0.59. CONCLUSIONS: We report novel lipid species that are associated with MBD in premenopausal women. Studies are needed to validate our results and the translational potential.

Breastfeeding and Mammographic Breast Density: A Cross-sectional Study.

Breastfeeding is inversely associated with breast cancer risk but the associations of breastfeeding with mammographic breast density (MBD) are not clear. We investigated the association between breastfeeding and volumetric measures of MBD [volumetric percent density (VPD), dense volume (DV), and non-dense volume (NDV)] and evaluated whether it differs by race, menopausal status, and body mass index (BMI). The study population was comprised of 964 women (67% non-Hispanic White, 29% non-Hispanic Black) who had screening mammography at Washington University School of Medicine, St. Louis, MO. VPD, DV and NDV were log10 transformed. We performed multivariable linear regression models adjusted for age, BMI, family history of breast cancer, race, and age at menarche among all participants and exclusively in parous women. Mean age was 50.7 years. VPD was 12% lower among women who breastfed 0-6 months, [10ß = 0.88, 95% confidence interval (CI; 0.79-0.98)] compared with nulliparous women. Breastfeeding was not associated with VPD among women who breastfed >7 months. Breastfeeding was inversely associated with DV [parous never breastfed: 10ß = 0.93; 95% CI (0.83-1.04), breastfed 0-6 months: 10ß = 0.91, 95% CI (0.79-1.05), breastfed 7-12 months: 10ß = 0.94; 95% CI (0.81-1.10), breastfed >12 months: 10ß = 0.87, 95% CI (0.78-0.98), Ptrend = 0.03]. BMI modified the association between breastfeeding and VPD. Women who breastfed for 0-6 months and had a BMI < 25 kg/m2 had lower VPD compared with nulliparous women, but among women with a BMI ≥ 25 kg/m2 there was no association (Pinteraction = 0.04). In this diverse study population, the association of breastfeeding with VPD appears to be modified by BMI, but not by race or menopausal status. Future research exploring the associations of breastfeeding with other mammographic features are needed. PREVENTION RELEVANCE: Breastfeeding for up to 6 months may be associated with lower VPD among women with a BMI < 25 kg/m2. The potential role of MBD in mediating the associations of breastfeeding with breast cancer risk in a select group of women deserves further evaluation. See related Spotlight, p. 309.

No survival benefit in never-smoker never-drinker patients with oral cavity cancer.

BACKGROUND: Although strongly associated with tobacco and alcohol use, many oral cavity squamous cell carcinoma (OCSCC) cases occur in patients without exposure to either, known as "never-smoker, never-drinkers" (NSND). We aimed to compare clinical outcomes between NSND and tobacco/alcohol-exposed populations and to define demographic characteristics of NSND. METHODS: We performed a retrospective, single-institution cohort study of 672 OCSCC patients. Cox models were used to estimate differences in overall survival (OS) and recurrence-free survival (RFS) between NSND and tobacco/alcohol-exposed patients while adjusting for confounders. RESULTS: NSND represented 25.6% of our cohort and were older, more female, and more economically advantaged. Among NSND, oral tongue tumors dominated in younger patients, while alveolar ridge tumors dominated in elderly patients. Multivariate survival analysis revealed no differences in OS or RFS between NSND and tobacco/alcohol-exposed patients. CONCLUSION: When adjusted for independent biologic features, clinical outcomes in OCSCC are similar between NSND and tobacco/alcohol-exposed patients.

The association between inflammatory biomarkers and statin use among patients with head and neck squamous cell carcinoma.

BACKGROUND: Tumor-infiltrating lymphocytes (TILs) and cytokines are associated with prognosis among patients with head and neck squamous cell carcinoma (HNSCC). Statins (cholesterol-lowering drugs) may improve HNSCC prognosis, particularly in human papillomavirus (HPV)-positive cases, but the mechanism remains unclear. METHODS: Statin use was collected from medical records for HNSCC cases (2008-2014). TILs were counted in tumor tissue, and a total weighted score (TILws) was created. Cytokines were measured in blood. The associations between statins and biomarkers were estimated using logistic (biomarker categories:

Statin use and head and neck squamous cell carcinoma outcomes.

Head and neck squamous cell carcinoma (HNSCC) is a morbid cancer with poor outcomes. Statins possess anticancer properties such as immunomodulatory and anti-inflammatory effects. The objective of our study is to identify the association between statin use among untreated HNSCC patients and overall death, disease-specific death and recurrence. HNSCC patients were recruited to participate in the University of Michigan Head and Neck Cancer Specialized Program of Research Excellence (SPORE) from 2003 to 2014. Statin use data were collected through medical record review. Participants were considered a statin user if they used a statin at or after diagnosis. Outcome data were collected through medical record review, Social Security Death Index or LexisNexis. Our analytic cohort included 1638 participants. Cox proportional hazard models were used to estimate the association between ever statin use and HNSCC outcomes. Statin use was seen in 36.0% of participants. We observed a statistically significant inverse association between ever using a statin and overall death (HR = 0.75, 95% CI = 0.63-0.88) and HNSCC-specific death (HR = 0.79, 95% CI = 0.63-0.99) and a nonstatistically significant inverse association for recurrence (HR = 0.85, 95% CI = 0.70-1.04). When investigating the association between statin use and HNSCC outcomes utilizing interaction terms between statin use and human papillomavirus (HPV), statistically significant interactions for HNSCC-specific death and recurrence were identified (HNSCC-specific death: HPV-positive HR = 0.41, 95% CI = 0.21-0.84; HPV-negative HR = 1.04, 95% CI = 0.71-1.51; p-int=0.02; recurrence: HPV-positive HR = 0.49, 95% CI = 0.29-0.84; HPV-negative HR = 1.03, 95% CI = 0.74-1.43; p=int-0.02). Statin use may be protective for adverse outcomes in HNSCC patients, particularly those with HPV-positive disease. If true, these findings could have a meaningful impact on tertiary prevention for this cancer.

Evaluation of strategies to communicate harmful and potentially harmful constituent (HPHC) information through cigarette package inserts: a discrete choice experiment.

BACKGROUND: The US Food and Drug Administration (FDA) has regulatory authority to use inserts to communicate with consumers about harmful and potentially harmful constituents (HPHCs) in tobacco products; however, little is known about the most effective manner for presenting HPHC information. METHODS: In a discrete choice experiment, participants evaluated eight choice sets, each of which showed two cigarette packages from four different brands and tar levels (high vs low), accompanied by an insert that included between-subject manipulations (ie, listing of HPHCs vs grouping by disease outcome and numeric values ascribed to HPHCs vs no numbers) and within-subject manipulations (ie, 1 of 4 warning topics; statement linking an HPHC with disease vs statement with no HPHC link). For each choice set, participants were asked: (1) which package is more harmful and (2) which motivates them to not smoke; each with a 'no difference' option. Alternative-specific logit models regressed choice on attribute levels. RESULTS: 1212 participants were recruited from an online consumer panel (725 18-29-year-old smokers and susceptible non-smokers and 487 30-64-year-old smokers). Participants were more likely to endorse high-tar products as more harmful than low-tar products, with a greater effect when numeric HPHC information was present. Compared with a simple warning statement, the statement linking HPHCs with disease encouraged quit motivation. CONCLUSIONS: Numeric HPHC information on inserts appears to produce misunderstandings that some cigarettes are less harmful than others. Furthermore, brief narratives that link HPHCs to smoking-related disease may promote cessation versus communications that do not explicitly link HPHCs to disease.

Family history of cancer and head and neck cancer survival.

OBJECTIVE: Patients with a family history of cancer may be genetically predisposed to carcinogenesis. This could affect risk of recurrence, second primary tumors, and overall outcomes after treatment of a primary cancer. We evaluated the association between family history of cancer and disease-specific survival in a cohort of patients with primary head and neck squamous carcinoma (HNSCC). STUDY DESIGN: Six hundred and forty-three incident HNSCC patients recruited through the University of Michigan Specialized Program of Research Excellence were followed for up to 5 years for survival. Participants were interviewed about personal and family cancer history, demographic information, and behavioral habits. METHODS: Cox proportional hazards models were used to estimate the association between family history of cancer in a first-degree relative and disease-specific survival. RESULTS: After multivariable adjustment, we found a nonsignificant inverse association between family history and HNSCC mortality (hazard ratio [HR] = 0.88, 95% confidence interval [CI] 0.57-1.35). This association was stronger and statistically significant among patients who currently both drank alcohol and smoked cigarettes at diagnosis (HR = 0.46, 95% CI = 0.22-0.97); no association was observed among participants who did not both drink and smoke at the time of diagnosis (HR = 1.14, 95% CI = 0.68-1.91; p-interaction = 0.046). CONCLUSION: Results from this study suggest that having a family history of cancer may be associated with improved disease-specific survival in patients who use tobacco and alcohol. Additional large studies, particularly in populations including nonwhites and women, are needed to confirm or refute the association and to elucidate the genetic factors that may underlie this potential association. LEVEL OF EVIDENCE: 2b. Laryngoscope, 127:1816-1820, 2017.

Patterns of Waterpipe Tobacco Smoking Among U.S. Young Adults, 2013-2014.

INTRODUCTION: Patterns of waterpipe smoking and associated other tobacco use were assessed among U.S. young adults (aged 18-24 years). METHODS: A descriptive analysis of baseline data (2013-2014) from the Population Assessment of Tobacco and Health Study was conducted in 2016. RESULTS: The study included 9,119 young adults-44% ever and 11% past-30 day waterpipe smokers (12% of men and 9% of women were past-30 day smokers). Among past-30 day smokers, waterpipe smoking frequency was distributed as follows: 4% daily, 23% weekly, 36% monthly, and 37% less than monthly. The average session exceeded 30 minutes for 79% of respondents. In this age group, 29% were exclusive waterpipe smokers, 16% were dual (waterpipe/cigarette) smokers, 8% were dual (waterpipe/e-cigarette) users, 19% were waterpipe/cigarette/e-cigarette users, and 28% presented with other combinations of poly use. CONCLUSIONS: Waterpipe smoking is widespread among U.S. young adults. Although waterpipe patterns are predominantly intermittent, the average smoking session provides prolonged exposure. Waterpipe smoking among young adults is primarily characterized by the use of flavored tobacco, the café culture, and poly tobacco use. Rising trends in waterpipe smoking among U.S. youth warrant a strong regulatory response to prevent future waterpipe-related morbidity and mortality.

Use of Electronic Cigarettes Among Cancer Survivors in the U.S.

INTRODUCTION: The population-level patterns of electronic cigarette (e-cigarette) use among cancer survivors in the U.S. are unknown. The objective of this study was to examine the prevalence and correlates of e-cigarette use among cancer survivors in a nationally representative sample. METHODS: A cross-sectional analysis was conducted of the 2014 National Health Interview Survey of the U.S. non-institutionalized civilian population. The main study outcomes were the prevalence and correlates of ever and current e-cigarette use among adults with self-reported history of cancer, excluding non-melanoma skin cancer (N=2,695). Multivariable logistic regression analyses examined whether e-cigarette use differed by cigarette smoking status and demographic subgroups. The analyses were performed in 2015. RESULTS: The prevalence of e-cigarette use among adult cancer survivors was lower than the general population: 2.8% of cancer survivors reported currently using e-cigarettes and an additional 6.3% had previously used e-cigarettes but were not currently using them. Use of e-cigarettes was most common among cancer survivors who currently smoked cigarettes: 34.3% of current smokers were ever e-cigarette users and 15.6% were current e-cigarette users, compared with former smokers (2.7% ever and 1.4% current e-cigarette users) and never smokers (small sample/estimates unavailable). CONCLUSIONS: E-cigarettes are not part of current evidence-based smoking-cessation strategies. However, the finding that cancer survivors who currently smoke cigarettes are more likely to use e-cigarettes highlights the importance of addressing e-cigarette use in patient-provider communications around tobacco cessation.

Waterpipe Tobacco Smoking and Susceptibility to Cigarette Smoking Among Young Adults in the United States, 2012-2013.

INTRODUCTION: Waterpipe tobacco smoking, also known as hookah and shisha, has surged in popularity among young people in the United States. Waterpipe is also increasingly becoming the first tobacco product that young people try. Given the limited access to and limited portability of waterpipes, waterpipe smokers who become more nicotine dependent over time may be more likely to turn to cigarettes. This study examined the relationship between waterpipe tobacco smoking and susceptibility to cigarette smoking among young adults in the United States. METHODS: Using data from the 2012-2013 National Adult Tobacco Survey, a nationally representative sample of US adults, we reported rates of current waterpipe smoking and susceptibility to cigarette smoking by demographic characteristics and by use of other tobacco products among survey participants aged 18 to 24 years. Multivariable logistic regression was used to examine the relationship between current waterpipe smoking and susceptibility to cigarette smoking, defined as the lack of a firm intention not to smoke soon or within the next year. RESULTS: Of 2,528 young adults who had never established cigarette smoking, 15.7% (n = 398) reported being waterpipe smokers (every day or some days [n = 97; 3.8%] or rarely [n = 301; 11.9%]); 44.2% (176/398) of waterpipe smokers reported being susceptible to cigarette smoking. Those who smoked waterpipe rarely were 2.3 times as susceptible to cigarette smoking as those who were not current waterpipe smokers (OR = 2.3; 95% CI, 1.6-3.4). CONCLUSION: Current waterpipe smoking is associated with susceptibility to cigarette smoking among young adults in the United States. Longitudinal studies are needed to demonstrate causality between waterpipe smoking and initiation of cigarette smoking.