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Aims To examine the association between alcohol consumption and mental health during the COVID-19 pandemic. Methods An anonymous online survey was distributed among US adults during May–August 2020 through social networks and ResearchMatch. We collected information on demographic, lifestyles and mental health symptoms including anxiety, depression, stress and post-traumatic stress disorder. Logistic regression models were used to examine the cross-sectional association between alcohol consumption and mental health symptoms. We also examined effect modification by race, age, gender, social support, financial insecurity and quarantine status. Results The analytical sample consists of 3623 adults. Stable drinking habits and regular drinking behaviors were found to co-exist with better mental health status. Participants who increased their alcohol use had higher odds of developing mental health disorders than those who maintained their pre-pandemic drinking habits. Additionally, participants who engaged in binge drinking during the pandemic had higher odds of depression and stress than those who did not. The associations regarding increased drinking and binge drinking in relation to adverse mental health outcomes were stronger among females, racial minorities, and individuals with financial concerns, poor social support and restricted quarantine status than their counterparts. Conclusions During the early stage of the COVID-19 pandemic, increased alcohol use and binge drinking are cross-sectionally associated with higher odds of mental health disorders, which highlighted the need for targeted intervention to address the mental health needs of individuals who have engaged in these behaviors, especially among females, minorities, those with insecurities or with restricted quarantine status.

Background Endometrial cancer risk stratification may help target interventions, screening, or prophylactic hysterectomy to mitigate the rising burden of this cancer. However, existing prediction models have been developed in select cohorts and have not considered genetic factors. Methods We developed endometrial cancer risk prediction models using data on postmenopausal White women aged 45-85 years from 19 case-control studies in the Epidemiology of Endometrial Cancer Consortium (E2C2). Relative risk estimates for predictors were combined with age-specific endometrial cancer incidence rates and estimates for the underlying risk factor distribution. We externally validated the models in 3 cohorts: Nurses’ Health Study (NHS), NHS II, and the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial. Results Area under the receiver operating characteristic curves for the epidemiologic model ranged from 0.64 (95% confidence interval [CI] = 0.62 to 0.67) to 0.69 (95% CI = 0.66 to 0.72). Improvements in discrimination from the addition of genetic factors were modest (no change in area under the receiver operating characteristic curves in NHS; PLCO = 0.64 to 0.66). The epidemiologic model was well calibrated in NHS II (overall expected-to-observed ratio [E/O] = 1.09, 95% CI = 0.98 to 1.22) and PLCO (overall E/O = 1.04, 95% CI = 0.95 to 1.13) but poorly calibrated in NHS (overall E/O = 0.55, 95% CI = 0.51 to 0.59). Conclusions Using data from the largest, most heterogeneous study population to date (to our knowledge), prediction models based on epidemiologic factors alone successfully identified women at high risk of endometrial cancer. Genetic factors offered limited improvements in discrimination. Further work is needed to refine this tool for clinical or public health practice and expand these models to multiethnic populations.

Background: Study results of prediagnostic dietary fat intake and breast cancer mortality have been inconclusive. While dietary fat subtypes [saturated (SFA), polyunsaturated (PUFA), and monounsaturated (MUFA) fatty acids] may have different biological effects, there is little evidence regarding the association of dietary fat and fat subtype intake with mortality after breast cancer diagnosis. Methods: Women with incident, pathologically confirmed invasive breast cancer and complete dietary data (n = 793) were followed in a population-based study, the Western New York Exposures and Breast Cancer study. Usual intake before diagnosis of total fat and subtypes were estimated from a food frequency questionnaire completed at baseline. HRs and 95% confidence intervals (CI) for all-cause and breast cancer–specific mortality were estimated with Cox proportional hazards models. Interactions by menopausal status, estrogen receptor (ER) status, and tumor stage were examined. Results: Median follow-up time was 18.75 years; 327 (41.2%) participants had died. Compared with lower intake, greater intake of total fat (HR, 1.05; 95% CI, 0.65–1.70), SFA (1.31; 0.82–2.10), MUFA (0.99; 0.61–1.60), and PUFA (0.99; 0.56–1.75) was not associated with breast cancer–specific mortality. There was also no association with all-cause mortality. Results did not vary by menopausal status, ER status, or tumor stage. Conclusions: Prediagnostic intake of dietary fat and fat subtypes was not associated with either all-cause or breast cancer mortality in a population-based cohort of breast cancer survivors. Impact: Understanding factors affecting survival among women diagnosed with breast cancer is critically important. Dietary fat intake prior to diagnosis may not impact that survival.

Supplementary Figure from Saliva and Lung Microbiome Associations with Electronic Cigarette Use and Smoking

The microbiome has increasingly been linked to cancer. Little is known about the lung and oral cavity microbiomes in smokers, and even less for electronic cigarette (EC) users, compared with never-smokers. In a cross-sectional study (n = 28) of smokers, EC users, and never-smokers, bronchoalveolar lavage and saliva samples underwent metatranscriptome profiling to examine associations with lung and oral microbiomes. Pairwise comparisons assessed differentially abundant bacteria species. Total bacterial load was similar between groups, with no differences in bacterial diversity across lung microbiomes. In lungs, 44 bacteria species differed significantly (FDR < 0.1) between smokers/never-smokers, with most decreased in smokers. Twelve species differed between smokers/EC users, all decreased in smokers of which Neisseria sp. KEM232 and Curvibacter sp. AEP1-3 were observed. Among the top five decreased species in both comparisons, Neisseria elongata, Neisseria sicca, and Haemophilus parainfluenzae were observed. In the oral microbiome, 152 species were differentially abundant for smokers/never-smokers, and 17 between smokers/electronic cigarette users, but only 21 species were differentially abundant in both the lung and oral cavity. EC use is not associated with changes in the lung microbiome compared with never-smokers, indicating EC toxicity does not affect microbiota. Statistically different bacteria in smokers compared with EC users and never-smokers were almost all decreased, potentially due to toxic effects of cigarette smoke. The low numbers of overlapping oral and lung microbes suggest that the oral microbiome is not a surrogate for analyzing smoking-related effects in the lung.Prevention Relevance:The microbiome affects cancer and other disease risk. The effects of e-cig usage on the lung microbiome are essentially unknown. Given the importance of lung microbiome dysbiosis populated by oral species which have been observed to drive lung cancer progression, it is important to study effects of e-cig use on microbiome.

Background: Comorbidities can affect survival of ovarian cancer patients by influencing treatment efficacy. However, little evidence exists on the association between individual concurrent comorbidities and prognosis in ovarian cancer patients.Methods: Among patients diagnosed with invasive ovarian carcinoma who participated in 23 studies included in the Ovarian Cancer Association Consortium, we explored associations between histories of endometriosis; asthma; depression; osteoporosis; and autoimmune, gallbladder, kidney, liver, and neurological diseases and overall and progression-free survival. Using Cox proportional hazards regression models adjusted for age at diagnosis, stage of disease, histology, and study site, we estimated pooled HRs and 95% confidence intervals to assess associations between each comorbidity and ovarian cancer outcomes.Results: None of the comorbidities were associated with ovarian cancer outcome in the overall sample nor in strata defined by histologic subtype, weight status, age at diagnosis, or stage of disease (local/regional vs. advanced).Conclusions: Histories of endometriosis; asthma; depression; osteoporosis; and autoimmune, gallbladder, kidney, liver, or neurologic diseases were not associated with ovarian cancer overall or progression-free survival.Impact: These previously diagnosed chronic diseases do not appear to affect ovarian cancer prognosis. Cancer Epidemiol Biomarkers Prev; 26(9); 1470–3. ©2017 AACR.

Description of the studies included in the pooled analysis and methods of data collection

PURPOSE: There is increasing evidence that exposures in utero and in infancy impact breast cancer risk. No previous studies have evaluated these associations among women in Puerto Rico. METHODS: In a population-based case–control study of breast cancer epidemiology in the San Juan metropolitan area in Puerto Rico, we examined the association of early life factors with breast cancer risk and breast cancer risk factors. Both cases (n = 315) and controls (n = 348) completed interviewer-administered questionnaires, including self-reported birth country, birthweight, and history of having been breastfed. Comparisons of characteristics of those with and without the early life factors were made with t-tests or chi-squared tests; associations between early life factors and breast cancer risk were estimated with unconditional logistic regression adjusting for age, education, body mass index (BMI), age at menarche, parity, and menopausal status. RESULTS: Women who had been breastfed tended to have higher adult body mass index (BMI), higher education, and lower parity (p < 0.05). Higher birthweight was associated with higher adult BMI and lower educational attainment (p < 0.05). Those born outside of Puerto Rico or the US were more likely to have higher educational attainment and earlier age at menarche than those born within Puerto Rico or the US (p < 0.05). We found no significant associations between any of the early life factors and breast cancer risk. CONCLUSION: We did not find evidence of an association of early life factors with breast cancer risk among women in Puerto Rico.

PURPOSE Hereditary cancer syndromes infer high cancer risks and require intensive surveillance. Identification of high-risk individuals among patients with colorectal cancer (CRC) needs improvement. METHODS Three thousand three hundred ten unselected adults who underwent surgical resection for primary invasive CRC were prospectively accrued from 51 hospitals across Ohio between January 1, 2013, and December 31, 2016. Universal Tumor screening (UTS) for mismatch repair (MMR) deficiency was performed for all, and pathogenic germline variants (PGVs) were identified using multigene panel testing (MGPT) in those who met at least one inclusion criterion: MMR deficiency, diagnosed < 50 years, multiple primary tumors (CRC or endometrial cancer), or with a first-degree relative with CRC or endometrial cancer. RESULTS Five hundred twenty-five patients (15.9%) had MMR deficiency. Two hundred thirty-four of 3,310 (7.1%; 16% of the 1,462 who received MGPT) had 248 PGVs in cancer susceptibility genes. One hundred forty-two (4.3%) had a PGV in an MMR gene, and 101 (3.1%) had a PGV in a non-MMR gene. Ten with Lynch syndrome (LS) also had a non-MMR PGV and were included in both groups. Two (0.06%) had constitutional MLH1 hypermethylation. Of unexplained MMR-deficient patients, 88.4% (76 of 86) had double somatic MMR mutations. Testing for only MMR genes in MMR-deficient patients would have missed 18 non-MMR gene PGVs (7.3% of total PGVs identified). Had UTS been the only method used to screen for hereditary cancer syndromes, 38.6% (91 of 236) would have been missed, including 6.3% (9 of 144) of those with LS. These results have treatment implications as 5.3% (175 of 3,310) had PGVs in genes with therapeutic targets. CONCLUSION UTS alone is insufficient for identifying a large proportion of CRC patients with hereditary syndromes, including some with LS. At a minimum, 7.1% of individuals with CRC have a PGV and pan-cancer MGPT should be considered for all patients with CRC.

Background Ovarian cancer is the fifth most common cause of cancer death among women in the US, yet few modifiable risk factors have been established. Diets high in glycemic index (GI) and glycemic load (GL) have been linked to several cancers, but epidemiologic studies of ovarian cancer have yielded inconsistent results. Objective In this study, we aimed to examine associations between GI or GL and ovarian cancer. Methods We used prospective data from the Prostate, Lung, Colorectal, and Ovarian cohort. GI and GL were calculated from validated FFQs. Participants were women who were aged 60 to 74 y, did not have a history of cancer, and had both ovaries. Cox proportional hazard models were used to calculate HRs and 95% CIs for risk of ovarian cancer associated with quartiles of GI and GL. Analyses were performed separately for those who completed the dietary questionnaire at baseline (DQX) or later in the study (DHQ). Results From the DQX sample set, 181 cases were identified among 24,633 women with median follow-up of 12.1 y; there were 211 cases among 42,410 women in the DHQ set, with median follow-up of 8.9 y. After adjusting for age at dietary questionnaire completion, year of randomization, year of questionnaire, study center, and oral contraceptive use, the risk of ovarian cancer decreased by 43% (HR: 0.57; 95% CI: 0.37, 0.88) among those in the highest compared with those in the lowest quartile of GL (DQX). Those in the highest compared with those in the lowest quartile of GI (DHQ), had a 38% lower risk (HR: 0.62; 95% CI: 0.42, 1.00). Conclusions We observed lower risk of ovarian cancer associated with higher GI and GL. Results should be interpreted with caution as they may have been influenced by limitations including lack of variability in dietary intake. Additional studies are needed to better understand what is driving these associations.

The microbiome has increasingly been linked to cancer. Little is known about the lung and oral cavity microbiomes in smokers, and even less for electronic cigarette (EC) users, compared with never-smokers. In a cross-sectional study (n = 28) of smokers, EC users, and never-smokers, bronchoalveolar lavage and saliva samples underwent metatranscriptome profiling to examine associations with lung and oral microbiomes. Pairwise comparisons assessed differentially abundant bacteria species. Total bacterial load was similar between groups, with no differences in bacterial diversity across lung microbiomes. In lungs, 44 bacteria species differed significantly (FDR < 0.1) between smokers/never-smokers, with most decreased in smokers. Twelve species differed between smokers/EC users, all decreased in smokers of which Neisseria sp. KEM232 and Curvibacter sp. AEP1-3 were observed. Among the top five decreased species in both comparisons, Neisseria elongata, Neisseria sicca, and Haemophilus parainfluenzae were observed. In the oral microbiome, 152 species were differentially abundant for smokers/never-smokers, and 17 between smokers/electronic cigarette users, but only 21 species were differentially abundant in both the lung and oral cavity. EC use is not associated with changes in the lung microbiome compared with never-smokers, indicating EC toxicity does not affect microbiota. Statistically different bacteria in smokers compared with EC users and never-smokers were almost all decreased, potentially due to toxic effects of cigarette smoke. The low numbers of overlapping oral and lung microbes suggest that the oral microbiome is not a surrogate for analyzing smoking-related effects in the lung. Prevention Relevance: The microbiome affects cancer and other disease risk. The effects of e-cig usage on the lung microbiome are essentially unknown. Given the importance of lung microbiome dysbiosis populated by oral species which have been observed to drive lung cancer progression, it is important to study effects of e-cig use on microbiome.

Background: There is growing evidence of an association between sugar-sweetened beverages (SSB) and increased risk of mortality in various populations. However, SSB influence on mortality among patients with breast cancer is unknown. Methods: We assessed the relationship between sugar-sweetened soda and both all-cause and breast cancer mortality among women with incident, invasive breast cancer from the Western New York Exposures and Breast Cancer Study. Breast cancer cases were followed for a median of 18.7 years, with ascertainment of vital status via the National Death Index. Frequency of sugar-sweetened soda consumption was determined via dietary recall using a food frequency questionnaire. Cox proportional hazards, adjusting for relevant variables, were used to estimate HRs and 95% confidence intervals (CI). Results: Of the 927 breast cancer cases, 386 (54.7%) had died by the end of follow-up. Compared with never/rarely sugar-sweetened soda drinkers, consumption at ≥5 times per week was associated with increased risk of both total (HR = 1.62; 95% CI, 1.16–2.26; Ptrend < 0.01) and breast cancer mortality (HR = 1.85; 95% CI, 1.16–2.94; Ptrend < 0.01). Risk of mortality was similarly increased among ER-positive, but not ER-negative patients; among women with body mass index above the median, but not below the median; and among premenopausal, but not postmenopausal women for total mortality only. Conclusions: Reported higher frequency of sugar-sweetened soda intake was associated with increased risks of both total and breast cancer mortality among patients with breast cancer. Impact: These results support existing guidelines on reducing consumption of SSB, including for women with a diagnosis of breast cancer.

Background: Nicotine-containing electronic cigarette (e-cig) use has become widespread. However, understanding the biological impact of e-cigs compared with smoking on the lung is needed. There are major gaps in knowledge for chronic effects and for an etiology to recent acute lung toxicity leading to death among vapers. Methods: We conducted bronchoscopies in a cross-sectional study of 73 subjects (42 never-smokers, 15 e-cig users, and 16 smokers). Using bronchoalveolar lavage and brushings, we examined lung inflammation by cell counts, cytokines, genome-wide gene expression, and DNA methylation. Results: There were statistically significant differences among never-smokers, e-cig users, and smokers for inflammatory cell counts and cytokines (FDR q < 0.1). The e-cig users had values intermediate between smokers and never-smokers, with levels for most of the biomarkers more similar to never-smokers. For differential gene expression and DNA methylation, e-cig users also more like never-smokers; many of these genes corresponded to smoking-related pathways, including those for xenobiotic metabolism, aryl hydrocarbon receptor signaling, and oxidative stress. Differentially methylated genes were correlated with changes in gene expression, providing evidence for biological effects of the methylation associations. Conclusions: These data indicate that e-cigs are associated with less toxicity than cigarettes for smoking-related pathways. What is unknown may be unique effects for e-cigs not measured herein, and a comparison of smokers completely switching to e-cigs compared with former smokers. Clinical trials for smokers switching to e-cigs who undergo serial bronchoscopy and larger cross-sectional studies of former smokers with and without e-cig use, and for e-cigs who relapse back to smoking, are needed. Impact: These data can be used for product regulation and for informing tobacco users considering or using e-cigs. What is unknown may be unique effects for e-cigs not measured herein, and clinical trials with serial bronchoscopy underway can demonstrate a direct relationship for changes in lung biomarkers.

Objectives To describe the self-reported oral health of participants in the Black Women's Health Study (BWHS), a national cohort of 59,000 Black women, and to assess factors associated with this self-report. Methods Annual follow-up of the BWHS cohort occurs via surveys. The 2011 questionnaire included oral health self-report items, on which 38,573 respondents had complete data. Sample characteristics were summarized using descriptive statistics. We assessed correlations with several covariates by estimating odds ratios using multivariable-adjusted logistic regression models. Results Those who reported fair or poor oral health were more likely to report current smoking, recent tooth loss, diabetes or hypertension diagnoses, lower education levels, obesity, and higher parity. Few factors were related to self-reported gum disease with bone loss. Conclusions The oral health of US Black women is poorly understood. Correlates of oral health in the BWHS are largely consistent with what has been observed in other populations.

While there is consistent evidence of increased risk of postmenopausal breast cancer associated with higher body mass index (BMI), higher adult weight gain and higher waist circumference in North American and European populations, there is little evidence for Hispanic women. Among Hispanic women in Puerto Rico (PR), breast cancer is the leading type of cancer, and leading cause of cancer related deaths. However, compared with the United States, breast cancer rates are lower but increasing more rapidly. Purpose: To determine associations between anthropometric characteristics and breast cancer risk in Hispanic women in PR. Methods: Data from a population-based case control study in the San Juan metropolitan region was used to examine associations between anthropometric measures and breast cancer risk, also considering menopausal status and hormone therapy (HT). Results: Among premenopausal women, BMI equal or higher than 25 kg/m2 and waist to height ratio (WHtR) of 0.53 or higher were associated with lower odds of breast cancer. For postmenopausal breast cancer, waist circumference of 86.4 cm or higher, WHtR of 0.57 or higher, waist to hip ratio of 0.84 or greater, and height of 150 cm or taller were associated with lower odds of breast cancer. Conclusion: Our study provides evidence that associations of risk with anthropometry may differ for Hispanic women. Future studies should include measures of fat and lean mass distribution to further understand anthropometric measures and breast cancer risk among Hispanic women.

Background: Though inconsistent, there is evidence that sun exposure is associated with reduced breast cancer risk. Previous studies have been conducted in geographical regions with seasonal variation in UV radiation, including periods of low to no exposure, and among participants mostly of European descent. Puerto Rico has no significant seasonal fluctuation, with continuous exposure to very high UV radiation. Methods: We conducted a population-based case–control study of breast cancer among women in metropolitan San Juan, Puerto Rico, examining a cumulative sun exposure index (SEI) based on a comparison of reflectance of sun-exposed and non-exposed skin. A chromameter was used to measure skin reflectance and estimate the difference between constitutive (unexposed) and facultative (exposed) skin pigmentation in 307 cases and 328 controls. Breast cancer risk factors were ascertained with interviewer-administered questionnaires. OR and 95% confidence intervals (CI) were estimated with unconditional logistic regression. Results: Adjusted breast cancer odds were lower for the highest tertile of the SEI (ORadj = 0.47; 95% CI, 0.29–0.74). Results were similar within strata of estrogen receptor status. In analyses stratified by constitutive skin pigmentation, among participants with darker skin color, breast cancer risk was lower with more sun exposure (ORadj = 0.33; 95% CI, 0.16–0.70). Conclusions: We found lower risk of breast cancer associated with greater sun exposure in a population living with high, continuous sun exposure. This beneficial finding should be placed in the context of other effects of sun exposure. Impact: Sun exposure is a modifiable factor that may contribute, directly or indirectly, to lower breast cancer risk.

Limited research exists on carbohydrate intake and oral microbiome diversity and composition assessed with next-generation sequencing. We aimed to better understand the association between habitual carbohydrate intake and the oral microbiome, as the oral microbiome has been associated with caries, periodontal disease, and systemic diseases. We investigated if total carbohydrates, starch, monosaccharides, disaccharides, fiber, or glycemic load (GL) were associated with the diversity and composition of oral bacteria in subgingival plaque samples of 1204 post-menopausal women. Carbohydrate intake and GL were assessed from a food frequency questionnaire, and adjusted for energy intake. The V3–V4 region of the 16S rRNA gene from subgingival plaque samples were sequenced to identify the relative abundance of microbiome compositional data expressed as operational taxonomic units (OTUs). The abundance of OTUs were centered log(2)-ratio transformed to account for the compositional data structure. Associations between carbohydrate/GL intake and microbiome alpha-diversity measures were examined using linear regression. PERMANOVA analyses were conducted to examine microbiome beta-diversity measures across quartiles of carbohydrate/GL intake. Associations between intake of carbohydrates and GL and the abundance of the 245 identified OTUs were examined by using linear regression. Total carbohydrates, GL, starch, lactose, and sucrose intake were inversely associated with alpha-diversity measures. Beta-diversity across quartiles of total carbohydrates, fiber, GL, sucrose, and galactose, were all statistically significant (p for PERMANOVA p Streptococcus mutans; GL and both Sphingomonas HOT 006 and Scardovia wiggsiae; and sucrose and Streptococcus lactarius. A negative association was observed between lactose and Aggregatibacter segnis, and between sucrose and both TM7_[G-1] HOT 346 and Leptotrichia HOT 223. Intake of total carbohydrate, GL, and sucrose were inversely associated with subgingival bacteria alpha-diversity, the microbial beta-diversity varied by their intake, and they were associated with the relative abundance of specific OTUs. Higher intake of sucrose, or high GL foods, may influence poor oral health outcomes (and perhaps systemic health outcomes) in older women via their influence on the oral microbiome.

During the COVID-19 pandemic, social distancing measures often resulted in individual isolation, which can lead to adverse mental outcomes. We collected online questionnaires from 3,952 US adults to examine the impact of “shelter-in-place” guidelines on mental health, and to explore potential disparities and modifiable factors. Self-reported anxiety, depression, and PTSD symptoms were associated with more restrictive quarantine. Younger adults, women, those with lower income, more insecurity, more media exposure, reduced physical activity, or worsened family relationships were particularly affected. Targeted prevention on susceptible subpopulations, including young adults and lower SES groups, might help mitigate disparities in COVID-19-related mental health problems.

Background: While periodontal disease has been linked to increased cancer risk, studies regarding an association with breast cancer are limited. Methods: We examined the relationship between self-reported diagnosis of periodontal bone loss and incidence of breast cancer in a large, prospective cohort study, the Nurses' Health Study (1998–2014). We calculated HRs using Cox proportional hazards modeling, adjusting for risk factors common to both periodontal disease and breast cancer. Results: During 1,023,647 person-years of follow-up, 5,110 of breast cancer cases were reported. We observed no association between periodontal disease and overall breast cancer risk (HR, 1.02; 95% confidence interval: 0.94–1.10); the association was not modified by smoking status, or other breast cancer risk factors or by breast tumor subtypes. Conclusions: We did not observe any association between periodontal disease and breast cancer risk. Impact: Given inconsistent findings in the literature, further research with standardized clinical measures of periodontitis is warranted.

Background: Up to 75% of ovarian cancers will become platinum resistant and survival following the development of resistance is typically less than one year. New therapies with higher curative rates are needed to improve prognosis. There has been increasing interest in inhibitors of sodium glucose cotransporter-2 (SGLT2) in suppressing tumor growth. Use of SGLT2 inhibitors show promise not only due to their ability to inhibit glucose uptake, but also from the subsequent improvements in other metabolic disorders that may affect cancer prognosis. Purpose: We evaluated the associations of tumor SGLT2 protein expression with survival following diagnosis of incident epithelial ovarian cancer (EOC). Methods: Tumor samples were obtained from 492 patients undergoing debulking surgery for primary EOC at Roswell Park Comprehensive Cancer Center between 1995 and 2002. Only incident cases and patients who did not receive neo-adjuvant chemotherapy were included in analyses (n=396). Tissue samples were compiled into tissue microarray blocks that were sectioned, stained, imaged, and analyzed for SGLT2 expression. Data on patient, clinical, and tumor characteristics, along with available information on components of metabolic disorders, were linked to each patient. Multivariate Cox proportional hazards models were performed to determine hazards ratios (HR) and 95% confidence intervals (CI) for EOC-specific and all-cause mortality. Results: In our analysis of 396 EOC patients seen at Roswell Park, we observed significant associations between high SGLT2 expression and decreased risk of both EOC-specific (HR: 0.68; 95% CI: 0.49-0.94) and all-cause mortality (HR: 0.71; 95% CI: 0.53-0.95). In particular, among those with advanced-stage tumors, there was a significant association between high SGLT2 expression and lower risk of EOC-specific (HR: 0.61; 95% CI: 0.42-0.91) and all-cause mortality (HR: 0.64; 95% CI: 0.45-0.90). A lower risk of all-cause mortality was observed among those with high-grade tumors (HR: 0.69; 95% CI: 0.48-0.98). Trends of increasing SGLT2 associated with decreased risk of mortality varied by histological subtype. The inverse association between high SGLT2 and EOC-death was stronger among those with a history of hyperlipidemia (HR: 0.46; 95% CI: 0.19-0.99) and obesity (HR: 0.43; 95% CI: 0.23-0.82) compared to other metabolic syndrome components. These associations were less robust for all-cause mortality. Conclusion: Contrary to our initial hypothesis, higher SGLT2 expression among EOC patients may be associated with more favorable prognosis. This association may be stronger for high grade and advanced stage tumors as well as non-serous subtypes. Identifying other factors associated with levels of expression could aid in the development of potential screening interventions and more personalized treatment. Citation Format: Jennifer M. Mongiovi, Jo L. Freudenheim, Jeff C. Miecznikowski, Susan E. McCann, Ashley E. Stenzel, Wiam Bshara, Agnieszka Witkiewicz, Leighton Stein, Lisa D. Kellenberger, Ahmad Al Sulimani, Kirsten B. Moysich. Associations of sodium glucose cotransporter-2 (SGLT2), metabolic disorders, and survival following incident epithelial ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6402.

Background: Somatic driver mutations in TP53 are associated with triple negative breast cancer (TNBC) and poorer outcomes. Breast cancers arising in women of African ancestry (AA) are more likely to be TNBC and have somatic TP53 mutations than non-Hispanic White (NHW) women. Missense driver mutations in TP53 are known to have different functional effects including loss-of function (LOF) or gain-of-function (GOF) activity. A subset of variants exhibit dominant negative (DNE) activity over wildtype TP53 or other TP53 family members. Methods: To determine if there were differences in TP53 mutation type by race or TNBC status we identified published and unpublished datasets with somatic mutation data, race, age, and hormone receptor status. Mutations were classified as LOF, GOF or CpG Island hotspot by published literature or type of mutation (e.g. frameshift and nonsense mutations were considered to be LOF). We used Fisher’s Exact test to assess for significant differences.Results: We identified 96 independent breast cancer studies with race and somatic TP53 mutation status available. The study comprised data from a total of 2964 women with somatic TP53 mutations: 715 (24.1%) Asian, 258 (8.7%) AA, 1931 (65.2%) NHW, and 60 (2%) Latina. Of the total TP53 mutations, 939 (31.7%) were GOF, 1739 (58.7%) were LOF, and the remaining 286 (9.6%) were not able to be classified. With respect to DNE activity, 1246 (42%) showed activity, 1190 (40.1%) showed no activity, and 528 (17.8%) were unknown status. The distribution of TP53 mutation type was similar by race and ethnicity. However, 35.8% of tumors from NHW individuals had GOF mutations compared to 29% in AA individuals (p=0.04). Mutations lacking DNE activity were positively associated with TNBC (OR=1.37, p=0.03) and estrogen receptor (ER) negative status (OR=1.38; p=0.005). Conclusions: In summary, ER negative and TNBC breast tumors are less likely to have DNE+ TP53 mutations which could reflect biological processes. Larger cohorts are needed to further elucidate some of these findings.

Background An outbreak of E-cigarette or Vaping Product Use-Associated Lung Injury (EVALI) with significant morbidity and mortality was reported in 2019. While most patients with EVALI report vaping tetrahydrocannabinol (THC) oils contaminated with vitamin E acetate, a subset report only vaping with nicotine-containing electronic cigarettes (e-cigs). Whether or not e-cigs cause EVALI, the outbreak highlights the need for identifying long term health effects of e-cigs. EVALI pathology includes alveolar damage, pneumonitis and/or organizing pneumonia, often with lipid-laden macrophages (LLM). We assessed LLM in the lungs of healthy smokers, e-cig users, and never-smokers as a potential marker of e-cig toxicity and EVALI. Methods A cross-sectional study using bronchoscopy was conducted in healthy smokers, e-cig users, and never-smokers (n = 64). LLM, inflammatory cell counts, and cytokines were determined in bronchial alveolar fluids (BAL). E-cig users included both never-smokers and former light smokers. Findings High LLM was found in the lungs of almost all smokers and half of the e-cig users, but not those of never-smokers. LLM were not related to THC exposure or smoking history. LLM were significantly associated with inflammatory cytokines IL-4 and IL-10 in e-cig users, but not smoking-related cytokines. Interpretation This is the first report of lung LLM comparing apparently healthy smokers, e-cig users, and never-smokers. LLM are not a specific marker for EVALI given the frequent positivity in smokers; whether LLMs are a marker of lung inflammation in some e-cig users requires further study. Funding The National Cancer Institute, the National Heart, Lung, and Blood Institute, the Food and Drug Administration Center for Tobacco Products, the National Center For Advancing Translational Sciences, and Pelotonia Intramural Research Funds

Globally, more than 2 million new cases of breast cancer are reported annually. The United States alone has more than 496,000 new cases every year. The worldwide prevalence is approximately 6.8 million cases. Although many risk factors for breast cancer are not modifiable, understanding the role of the factors that can be altered is critical. Alcohol consumption is a modifiable factor. Studies of alcohol in relation to breast cancer incidence have included hundreds of thousands of women. Evidence is consistent that intake, even intake of less than 10-15 grams per day, is associated with increased risk of this disease. In addition, evidence, although less extensive, shows that possible early indicators of risk, such as benign breast disease and increased breast density, are associated with alcohol consumption. Evidence is less strong for differences based on geographic region, beverage type, drinking pattern, or breast cancer subtype. Some studies have examined the association between alcohol and recurrence or survival after a breast cancer diagnosis. These findings are less consistent. Public awareness of alcohol as a risk factor for breast cancer is low, and public health measures to increase that awareness are warranted.

Breast cancer is a heterogeneous disease, characterized by molecularly and phenotypically distinct tumor subtypes, linked to disparate clinical outcomes. American women of African ancestry (AA) are more likely than those of European ancestry (EA) to be diagnosed with aggressive, estrogen receptor negative (ER−) or triple negative breast cancer, and to die of this disease. However, the underlying causes of AA predisposition to ER−/triple negative breast cancer are still largely unknown. In this study, we performed high-throughput whole-genome miRNA expression profiling in breast tissue samples from both AA and EA women. A number of differentially expressed miRNAs, i.e., DEmiRs defined as >2-fold change in expression and false discovery rate

Background We previously reported increased risk of breast cancer associated with early life exposure to two measures of air pollution exposure, total suspended particulates (TSP) and traffic emissions (TE), possible proxies for exposure to polycyclic aromatic hydrocarbons (PAHs). Exposure to PAHs has been shown to be associated with aberrant patterns of DNA methylation in peripheral blood of healthy individuals. Exposure to PAHs and methylation in breast tumor tissue has received little attention. We examined the association of early life exposure to TSP and TE with patterns of DNA methylation in breast tumors. Methods We conducted a study of women enrolled in the Western New York Exposures and Breast Cancer (WEB) Study. Methylation of nine genes (SFN, SCGB3A1, RARB, GSTP1, CDKN2A CCND2, BRCA1, FHIT, and SYK) was assessed using bisulfite-based pyrosequencing. TSP exposure at each woman's home address at birth, menarche, and when she had her first child was estimated. TE exposure was modeled for each woman's residence at menarche, her first birth, and twenty and ten years prior to diagnosis. Unconditional logistic regression was employed to estimate odds ratios (OR) of having methylation greater than the median value, adjusting for age, secondhand smoke exposure before age 20, current smoking status, and estrogen receptor status. Results Exposure to higher TSP at a woman's first birth was associated with lower methylation of SCGB3A1 (OR = 0.48, 95% CI: 0.23–0.99) and higher methylation of SYK (OR = 1.86, 95% CI: 1.03–3.35). TE at menarche was associated with increased methylation of SYK (OR = 2.37, 95% CI: 1.05–5.33). TE at first birth and ten years prior to diagnosis was associated with decreased methylation of CCND2 (OR ten years prior to diagnosis=0.48, 95% CI: 0.26–0.89). Although these associations were nominally significant, none were significant after adjustment for multiple comparisons (p Conclusions We observed suggestive evidence that exposure to ambient air pollution throughout life, measured as TSP and TE, may be associated with DNA methylation of some tumor suppressor genes in breast tumor tissue. Future studies with a larger sample size that assess methylation of more sites are warranted.

Night shift work is associated with increased breast cancer risk, possibly from altered sleep. Epidemiologic evidence is sparse regarding sleep disturbances and breast cancer tumor markers. We examined sleep disturbance in association with breast tumor aggressiveness and mortality following diagnosis.We analyzed associations of measures of sleep disturbance in a sample of 1,122 incident breast cancer cases from the Western New York Exposures and Breast Cancer (WEB) Study. Sleep disturbance was assessed using self-administered questionnaires; responses about difficulty falling asleep, waking up frequently, having trouble staying asleep, and waking up feeling tired and worn out were used to create a summary sleep disturbance score. We used general linear models to examine associations of sleep disturbance with markers of tumor aggressiveness among cases: estrogen receptor (ER) status, progesterone receptor (PR) status, and human epidermal growth factor receptor-2 (HER2) status; tumor size, stage, grade, lymph node involvement, and presence of metastasis. In addition, we examined the association between sleep disturbance and survival using Cox regression.Among breast cancer cases, sleep disturbance was higher for women with ER- / PR- tumors compared to women with ER+ / PR+ tumors, even after adjusting for potential covariates (Sleep disturbance may be associated with aggressive subtypes of breast cancer; however, further studies are needed.

Background: Electronic cigarettes (e-cigs) are one of the most popular tobacco products in the US. Little is known regarding their pulmonary effects. E-cigs induce similar oxidant reactivity as cigarette smoke and promote oxidative damage/inflammation in airway cells. Given that mtDNA is more prone to oxidative stress than nuclear DNA because of a less effective proofreading system, mtDNA alterations may be important indicators of e-cigs' toxic effects. Clinically, mitochondrial DNA alteration is an emerging biomarker of respiratory diseases. Methods: We compared mtDNA copy number (mtDNA-CN) from lung brushings in a cross-sectional bronchoscopy study of healthy young adults, e-cig users (EC)(n=15), non-smokers, non-EC users (NS)(n=43), and smokers (SM)(n=26). We examined associations of mtDNA-CN with immune response (differential cell counts and cytokines in bronchoalveolar lavage), DNA methylation and gene expression brushings. Associations for: 1) EC vs NS vs SM, and 2) tobacco product users (EC+SM) vs NS for MtDNA-CN with immune response, methylation, and expression were made using linear regression. Further, significant features by group interactions were followed up by within-group tests. False Discovery Rate (FDR) at 0.1 was considered significant. Ingenuity pathway analysis was used to identify the most significantly enriched pathways/molecular functions/diseases. Results: MtDNA-CN was not significantly different among the three groups (P=0.06). MtDNA-CN was higher in SM than NS (P=0.02), and in tobacco product users than NS (P=0.02); EC mtDNA-CN tended to be intermediate between the 2 other groups. There were significantly positive associations of IL-2 and IL-4 with mtDNA-CN in EC, but not in SM or NS (Interaction FDR=0.06 for both). We found 147 transcripts (60 genes) and 1,153 CpGs (713 genes) to be significantly associated with mtDNA-CN in all three groups. The most common canonical pathway of the signatures for both expression and methylation were immune responses. The top molecular and cellular functions for both included cell death and survival. Ten transcripts (LINC01184, SNU13, RPL35A, COLCA1, HLA-DRB1, LOC105379655, TRIM9, TCIRG1, CLPB, MIR2114) and 3,929 CpGs (top: ULK4, STARD13, HLCS, FLT1, TMEM91, CYP2J2) were associated with mtDNA-CN in E-cig users only. Some of these genes are known to play a role in lung diseases, including cancer. For the signatures associated in all groups, we found many more significant signatures (236 vs 147 transcripts and 40,830 vs 1,153 CpGs) in the two group vs. three group comparisons, respectively. Conclusion: While the sample size was small, this study is the first to suggest that mtDNA-CN is a site of pulmonary toxic effects. We found associations of mtDNA-CN with inflammatory markers among EC users, and with a number of biological signatures, particularly genes related to immune response, in the lungs of EC, SM, and NS, but differently by groups for some. Citation Format: Kellie M. Mori, Joseph P. McElroy, Daniel Y. Weng, Sangwoon Chung, Sarah A. Reisinger, Kevin L. Ying, Quentin A. Nickerson, Theodore M. Brasky, Mark D. Wewers, Jo L. Freudenheim, Peter G. Shields, Min-Ae Song. Lung mitochondrial DNA copy number variations: E-cig users, smokers, and never-smokers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 751.

OBJECTIVES: Magnesium, an essential mineral, are antagonistic in many physiologic processes. However, few studies have investigated the associations of magnesium intake with liver cancer risk. METHODS: We evaluated the association between intake of magnesium and risk of liver cancer in the Women's Health Initiative (WHI) Observational Study. This analysis included 77,170 participants who completed a food frequency questionnaire, free of cancer, and without missing values for follow-up dates and body mass index (BMI). Magnesium intakes from diet and supplements were estimated through the baseline food frequency questionnaire. Cox regression models were used to estimate hazard ratios (HR) and 95% confidence intervals (95% CI). RESULTS: After 15.8 years’ cumulative follow-up, there were 207 liver cancer cases. After adjustment for known risk factors of liver cancer, and intakes of energy, total vitamin D and calcium, higher intake of magnesium was inversely associated with risk of liver cancer (HR = 0.26, 95% CI, 0.09–0.76) for highest vs. lowest quartile; P trend = 0.01). Every 100 mg increase in intake of magnesium was associated with a 34% reduction in the risk of liver cancer. Although interactions between magnesium intake and alcohol use and BMI at baseline were not significant (P > 0.05), inverse associations between magnesium intake and liver cancer risk were primarily presented among postmenopausal women who were current alcohol drinkers at the baseline and had BMI ≥ 25. CONCLUSIONS: We found that higher magnesium intake may reduce liver cancer incidence among postmenopausal women particularly among those who were current alcohol drinkers and overweight/obese. FUNDING SOURCES: No

Despite known age-related DNA methylation (aDNAm) changes in breast tumors, little is known about aDNAm in normal breast tissues. Breast tissues from a cross-sectional study of 121 cancer-free women, were assayed for genome-wide DNA methylation. mRNA expression was assayed by microarray technology. Analysis of covariance was used to identify aDNAm's. Altered methylation was correlated with expression of the corresponding gene and with DNA methyltransferase protein DNMT3A, assayed by immunohistochemistry. Publically-available TCGA-BRCA data were used for replication. 1,214 aDNAm's were identified; 97% with increased methylation, and all on autosomes. Sites with increased methylation were predominantly in CpG lslands and non-enhancers. aDNAm's with decreased methylation were generally located in intergenic regions, non-CpG Islands, and enhancers. Of the aDNAm's identified, 650 are known to be involved in cancer, including ESR1 and beta-estradiol responsive genes. Expression of DNMT3A was positively associated with age. Two aDNAm's showed borderline significant associations with DNMT3A expression; KRR1 (OR 6.57, 95% CI: 2.51-17.23) and DHRS12 (OR 6.08, 95% CI: 2.33-15.86). A subset of aDNAm's co-localized within vulnerable regions for somatic mutations in cancers including breast cancer. Expression of C19orf48 was inversely and significantly correlated with its methylation level. In the TCGA dataset, 84% and 64% of the previously identified aDNAm's were correlated with age in both normal-adjacent and tumor breast tissues, with differential associations by histological subtype. Given the similarity of findings in the breast tissues of healthy women and breast tumors, aDNAm's may be one pathway for increased breast cancer risk with age.

Background: Periodontal pathogens have been isolated from precancerous and cancerous lesions and also shown to promote a procarcinogenic microenvironment. Few studies have examined periodontal disease as a risk factor for total cancer, and none have focused on older women. We examined whether periodontal disease is associated with incident cancer among postmenopausal women in the Women's Health Initiative Observational Study. Methods: Our prospective cohort study comprised 65,869 women, ages 54 to 86 years. Periodontal disease information was obtained via self-report questionnaires administered between 1999 and 2003, whereas ascertainment of cancer outcomes occurred through September 2013, with a maximum follow-up period of 15 years. Physician-adjudicated incident total cancers were the main outcomes and site-specific cancers were secondary outcomes. HRs and 95% confidence intervals (CI) were calculated using Cox proportional hazards regression. All analyses were conducted two-sided. Results: During a mean follow-up of 8.32 years, 7,149 cancers were identified. Periodontal disease history was associated with increased total cancer risk (multivariable-adjusted HR, 1.14; 95% CI, 1.08–1.20); findings were similar in analyses limited to 34,097 never-smokers (HR, 1.12; 95% CI, 1.04–1.22). Associations were observed for breast (HR, 1.13; 95% CI, 1.03–1.23), lung (HR, 1.31; 95% CI, 1.14–1.51), esophagus (HR, 3.28; 95% CI, 1.64–6.53), gallbladder (HR, 1.73; 95% CI, 1.01–2.95), and melanoma skin (HR, 1.23; 95% CI, 1.02–1.48) cancers. Stomach cancer was borderline (HR, 1.58; 95% CI, 0.94–2.67). Conclusions: Periodontal disease increases risk of total cancer among older women, irrespective of smoking, and certain anatomic sites appear to be vulnerable. Impact: Our findings support the need for further understanding of the effect of periodontal disease on cancer outcomes. Cancer Epidemiol Biomarkers Prev; 26(8); 1255–65. ©2017 AACR.

Background Magnesium and calcium are antagonistic in many physiologic processes. However, few studies have investigated the associations of supplemental calcium with lung cancer risk taking this antagonism into account. We evaluated the effect of calcium and vitamin D supplementation on lung cancer incidence and explored whether the ratio of baseline calcium to magnesium (Ca:Mg) intake modifies the association in the Women’s Health Initiative (WHI) calcium plus vitamin D supplementation (CaD) trial. Methods The intervention phase of the WHI CaD was a double-blinded, randomized, placebo-controlled trial in 36,382 postmenopausal women aged 50–79 years, recruited at 40 U.S. centers. Post-intervention follow-up continued among 29,862 (86%) of the surviving participants. Risk of lung cancer in association with CaD supplementation was evaluated using proportional hazard regression models. Results After 11 years’ cumulative follow-up, there were 207 lung cancers (incidence 0.11% per year) in the supplement arm and 241 (0.12%) in the placebo arm (hazard ratio (HR) for the intervention, 0.91; 95% confidence interval (CI), 0.71–1.17). Subgroup analyses suggested that the HR for lung cancer varied by baseline Ca:Mg intake ratio among women who were current smokers at enrollment ( p = 0.04 for interaction). Conclusions Over the entire follow-up period, calcium and vitamin D supplementation did not reduce lung cancer incidence among postmenopausal women. In exploratory analyses, an interaction was found for the baseline Ca:Mg intake ratio on lung cancer among current smokers at the trial entry. This findings need to be further studied for the role of calcium with magnesium in lung carcinogenesis in current smokers.

Objectives To identify the types of cancer patients admitted to inpatient medical rehabilitation and to describe their rehabilitation outcomes. Design Retrospective cohort study. Setting U.S. inpatient rehabilitation facilities (IRFs). Participants Adult patients (N=27,952) with a malignant cancer diagnosis admitted to an IRF with a cancer-related impairment between October 2010 and September 2012 were identified from the Uniform Data System for Medical Rehabilitation database. Interventions Not applicable. Main Outcome Measures Demographic, medical, and rehabilitation characteristics for patients with various cancer tumor types were summarized using data collected from the Inpatient Rehabilitation Facility–Patient Assessment Instrument. Rehabilitation outcomes included the percentage of patients discharged to the community and acute care settings, and functional change from admission to discharge. Functional status was measured using the FIM instrument. Results Cancer patients constituted about 2.4% of the total IRF patient population. Cancer types included brain and nervous system (52.9%), digestive (12.0%), bone and joint (8.7%), blood and lymphatic (7.6%), respiratory (7.1%), and other (11.7%). Overall, 72% were discharged to a community setting, and 16.5% were discharged back to acute care. Patients with blood and lymphatic cancers had the highest frequency of discharge back to acute care (28%). On average, all cancer patient groups made significant functional gains during their IRF stay (mean FIM total change ± SD, 23.5±16.2). Conclusions In a database representing approximately 70% of all U.S. patients in IRFs, we found that patients with a variety of cancer types are admitted to inpatient rehabilitation. Most cancer patients admitted to IRFs were discharged to a community setting and, on average, improved their function. Future research is warranted to understand the referral patterns of admission to postacute care rehabilitation and to identify factors that are associated with rehabilitation benefit in order to inform the establishment of appropriate care protocols.

Epidemiological studies suggest that short sleep duration and poor sleep quality may increase breast cancer risk. However, whether sleep is associated with breast tumor aggressiveness characteristics has largely been unexplored.The study included 4171 non-Hispanic whites (NHW) and 235 African Americans (AA) diagnosed with incident, primary, invasive breast cancer in the Women's Health Initiative (WHI) Observational Study (1994-2013). We used logistic regression to examine the association of baseline sleep (sleep duration, sleep quality, WHI Insomnia Rating Scale) with tumor grade, stage, hormone receptor status, HER2 status.In NHW, women who reported 6 h of sleep/night were more likely to have tumors classified as regional/distant stage at diagnosis compared to women who slept 7-8 h/night (adjusted odds ratio (OR): 1.25, 95% confidence interval (CI): 1.05-1.48). AA women who reported their typical night's sleep as 'average quality' or 'restless or very restless sleep' were more likely to be diagnosed with triple-negative tumors than those who reported 'sound or restful' sleep (adjusted ORs: 2.91 (1.11, 7.63) and 3.74 (1.10, 12.77), respectively).Our findings provide indications that aspects of sleep (sleep duration and quality), partially modifiable health behaviors, may be associated with development of aggressive tumor characteristics in postmenopausal women. The role of these sleep attributes may differ for NHW and AA women; however, further study in robust, racial diverse samples is needed. This study provides evidence that facets of sleep behavior are associated with the development of aggressive tumor features and these associations differ by race.

The relationship between obesity and depression is well described. However, the evidence linking depression and body mass index (BMI) across the broad range of body size is less consistent. We examined the association between depressive symptoms and BMI in a sample of adult women in the Buffalo-Niagara region between 1997 and 2001. Using logistic regression, we investigated whether increased weight status beyond normal-weight was associated with a higher prevalence of depressive symptoms, and if educational attainment modified the association between obesity and depression. There was a trend for increased weight status to be associated with higher depressive symptoms (obese II/III, OR 1.57, 95% CI 1.03–2.41), whereas higher education was associated with lower odds of depressive symptoms, in an adjusted model including BMI (more than 12 but less than 16 years, OR 0.70, 95% CI 0.49–0.98; 16 or more years of education, OR 0.61, 95% CI 0.40–0.93). The association of being obese I with depressive symptoms was different for more educated (OR 2.15, 95% CI 1.27–3.62) compared to less educated women (OR 0.90, 95% CI 0.50–1.62); the sample was larger for the more educated women and reached statistical significance. There were no differences in the association for obese II/III women in strata of education. There was evidence of risk-difference heterogeneity (0.88, 95% CI 0.84–0.93). In this population-based sample of women in western New York State, increased weight was negligibly associated with depressive symptoms. The association of being obese I with depressive symptoms was different for more compared to less educated women.