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Background: Cell-to-cell adhesion and angiogenesis are hallmarks of cancer. No studies have examined associations of adhesion molecules and angiogenesis biomarkers with clinical outcomes in colorectal cancer. Methods: In presurgery serum from n = 426 patients with colorectal cancer (stage I–III), we investigated associations of CRP, SAA, adhesion molecules (sICAM-1, sVCAM-1), and angiogenesis markers (VEGF-A and VEGF-D) with overall survival (OS), disease-free survival (DFS), and risk of recurrence. We computed HRs and 95% confidence intervals; adjusted for age, sex, BMI, stage, site, and study site, stratified by tumor site in exploratory analyses. Results: N = 65 (15%) were deceased, and 39 patients (14%) had a recurrence after a median follow-up of 31 months. We observed significant associations of biomarkers with OS, DFS, and risk of recurrence on a continuous scale and comparing top to bottom tertile, with HRs ranging between 1.19 and 13.92. CRP was associated with risk of death and recurrence in patients in the top tertile compared with patients in the bottom tertile, for example, risk of recurrence HRQ3-Q1: 13.92 (1.72–112.56). Significant heterogeneity between biomarkers and clinical outcomes was observed in stratified analysis by tumor site for CRP, SAA, sICAM-1, sVCAM-1, and VEGF-D. VEGF-D was associated with a 3-fold increase in risk of death for rectal cancer (HRlog2: 3.26; 95% CI, 1.58–6.70) compared with no association for colon cancer (HRlog2: 0.78; 95% CI, 0.35–1.73; Pheterogenity = 0.01). Conclusions: Adhesion molecules and angiogenesis biomarkers are independent prognostic markers for colorectal cancer, with differences by tumor site. Impact: There is need for tailored treatment for colon and rectal cancer.

There is limited information on how the COVID-19 pandemic has changed health behaviors among cancer patients. We examined changes in exercise behaviors since the pandemic and identified characteristics associated with these changes among cancer patients.Cancer patients (n = 1,210) completed a survey from August to September 2020 to assess COVID-19 pandemic-related changes in health behaviors and psychosocial factors. Patients were categorized into three groups: exercising less, exercising did not change, and exercising more. Patient characteristics were compared by exercise groups.One-third of the patients reported a decreased amount of regular exercise, while 10% reported exercising more during the pandemic. Patients who exercised less were more likely to be unemployed/retired and have poor health status and psychosocial stressors such as disruptions in daily life while less likely to be former smokers (all p 0.05). In contrast, patients who exercised more were younger, had stage IV diagnosis, and also reported disruptions in daily life (all p 0.05). Patients who were living in rural areas were also more likely not to experience changes in exercise habits (all p 0.05), although rural-urban status was not identified as a strong predictor.A significant proportion of cancer patients experienced changes in exercise habits, especially exercising less, during the first 6 months of the COVID-19 pandemic. Age, employment status, tumor stage, health status, smoking status, and psychosocial factors were associated with changes in exercise behaviors. Our results highlight the importance of promoting physical activity guidelines for cancer survivorship during the COVID-19 pandemic and may help improve the identification of cancer patients susceptible to exercising less.

INTRODUCTION: Telomere shortening, as seen with aging, can cause chromosomal instability and promote cancer progression. We investigated the association between circulating telomere length and overall and disease-free survival in a sub-cohort of patients with colorectal cancer. METHODS: Baseline genomic DNA from blood leukocytes was extracted from N=92 newly diagnosed stage I-IV patients with colorectal cancer enrolled at the ColoCare Study site in Heidelberg, Germany. Detailed information on clinicodemographic (including age) and lifestyle risk factors, and clinical outcomes (including recurrence and survival) was collected. Telomere length was measured in DNA using multiplex quantitative polymerase chain reaction. Kaplan Meier survival curves were generated comparing shorter to longer telomere lengths with log-rank testing. RESULTS: The mean T/S ratio for study patients was 0.5 (range: 0.3-0.9). Shorter telomeres were associated with older age at baseline. Patients with shorter telomeres experienced a worse overall and disease-free survival, although this association did not reach statistical significance. Kaplan-Meier survival curves for those with circulating telomere length below vs. above the median showed poorer overall (log-rank p=0.31) and disease-free survival (long-rank p=0.23). CONCLUSIONS: Our results suggest that individuals with shorter telomeres, as seen with aging, may experience a worse overall and disease-free survival after colorectal cancer diagnosis. Larger sample sizes with longer follow-up are needed to further evaluate telomere length as a prognostic biomarker in colorectal cancer progression.

BACKGROUND: Genetic variation in one-carbon metabolism may affect nutrient concentrations and biological functions. However, data on genetic variants associated with blood biomarkers of one-carbon metabolism in US postmenopausal women are limited, and whether these associations were affected by the nationwide folic acid (FA) fortification program is unclear. OBJECTIVES: We investigated associations between genetic variants and biomarkers of one-carbon metabolism using data from the Women's Health Initiative Observational Study. METHODS: In 1573 non-Hispanic White (NHW) and 282 Black/African American, American Indian/Alaska Native, Asian/Pacific Islander, and Hispanic/Latino women aged 50–79 y, 288 nonsynonymous and tagging single-nucleotide variants (SNVs) were genotyped. RBC folate, plasma folate, pyridoxal-5′-phosphate (PLP), vitamin B-12, homocysteine, and cysteine concentrations were determined in 12-h fasting blood. Multivariable linear regression tested associations per variant allele and for an aggregated genetic risk score. Effect modifications before, during, and after nationwide FA fortification were examined. RESULTS: After correction for multiple comparisons, among NHW women, 5,10-methylenetetrahydrofolate reductase (MTHFR) rs1801133 (677C→T) variant T was associated with lower plasma folate (−13.0%; 95% CI: −17.3%, −8.6%) and higher plasma homocysteine (3.5%; 95% CI: 1.7%, 5.3%) concentrations. Other associations for nonsynonymous SNVs included DNMT3A rs11695471 (T→A) with plasma PLP; EHMT2 rs535586 (G→A), TCN2 rs1131603 (L349S A→G), and TCN2 rs35838082 (R188W G→A) with plasma vitamin B-12; CBS rs2851391 (G→A) with plasma homocysteine; and MTHFD1 rs2236224 (G→A) and rs2236225 (R653Q G→A) with plasma cysteine. The influence of FA fortification on the associations was limited. Highest compared with lowest quartiles of aggregated genetic risk scores from SNVs in MTHFR and MTRR were associated with 14.8% to 18.9% lower RBC folate concentrations. Gene–biomarker associations were similar in women of other races/ethnicities. CONCLUSIONS: Our findings on genetic variants associated with several one-carbon metabolism biomarkers may help elucidate mechanisms of maintaining B vitamin status in postmenopausal women.

PurposeThe Joanne Knight Breast Health Cohort was established to link breast cancer risk factors, mammographic breast density, benign breast biopsies and associated tissue markers, and blood markers in a diverse population of women undergoing routine mammographic screening to study risk factors and validate models for breast cancer risk prediction.MethodsWomen were recruited from November 2008 to April 2012 through the mammography service at the Joanne Knight Breast Health Center at Washington University in St. Louis, Missouri. Baseline questionnaire risk factors, blood, and screening mammograms were collected from 12,153 women. Of these, 1,672 were excluded for prior history of any cancer (except non-melanoma skin) or diagnosis of breast cancer within 6 months of blood draw/registration for the study, for a total of 10,481 women. Follow-up is through linking to electronic health records, tumor registry, and death register. Routine screening mammograms are collected every 1–2 years and incident benign breast biopsies and cancers are identified through record linkage to pathology and tumor registries. Formal fixed tissue samples are retrieved and stored for analysis. County-level measures of structural inequality were derived from publicly available resources.ResultsCohort Composition: median age at entry was 54.8 years and 26.7% are African American. Through 2020, 74% of participants have had a medical center visit within the past year and 80% within the past 2 years representing an average of 9.7 person-years of follow-up from date of blood draw per participant. 9,997 women are continuing in follow-up. Data collected at baseline include breast cancer risk factors, plasma and white blood cells, and mammograms prior to baseline, at baseline, and during follow-up.ConclusionThis cohort assembled and followed in a routine mammography screening and care setting that serves a diverse population of women in the St. Louis region now provides opportunities to integrate study of questionnaire measures, plasma and DNA markers, benign and malignant tissue markers, and repeated breast image features into prospective evaluation for breast cancer etiology and outcomes.

Background: Physical activity and obesity are well-established factors of colorectal cancer risk and prognosis. Here, we investigate associations of individual and combined physical activity and body mass index (BMI) groups with proinflammatory biomarkers in colorectal cancer patients. Methods: Self-reported physical activity levels were classified as “active” (≥8.75 MET-hours/week) versus “inactive” ( Results: “Inactive” patients had non-statistically significant higher IL6 levels compared with “active” patients (+36%, P = 0.10). “Obese” patients had 88% and 17% higher CRP and TNFα levels compared with “normal weight” patients (P = 0.03 and 0.02, respectively). Highest CRP levels were observed among “overweight or obese/inactive” compared with “normal weight/active” patients (P = 0.03). Conclusions: We provide evidence of associations between individual and combined physical activity and BMI groups with proinflammatory biomarkers. Although BMI was identified as the key driver of inflammation, biomarker levels were higher among “inactive” patients across BMI groups. Impact: This is the largest study in colorectal cancer patients investigating associations of energy balance components with inflammatory biomarkers. Our results suggest that physical activity may reduce obesity-induced inflammation in colorectal cancer patients and support the design of randomized controlled trials testing this hypothesis.

BACKGROUND: Evidence suggests a positive association between sugar intake and colorectal cancer (CRC) outcomes. We sought to investigate inflammation and angiogenesis as underlying mechanisms behind increased sugar intake and worse CRC outcomes. METHOD: Pre-surgery serum samples were obtained from 191 patients diagnosed with primary invasive stage I-IV CRC. Biomarkers of inflammation (CRP, SAA, IL-6, IL-8, MCP-1, TNFα) and angiogenesis (VEGFA, VEGFD, sICAM-1 and sVCAM-1) were analyzed (Meso-Scale-Discovery). Fructose, glucose, sucrose, and total sugar intake (calories/day, % total calories) were assessed by FFQ. Pearson’s correlation and multiple linear regression analyses were performed. RESULTS: Patients were on average 64 years old, 64% were male, the majority was diagnosed with stage II-III (58%) cancers, and 67% were either overweight or obese. Among normalweight individuals (BMI

PURPOSE: A dense breast on mammogram is a strong risk factor for breast cancer. Identifying factors that reduce mammographic breast density could thus provide insight into breast cancer prevention. Due to the limited number of studies and conflicting findings, we investigated the associations of medication use (specifically statins, aspirin, and ibuprofen) with mammographic breast density. METHODS: We evaluated these associations in 775 women who were recruited during an annual screening mammogram at Washington University School of Medicine, St. Louis. We measured mammographic breast density using Volpara. We used multivariable-adjusted linear regressions to determine the associations of medication use (statins, aspirin, and ibuprofen) with mammographic breast density. Least squared means were generated and back-transformed for easier interpretation. RESULTS: The mean age of study participants was 52.9 years. Statin use in the prior 12 months was not associated with volumetric percent density or dense volume, but was positively associated with non-dense volume. The mean volumetric percent density was 8.6% among statin non-users, 7.2% among women who used statins 1–3 days/week, and 7.3% among women who used statins ≥4 days/week (p-trend=0.07). The non-dense volume was 1297.1cm(3) among statin non-users, 1368.7cm(3) among women who used statins 1–3 days/week, and 1408.4cm(3) among those who used statins ≥4 days/week (p-trend=0.02). We did not observe statistically significant differences in mammographic breast density by aspirin or ibuprofen use. CONCLUSION: Statin, aspirin, and ibuprofen use was not associated with volumetric percent density and dense volume, but statin use was positively associated with non-dense volume. Any potential associations of these medications with breast cancer risk are unlikely to be mediated through an effect on volumetric percent density.

Mammographic breast density (MBD) is a risk factor for breast cancer, but its molecular basis is poorly understood. Growth factors stimulate cellular and epithelial proliferation and could influence MBD via these mechanisms. Studies investigating the associations of circulating growth factors with MBD have, however, yielded conflicting results especially in postmenopausal women. We, therefore, investigated the associations of plasma growth factor gene expression [insulin-like growth factor (IGF)-1, IGF-binding protein 3, FGF-1, FGF-12, TGFβ1 and bone morphogenetic protein (BMP)-2] with MBD in postmenopausal women. We used NanoString nCounter platform to quantify plasma growth factor gene expression and Volpara to evaluate volumetric MBD measures. We investigated the associations of growth factor gene expression with MBD using both multiple linear regression (fold change) and multinomial logistic regression models, adjusted for potential confounders. The mean age of the 368 women enrolled was 58 years (range, 50–64). In analyses using linear regression models, one unit increase in IGF-1 gene expression was associated with a 35% higher volumetric percent density (VPD, 1.35; 95% confidence interval (CI), 1.13–1.60; P = 0.001). There were suggestions that TGFβ1 gene expression was positively associated with VPD while BMP-2 gene expression was inversely associated with VPD, but these were not statistically significant. In analyses using multinomial logistic regression, TGFβ1 gene expression was 33% higher (OR = 1.33; 95% CI, 1.13–1.56; P = 0.0008) in women with extremely dense breasts than those with almost entirely fatty breasts. There were no associations between growth factor gene expression and dense volume or nondense volume. Our study provides insights into the associations of growth factors with MBD in postmenopausal women and requires confirmation in other study populations. Prevention Relevance: Mammographic breast density is a strong risk factor for breast cancer. Understanding its underlying biological mechanisms could have utility in breast cancer prevention.

PURPOSE: Fatalism is defined by feelings of pessimism, hopelessness, and powerlessness regarding cancer outcomes. Early researchers reported associations between race and cancer fatalism. Yet current evidence suggests that social determinants of health are better predictors of cancer fatalism than race. Therefore, the aim of this study was to examine the association between age, race, education, and cancer fatalism. METHODS: Three hundred ninety (n=390) women who attended a screening mammogram at the Joanne Knight Breast Health Center, at Siteman Cancer Center at Washington University School of Medicine (St. Louis, MO) completed the Powe Fatalism Inventory (PFI), a 15-item self-report instrument used to operationalize cancer fatalism. We used Pearson’s correlation, independent samples t-tests, one-way ANOVA with post-hoc tests, and linear regression to analyze the relationships between PFI total scores and age, race, and education. RESULTS: There were no differences between the mean PFI scores for Non-Hispanic Whites (1.89, SD 0.55) and African Americans (2.02, SD 0.76, p=0.092, 95%CI-0.27 to 0.02). We found significant differences between the mean PFI scores across levels of education. Women who attained a high school degree or less (n=72) reported higher PFI scores (2.24, SD 0.77) than women who attended some college or post high school vocational training (n=111; 1.95, SD 0.61) and women with a college or postgraduate degree (n=206; 1.83, SD 0.57). When PFI score was regressed onto age, race, and education, only education significantly explained fatalism (B=−0.19, p

The COVID-19 pandemic has disrupted many facets of life. We evaluated pandemic-related health care experiences, COVID-19 prevention behaviors and measures, health behaviors, and psychosocial outcomes among rural and urban cancer patients.Among 1,472 adult cancer patients, who visited Huntsman Cancer Institute in the past 4 years and completed a COVID-19 survey (August-September 2020), we assessed the impact of the pandemic on medical appointments, prevention/health behaviors, and psychosocial factors, stratified by urbanicity.Mean age was 61 years, with 52% female, 97% non-Hispanic White, and 27% were residing in rural areas. Rural versus urban patients were more likely to be older, not employed, uninsured, former/current smokers, consume alcohol, and have pandemic-related changes/cancellations in surgery appointments (all P.05). Changes/cancellations in other health care access (eg, doctor's visits) were also common, particularly among urban patients. Urban versus rural patients were more likely to socially distance, use masks and hand sanitizer, and experience changes in exercise habits and in their daily lives (all P.05). Less social interaction and financial stress were common among cancer patients but did not differ by urbanicity.These findings suggest that the COVID-19 pandemic had a substantial impact on cancer patients, with several challenges specific to rural patients. This comprehensive study provides unique insights into the first 6 months of COVID-19 pandemic-related experiences and continuity of care among rural and urban cancer patients predominantly from Utah. Further research is needed to better characterize the pandemic's short- and long-term effects on rural and urban cancer patients and appropriate interventions.

Family history of breast cancer (FHBC) and mammographic breast density are independent risk factors for breast cancer, but the association of FHBC and mammographic breast density in premenopausal women is not well understood.To investigate the association of FHBC and mammographic breast density in premenopausal women using both quantitative and qualitative measurements.This single-center cohort study examined 2 retrospective cohorts: a discovery set of 375 premenopausal women and a validation set of 14 040 premenopausal women. Data from women in the discovery set was collected between December 2015 and October 2016, whereas data from women in the validation set was collected between June 2010 and December 2015. Data analysis was performed between June 2018 and June 2020.Family history of breast cancer (FHBC).The primary outcomes were mammographic breast density measured quantitatively as volumetric percent density using Volpara (discovery set) and qualitatively using BI-RADS (Breast Imaging Reporting and Data System) breast density (validation set). Multivariable regressions were performed using a log-transformed normal distribution for the discovery set and a logistic distribution for the validation set.Of 14 415 premenopausal women included in the study, the discovery set and validation set had similar characteristics (discovery set with FHBC: mean [SD] age, 47.1 [5.6] years; 15 [17.2%] were Black or African American women and 64 [73.6%] were non-Hispanic White women; discovery set with no FHBC: mean [SD] age, 47.7 [4.5] years; 87 [31.6%] were Black or African American women and 178 [64.7%] were non-Hispanic White women; validation set with FHBC: mean [SD] age, 46.8 [7.3] years; 720 [33.4%] were Black or African American women and 1378 [64.0%] were non-Hispanic White women]; validation set with no FHBC: mean [SD] age, 47.5 [6.1] years; 4572 [38.5%] were Black or African American women and 6632 [55.8%] were non-Hispanic White women]). In the discovery set, participants who had FHBC were more likely to have a higher mean volumetric percent density compared with participants with no FHBC (11.1% vs 9.0%). In the multivariable-adjusted model, volumetric percent density was 25% higher (odds ratio [OR], 1.25 ;95% CI, 1.12-1.41) in women with FHBC compared with women without FHBC; and 24% higher (OR, 1.24; 95% CI, 1.10-1.40) in women who had 1 affected relative, but not significantly higher in women who had at least 2 affected relatives (OR, 1.40; 95% CI, 0.95-2.07) compared with women with no relatives affected. In the validation set, women with a positive FHBC were more likely to have dense breasts (BI-RADS 3-4) compared with women with no FHBC (BI-RADS 3: 41.1% vs 38.8%; BI-RADS 4: 10.5% vs 7.7%). In the multivariable-adjusted model, the odds of having dense breasts (BI-RADS 3-4) were 30% higher (OR, 1.30; 95% CI, 1.17-1.45) in women with FHBC compared with women without FHBC; and 29% higher (OR, 1.29; 95% CI, 1.14-1.45) in women who had 1 affected relative, but not significantly higher in women who had at least 2 affected relatives (OR, 1.38; 95% CI, 0.85-2.23) compared with women with no relatives affected.In this cohort study, having an FHBC was positively associated with mammographic breast density in premenopausal women. Our findings highlight the heritable component of mammographic breast density and underscore the need to begin annual screening early in premenopausal women with a family history of breast cancer.

PURPOSE: Cancer-related distress is known to persist long after completion of treatment. Factors related to distress are largely unexplored in colorectal cancer (CRC) survivors. We examined changes over time and risk factors for distress in CRC patients over the first year after surgery. METHODS: We included 212 CRC patients with data at 6 and 12 months post-surgery from the ColoCare Study in Heidelberg, Germany. Sociodemographic and lifestyle factors, social support and health-related quality of life (HrQOL) prior to surgery were evaluated as predictors of cancer-related distress. Distress was measured with the Cancer and Treatment Distress instrument (CTXD). Linear regression analyses examined associations between risk factors and distress. RESULTS: Distress subscale scores varied significantly over time: health burden subscale score increased (P < .001), while finances (P = .004), medical demands (P < .001), and identity (P < .001) subscale scores decreased over time. Uncertainty and family strain subscale scores did not change. Younger age, lower income, advanced tumor stage, poorer social support, and poorer baseline HrQOL predicted higher level distress at 6 and 12 months. CONCLUSIONS: Cancer-related distress continues unresolved after surgery. Although some risk factors are difficult to alter, those at highest risk can be identified earlier for possible preventive strategies. IMPLICATIONS FOR CANCER SURVIVORS: Screening for risk factors pre-surgery would allow for targeted interventions including strategies to improve resources for those with low support, thereby reducing long-term distress in CRC survivors.

Background: The effect of metformin use on survival among patients with pancreatic ductal adenocarcinoma (PDAC) is controversial. Furthermore, there are no data on African American patients. To address these, we analyzed data from the United States Veterans Health Administration (VHA). Methods: A population-based retrospective cohort study evaluating overall survival among 3,811 patients with PDAC with preexisting diabetes mellitus, diagnosed with PDAC within the VHA between 1998 and 2013. We calculated HRs and 95% confidence intervals (CI) using multivariable adjusted time-varying Cox proportional hazards regression to control for immortal time bias and confounders. Results: Metformin use was not associated with overall survival in the complete analyses (HR = 1.05; 95% CI, 0.92–1.14; P = 0.28). However, among patients who were metformin naïve at the time of PDAC diagnosis (N = 1,158), metformin use was associated with improved overall survival in non-Hispanic white patients (HR = 0.78; 95% CI, 0.61–0.99; P = 0.04), but not African American patients (HR = 1.20; 95% CI, 0.75–1.93; P = 0.45). The survival benefit among non-Hispanic whites was limited to patients with metastatic disease (HR = 0.67; 95% CI, 0.44–1.01; P = 0.06). Among African American patients with metastatic disease, HR was 1.30 (95% CI, 0.77–2.53; P = 0.28). There was a suggestion of heterogeneity by race in patients with metastatic disease (Pheterogeneity = 0.05). Conclusions: We observed no associations between metformin use and survival in patients with PDAC, but there appears to be a survival benefit among non-Hispanic white patients who were metformin naïve at the time of PDAC diagnosis. Impact: If confirmed in other studies, our findings suggest that metformin as an adjunctive treatment for PDAC may not improve survival among African American patients.

Studies have investigated the associations of coffee and tea with mammographic breast density (MBD) in premenopausal women with inconsistent results. We analyzed data from 375 premenopausal women who attended a screening mammogram at Washington University School of Medicine, St. Louis, MO in 2016, and stratified the analyses by race (non-Hispanic White (NHW) vs. Black/African American). Participants self-reported the number of servings of coffee, caffeinated tea, and decaffeinated tea they consumed. Volpara software was used to determine volumetric percent density (VPD), dense volume (DV), and non-dense volume (NDV). We used generalized linear regression models to quantify the associations of coffee and tea intake with MBD measures. Coffee: ≥1 time/day (β = 1.06, 95% CI = 0.93–1.21, p-trend = 0.61) and caffeinated tea: ≥1 time/day (β = 1.01, 95% CI = 0.88–1.17, p-trend = 0.61) were not associated with VPD. Decaffeinated tea (≥1 time/week) was positively associated with VPD in NHW women (β = 1.22, 95% CI = 1.06–1.39) but not in African American women (β = 0.93, 95% CI = 0.73–1.17, p-interaction = 0.02). Coffee (≥1 time/day) was positively associated with DV in African American women (β = 1.52, 95% CI = 1.11–2.07) but not in NHW women (β = 1.10, 95% CI = 0.95–1.29, p-interaction = 0.02). Our findings do not support associations of coffee and caffeinated tea intake with VPD in premenopausal women. Positive associations of decaffeinated tea with VPD, with suggestions of effect modification by race, require confirmation in larger studies with diverse study populations.

Background Hormones impact breast tissue proliferation. Studies investigating the associations of circulating hormone levels with mammographic breast density have reported conflicting results. Due to the limited number of studies, we investigated the associations of hormone gene expression as well as their downstream mediators within the plasma with mammographic breast density in postmenopausal women. Methods We recruited postmenopausal women at their annual screening mammogram at Washington University School of Medicine, St. Louis. We used the NanoString nCounter platform to quantify gene expression of hormones (prolactin, progesterone receptor (PGR), estrogen receptor 1 (ESR1), signal transducer and activator of transcription (STAT1 and STAT5), and receptor activator of nuclear factor-kB (RANK) pathway markers (RANK, RANKL, osteoprotegerin, TNFRSF18, and TNFRSF13B) in plasma. We used Volpara to measure volumetric percent density, dense volume, and non-dense volume. Linear regression models, adjusted for confounders, were used to evaluate associations between gene expression (linear fold change) and mammographic breast density. Results One unit increase in ESR1, RANK, and TNFRSF18 gene expression was associated with 8% (95% CI 0–15%, p value = 0.05), 10% (95% CI 0–20%, p value = 0.04) and % (95% CI 0–9%, p value = 0.04) higher volumetric percent density, respectively. There were no associations between gene expression of other markers and volumetric percent density. One unit increase in osteoprotegerin and PGR gene expression was associated with 12% (95% CI 4–19%, p value = 0.003) and 7% (95% CI 0–13%, p value = 0.04) lower non-dense volume, respectively. Conclusion These findings provide new insight on the associations of plasma hormonal and RANK pathway gene expression with mammographic breast density in postmenopausal women and require confirmation in other studies.

Higher mammographic breast density (MBD) is associated with an increased risk of breast cancer when compared with lower MBD, especially in premenopausal women. However, little is known about the effectiveness of chemoprevention agents in reducing MBD in premenopausal women without a history of breast cancer. Findings from this review should provide insight on how to target MBD in breast cancer prevention in premenopausal women with dense breasts.We searched 9 electronic databases for clinical trials in English, Spanish, French, or German published until January 2020. Articles evaluating the association of pharmacological agents and MBD were included. Data were extracted on methods, type and dose of intervention, outcomes, side effects, and follow up. Quality of the studies was assessed using the US Preventive Services Task Force criteria.We identified 7 clinical trials evaluating the associations of 6 chemoprevention agents with changes in MBD in premenopausal women without history of breast cancer. The studies evaluated selective estrogen-receptor modulators (n = 1); gonadotropin-releasing hormone agonists (n = 2); isoflavones (n = 1); vitamin D (n = 1); and Boswellia, betaine, and mayo-inositol compound (n = 1). Hormonal interventions were associated with net reductions in percent density (tamoxifen [13.4%], leuprolide acetate [8.9%], and goserelin [2.7%]), whereas nonhormonal (vitamin D and isoflavone) interventions were not. However, MBD returned to preintervention baseline levels after cessation of gonadotropin-releasing hormone agonists.A limited number of chemoprevention agents have been shown to reduce MBD in premenopausal women. Identification of new and well-tolerated chemoprevention agents targeting MBD and larger studies to confirm agents that have been studied in small trials are urgent priorities for primary breast cancer prevention in premenopausal women with dense breasts.

Ovarian cancer is the deadliest gynecologic malignancy, yet the effects on survival of modifiable pre-diagnosis lifestyle factors, such as obesity and physical activity, remain largely unexplored. Our objective was to evaluate the effect of pre-diagnosis BMI and physical activity on ovarian cancer mortality using prospectively collected data.Data on women who developed ovarian cancer after enrollment into the NIH-AARP Diet and Health Study were analyzed. Cancer incidence was ascertained through linkage state cancer registries and consisted of 741 cases of epithelial ovarian cancer.Higher pre-diagnosis BMI was associated with increased overall and ovarian cancer-specific mortality. Comparing women with BMI 25-29.9, 30-34.9 and ≥ 35 to normal weight women, the HRs of overall mortality were 1.18 (95%CI 0.96-1.45), 1.05 (0.82-1.36) and 1.59 (1.14-2.18, p-trend = 0.02). The findings were similar for ovarian cancer-specific mortality comparing women with BMI ≥ 35 to normal weight women (BMI25) with a HR of 1.47 (95%CI 1.03-2.09, p-trend 0.08). Pre-diagnosis physical activity was not associated with mortality, with HRs for overall mortality of 1.06 (95%CI 0.79-1.43), 0.94 (0.72-1.23), 0.98 (0.76-1.25), and 0.98 (0.75-1.28, p-trend = 0.91), comparing women who engaged in vigorous physical activity 1-3 times/month, 1-2 times/week, 3-4 times/week and 5 times/week, respectively, with those who never/rarely engaged in such activity.Women who were obese before developing ovarian cancer had increased mortality than those who were normal weight, but physical activity before diagnosis was not associated with mortality in this study population. These results suggest that maintaining a healthy weight is a powerful preventative tool.

PURPOSE: Nutritional factors during different periods in life impact breast cancer risk. Because benign breast disease (BBD) is a well-established risk factor for breast cancer, we investigated childhood nutrition from birth through age 14yr and subsequent BBD. METHODS: A prospective cohort study of 9031 females, 9–15yr at baseline, completed questionnaires (including heights, weights) annually from 1996–2001, in 2003, 2005, 2007, 2010, 2013 and 2014. In 1996, mothers reported infant feeding practices during their daughters’ first year of life. Beginning in 1996, participants completed annual food frequency questionnaires. In 2005, participants (18yr+) began reporting whether they had ever been diagnosed with biopsy-confirmed BBD (N=173 cases). Multivariable logistic regression models estimated associations between childhood nutrition and BBD, adjusted for maternal breast disease and childhood body size factors. RESULTS: Although no infant nutrition factors were associated with biopsy-confirmed BBD, certain adolescent dietary factors were. A multivariable model simultaneously included the most important diet and body size factors from different age periods: higher BBD risk was associated with greater age 10yr consumption of animal (non-dairy, energy-adjusted) fat (OR=2.27, p

The receptor activator of nuclear factor-κB (RANK) pathway plays essential roles in breast development. Mammographic density is a strong risk factor for breast cancer, especially in premenopausal women. We, therefore, investigated the associations of circulating RANK and soluble RANK ligand (sRANKL) with mammographic density in premenopausal women. Mammographic density was measured as volumetric percent density in 365 cancer-free premenopausal women (mean age, 47.5 years) attending screening mammogram at the Washington University School of Medicine (St. Louis, MO). We used linear regression models adjusted for confounders, to compare the least-square means of volumetric percent density across tertiles of circulating RANK and sRANKL. Furthermore, because RANKL levels in mammary tissue are modulated by progesterone, we stratified analyses by progesterone levels. The mean volumetric percent density increased across tertiles of circulating RANK from 8.6% in tertile 1, to 8.8% in tertile 2, and 9.5% in tertile 3 (Ptrend = 0.02). For sRANKL, the mean volumetric percent density was 8.5% in tertile 1, 9.4% in tertile 2, and 9.0% in tertile 3 (Ptrend = 0.30). However, when restricted to women with higher progesterone levels, the mean volumetric percent density increased from 9.1% in sRANKL tertile 1 to 9.5% in tertile 2, and 10.1% in tertile 3 (Ptrend = 0.01). Circulating RANK was positively associated with volumetric percent density, while circulating sRANKL was positively associated with volumetric percent density among women with higher progesterone levels. These findings support the inhibition of RANKL signaling as a pathway to reduce mammographic density and possibly breast cancer incidence in high-risk women with dense breasts.

Background Fusobacterium nucleatum (Fn), a bacterium associated with a wide spectrum of infections, has emerged as a key microbe in colorectal carcinogenesis. However, the underlying mechanisms and clinical relevance of Fn in colorectal cancer (CRC) remain incompletely understood. Patients and Methods We examined associations between Fn abundance and clinicopathologic characteristics among 105 treatment-naive CRC patients enrolled in the international, prospective ColoCare Study. Electronic medical charts, including pathological reports, were reviewed to document clinicopathologic features. Quantitative real-time polymerase chain reaction (PCR) was used to amplify/detect Fn DNA in preoperative fecal samples. Multinomial logistic regression was used to analyze associations between Fn abundance and patient sex, age, tumor stage, grade, site, microsatellite instability, body mass index (BMI), alcohol consumption, and smoking history. Cox proportional hazards models were used to investigate associations of Fn abundance with overall survival in adjusted models. Results Compared to patients with undetectable or low Fn abundance, patients with high Fn abundance (n = 22) were 3-fold more likely to be diagnosed with rectal versus colon cancer (odds ratio [OR] = 3.01; 95% confidence interval [CI], 1.06-8.57; P = .04) after adjustment for patient sex, age, BMI, and study site. Patients with high Fn abundance also had a 5-fold increased risk of being diagnosed with rectal cancer versus right-sided colon cancer (OR = 5.32; 95% CI, 1.23-22.98; P = .03). There was no statistically significant association between Fn abundance and overall survival. Conclusion Our findings suggest that Fn abundance in fecal samples collected prior to surgery varies by tumor site among treatment-naive CRC patients. Overall, fecal Fn abundance may have diagnostic and prognostic significance in the clinical management of CRC.

To determine associations between physical activity (PA), sedentary behavior (SB), and oxidative stress in colorectal cancer patients, ColoCare Study participants in Germany wore an accelerometer 6 and/or 12 months after surgery. Spearman partial correlations were used to assess associations between PA and urinary concentrations of oxidized guanine, a validated marker of oxidative stress. There were no significant associations between PA or SB and oxidized guanine in n = 76 measurements (ng/mg creatinine; r = 0.03, p = 0.76 for PA, r = –0.05, p = 0.69 for SB). Novelty Objectively measured PA was not associated with a marker of oxidative stress in colorectal cancer patients.

Background: Obesity, defined by body mass index (BMI), measured at colorectal cancer (CRC) diagnosis has been associated with postoperative complications and survival outcomes. However, BMI does not allow for a differentiation between fat and muscle mass. Computed tomography (CT)-defined body composition more accurately reflects different types of tissue and their associations with health-related quality of life (HRQoL) during the first year of disease, but this has not been investigated yet. We studied the role of visceral and subcutaneous fat area (VFA and SFA) and skeletal muscle mass (SMM) on longitudinally assessed HRQoL in CRC patients. Methods: A total of 138 newly diagnosed CRC patients underwent CT scans at diagnosis and completed questionnaires prior to and six and twelve months post-surgery. We investigated the associations of VFA, SFA, and SMM with HRQoL at multiple time points. Results: A higher VFA was associated with increased pain six and twelve months post-surgery (&beta, = 0.06, p = 0.04 and &beta, = 0.07, p = 0.01) and with worse social functioning six months post-surgery (&beta, = &minus, 0.08, p = 0.01). Higher SMM was associated with increased pain twelve months post-surgery (&beta, = 1.03, p &lt, 0.01). Conclusions: CT-quantified body composition is associated with HRQoL scales post-surgery. Intervention strategies targeting a reduction in VFA and maintaining SMM might improve HRQoL in CRC patients during the first year post-surgery.

Mammographic breast density is a strong risk factor for breast cancer. We comprehensively investigated the associations of body mass index (BMI) change from ages 10, 18, and 30 to age at mammogram with mammographic breast density in postmenopausal women. We used multivariable linear regression models, adjusted for confounders, to investigate the associations of BMI change with volumetric percent density, dense volume, and nondense volume, assessed using Volpara in 367 women. At the time of mammogram, the mean age was 57.9 years. Compared with women who had a BMI gain of 0.1–5 kg/m2 from age 10, women who had a BMI gain of 5.1–10 kg/m2 had a 24.4% decrease [95% confidence interval (CI), 6.0%–39.2%] in volumetric percent density; women who had a BMI gain of 10.1–15 kg/m2 had a 46.1% decrease (95% CI, 33.0%–56.7%) in volumetric percent density; and women who had a BMI gain of >15 kg/m2 had a 56.5% decrease (95% CI, 46.0%–65.0%) in volumetric percent density. Similar, but slightly attenuated associations were observed for BMI gain from ages 18 and 30 to age at mammogram and volumetric percent density. BMI gain over the life course was positively associated with nondense volume, but not dense volume. We observed strong associations between BMI change over the life course and mammographic breast density. The inverse associations between early-life adiposity change and volumetric percent density suggest that childhood adiposity may confer long-term protection against postmenopausal breast cancer via its effect of mammographic breast density.

BACKGROUND: Choline plays an integral role in one-carbon metabolism in the body, but it is unclear whether genetic polymorphisms are associated with variations in plasma choline and its metabolites. OBJECTIVES: This study aimed to evaluate the association of genetic variants in choline and one-carbon metabolism with plasma choline and its metabolites. METHODS: We analyzed data from 1423 postmenopausal women in a case-control study nested within the Women's Health Initiative Observational Study. Plasma concentrations of choline, betaine, dimethylglycine (DMG), and trimethylamine N-oxide were determined in 12-h fasting blood samples collected at baseline (1993–1998). Candidate and tagging single-nucleotide polymorphisms (SNPs) were genotyped in betaine-homocysteine S-methyltransferase (BHMT), BHMT2, 5,10-methylenetetrahydrofolate reductase (MTHFR), methylenetetrahydrofolate dehydrogenase (NADP+ dependent 1) (MTHFD1), 5-methyltetrahydrofolate-homocysteine methyltransferase (MTR), and 5-methyltetrahydrofolate-homocysteine methyltransferase reductase (MTRR). Linear regression was used to derive percentage difference in plasma concentrations per variant allele, adjusting for confounders, including B-vitamin biomarkers. Potential effect modification by plasma vitamin B-12, vitamin B-6, and folate concentrations and folic-acid fortification periods was examined. RESULTS: The candidate SNP BHMT R239Q (rs3733890) was associated with lower concentrations of plasma betaine and DMG concentrations (−4.00% and −6.75% per variant allele, respectively; both nominal P G, was associated with higher plasma DMG concentration (13.0%; P < 0.0001). Several tagSNPs in these 2 genes were associated with plasma concentrations after correction for multiple comparisons. Vitamin B-12 status was a significant effect modifier of the association between the genetic variant BHMT2 rs626105 A>G and plasma DMG concentration. CONCLUSIONS: Genetic variations in metabolic enzymes were associated with plasma concentrations of choline and its metabolites. Our findings contribute to the knowledge on the variation in blood nutrient concentrations in postmenopausal women.

Background Cancer is the second leading cause of death in the Caribbean, including the islands of Trinidad and Tobago (TT). The population of TT consists of over 1.3 million people with diverse ancestral and sociocultural backgrounds, both of which may influence cancer incidence and mortality. The objective of this study was to examine incidence and mortality patterns and trends in TT. Methods Cancer surveillance data on 29,512 incident cancer cases reported to the Dr. Elizabeth Quamina Cancer Registry (population-based cancer registry of TT) between 1995 and 2009 were analyzed. Age-standardized rates, overall and by sex, ancestry, and geography, were reported. Results The highest incidence and mortality rates were observed for cancers related to reproductive organs in women, namely, breast, cervical, and uterine cancers, and prostate, lung and colorectal cancers among men. Average incidence rates were highest in areas covered by the Tobago Regional Health Authority (TRHA) (188 per 100,000), while average mortality rates were highest in areas covered by the North West Regional Health Authority (108 per 100,000). Nationals of African ancestry exhibited the highest rates of cancer incidence (243 per 100,000) and mortality (156 per 100,000) compared to their counterparts who were of East Indian (incidence, 125 per 100,000; mortality, 66 per 100,000) or mixed ancestry (incidence, 119 per 100,000; mortality, 66 per 100,000). Conclusions Our findings highlight the need for national investment to improve the understanding of the epidemiology of cancer in Trinidad and Tobago, and to ultimately guide much needed cancer prevention and control initiatives in the near future. Electronic supplementary material The online version of this article (10.1186/s12885-018-4625-x) contains supplementary material, which is available to authorized users.

Objective Obesity, inflammation, and circulating 25-hydroxyvitamin D (25-OHD) have distinct roles in cancer prognosis. We investigated their interplay by evaluating the associations of body mass index (BMI) with circulating 25-OHD levels in cancer survivors, and determining whether associations were modified by inflammation, defined by C-reactive protein (CRP) levels. Methods Data on cancer survivors were aggregated from the U.S. National Health and Nutrition Examination Survey (2001–2010). Multivariable linear regression models were used to evaluate the associations of BMI with circulating 25-OHD. We stratified the analyses by CRP levels: low 3.0–9.9mg/L. Results Among 1,305 cancer survivors (mean age=60.8 years, mean BMI=28.0 kg/m2), circulating 25-OHD levels were 8.74 nmol/L lower (95%CI: 4.71 to 12.77) in cancer survivors with BMI ≥30kg/m2 compared to those with BMI

Background The benefits of chemotherapy in node-negative, hormone receptor-positive, and human epidermal growth factor receptor 2 (HER2)-negative breast cancer patients with the 21-gene recurrence score (RS) of 18–30, particularly those with RS 26–30, are not known. Methods Using the Surveillance, Epidemiology, and End Results (SEER) data, we retrospectively identified 29,137 breast cancer patients with the 21-gene RS of 18–30 diagnosed between 2004 and 2015. Mortality risks according to the RS and chemotherapy use were compared by the Kaplan-Meier method and Cox’s proportional hazards model. Results Among the breast cancer patients with the RS 18–30, 21% of them had RS 26–30. Compared to breast cancer patients with RS 18–25, patients with RS 26–30 had more aggressive tumor characteristics and chemotherapy use and increased risk of breast cancer-specific mortality and overall mortality. In breast cancer patients who were aged ≤ 70 years and had RS of 26–30, chemotherapy administration was associated with a 32% lower risk of breast cancer-specific mortality (hazard ratio [HR], 0.68; 95% confidence interval [CI], 0.47–0.99) and a 42% lower risk of overall mortality (HR, 0.58; 95% CI, 0.44–0.76). Survival benefits were most pronounced in breast cancer patients who were younger or had grade III tumor. Conclusions The 21-gene RS of 18–30 showed heterogeneous outcomes, and the RS 26–30 was a significant prognostic factor for an increased risk of mortality. Adjuvant chemotherapy could improve the survival of node-negative, hormone receptor-positive, and HER2-negative breast cancer patients with the 21-gene RS 26–30 and should be considered for patients, especially younger patients or patients with high-grade tumors.

PURPOSE: Mammographic density is a strong risk factor for breast cancer. Although diet is associated with breast cancer risk, there are limited studies linking adult milk intake with mammographic density. Here, we investigate the association of milk intake with mammographic density in premenopausal women. METHODS: We analyzed data from 375 cancer-free premenopausal women who had routine screening mammography at Washington University in St. Louis in 2016. We used Volpara to measure volumetric percent density, dense volume, and non-dense volume. We collected information of recent milk intake (past 12 months), and categorized skim milk and low/reduced-fat milk intake into 4 groups

Summary Background In pancreatic ductal adenocarcinoma, the CCL2–CCR2 chemokine axis is used to recruit tumour-associated macrophages for construction of an immunosuppressive tumour microenvironment. This pathway has prognostic implications in pancreatic cancer, and blockade of CCR2 restores anti-tumour immunity in preclinical models. We aimed to establish the safety, tolerability, and recommended phase 2 oral dose of the CCR2 inhibitor PF-04136309 in combination with FOLFIRINOX chemotherapy (oxaliplatin and irinotecan plus leucovorin and fluorouracil). Methods We did this open-label, dose-finding, non-randomised, phase 1b study at one centre in the USA. We enrolled treatment-naive patients aged 18 years or older with borderline resectable or locally advanced biopsy-proven pancreatic ductal adenocarcinoma, an Eastern Cooperative Oncology Group performance status of 1 or less, measurable disease as defined by Response Evaluation Criteria in Solid Tumors version 1.1, and normal end-organ function. Patients were allocated to receive either FOLFIRINOX alone (oxaliplatin 85 mg/m 2 , irinotecan 180 mg/m 2 , leucovorin 400 mg/m 2 , and bolus fluorouracil 400 mg/m 2 , followed by 2400 mg/m 2 46-h continuous infusion), administered every 2 weeks for a total of six treatment cycles, or in combination with oral PF-04136309, administered at a starting dose of 500 mg twice daily in a standard 3 + 3 dose de-escalation design. Both FOLFIRINOX and PF-04136309 were simultaneously initiated with a total treatment duration of 12 weeks. The primary endpoints were the safety, tolerability, and recommended phase 2 dose of PF-04136309 plus FOLFIRINOX, with an expansion phase planned at the recommended dose. We analysed the primary outcome by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01413022. Results Between April 19, 2012, and Nov 12, 2014, we treated 47 patients with FOLFIRINOX alone (n=8) or with FOLFIRINOX plus PF-04136309 (n=39). One patient had a dose-limiting toxic effect in the dose de-escalation group receiving FOLFIRINOX plus PF-04136309 at 500 mg twice daily (n=6); this dose was established as the recommended phase 2 dose. We pooled patients in the expansion-phase group (n=33) with those in the dose de-escalation group that received PF-04136309 at the recommended phase 2 dose for assessment of treatment-related toxicity. Six (75%) of the eight patients receiving FOLFIRINOX alone were assessed for treatment toxicity, after exclusion of two (25%) patients due to insurance coverage issues. The median duration of follow-up for treatment toxicity was 72·0 days (IQR 49·5–89·0) in the FOLFIRINOX alone group and 77·0 days (70·0–90·5) in the FOLFIRINOX plus PF-04136309 group. No treatment-related deaths occurred. Two (5%) patients in the FOLFIRINOX plus PF-04136309 group stopped treatment earlier than planned due to treatment-related toxic effects. Grade 3 or higher adverse events reported in at least 10% of the patients receiving PF-04136309 included neutropenia (n=27), febrile neutropenia (n=7), lymphopenia (n=4), diarrhoea (n=6), and hypokalaemia (n=7). Grade 3 or higher adverse events reported in at least 10% of patients receiving FOLFIRINOX alone were neutropenia (n=6), febrile neutropenia (n=1), anaemia (n=2), lymphopenia (n=1), diarrhoea (n=2), hypoalbuminaemia (n=1), and hypokalaemia (n=3). Therapy was terminated because of treatment-related toxicity in one (17%) of the six patients receiving FOLFIRINOX alone. 16 (49%) of 33 patients receiving FOLFIRINOX plus PF-04136309 who had undergone repeat imaging achieved an objective tumour response, with local tumour control achieved in 32 (97%) patients. In the FOLFIRINOX alone group, none of the five patients with repeat imaging achieved an objective response, although four (80%) of those patients achieved stable disease. Interpretation CCR2-targeted therapy with PF-04136309 in combination with FOLFIRINOX is safe and tolerable. Funding Washington University–Pfizer Biomedical Collaborative.

Background: Colorectal cancer is a leading cause of cancer death. Biomarkers to predict treatment outcomes are needed, as is evidence whether postdiagnosis diet and lifestyle can affect well-being and clinical outcomes. The international ColoCare Consortium aims to identify new biologic markers (e.g., metabolomic, transcriptomic, metagenomic, genetic, epigenetic, proteomic markers) that predict clinical outcomes, and to characterize associations between modifiable risk factors (e.g., diet, supplement use, physical activity) with short-term and long-term patient-reported and clinical outcomes among patients with colorectal cancer. Methods/Results: ColoCare is recruiting newly diagnosed patients with colorectal cancer across six sites in the United States and one site in Germany. As of April 2018, we have recruited >2,000 patients across all sites. Our projected enrollment is >4,000 multiethnic patients with colorectal cancer. The study includes uniformly collected, comprehensive sets of data and biospecimens at multiple time points up to 5 years after diagnosis. Treatment and clinical data are abstracted from medical records and centrally harmonized. Biospecimens are archived according to standardized procedures. Our initial studies demonstrated metabolic differences in adipose tissue types. We further reported on associations of biological factors (e.g., inflammation, DNA methylation, metabolomics) with lifestyle factors (e.g., adiposity, smoking, physical activity, dietary supplement use) or joint associations with clinical outcomes. Conclusions: ColoCare is a consortium for the investigation of multilevel factors relevant to colorectal cancer survivorship. Impact: The combination of a comprehensive set of biospecimens collected at multiple time points, jointly with detailed assessments of health behaviors and other prognostic factors, results in a unique resource that facilitates wide-ranging, innovative, and impactful research on colorectal cancer.

BACKGROUND: We evaluated the associations of handgrip strength and cognitive function in cancer survivors ≥ 60 years old using data from the National Health and Nutrition Examination Survey (NHANES). METHODS: Data in two waves of NHANES (2011-2014) were aggregated. Handgrip strength in kilogram (kg) was defined as the maximum value achieved using either hand. Two cognitive function tests were conducted among adults 60 years and older. The Animal Fluency Test (AFT) examines categorical verbal fluency (a component of executive function), and the Digital Symbol Substitution test (DSST) assesses processing speed, sustained attention, and working memory. Survey analysis procedures were used to account for the complex sampling design of the NHANES. Multiple linear regression models were used to estimate associations of handgrip strength with cognitive test scores, adjusting for confounders (age, gender, race/ethnicity, education, marital status, smoking status, depressive symptoms and leisure time physical activity). RESULTS: Among 383 cancer survivors (58.5% women, mean age = 70.9 years, mean BMI = 29.3 kg/m2), prevalent cancer types were breast (22.9%), prostate (16.4%), colon (6.9%) and cervix (6.2%). In women, each increase in kg of handgrip strength was associated with 0.20 (95% CI: 0.08 to 0.33) higher score on AFT and 0.83 (95% CI: 0.30 to 1.35) higher score on DSST. In men, we observed an inverted U-shape association where cognitive function peaked at handgrip strength of 40-42 kg. CONCLUSIONS: Handgrip strength, a modifiable factor, appears to be associated with aspects of cognitive functions in cancer survivors. Prospective studies are needed to address their causal relationship. ispartof: PLOS ONE vol:13 issue:6 ispartof: location:United States status: published

Objectives It is unclear whether long-standing diabetes or new-onset pancreatogenic diabetes contributes to poor prognosis in patients with pancreatic ductal adenocarcinoma (PDAC). Methods We investigated the influence of diabetes diagnosed shortly before PDAC and long-term diabetes on overall survival in 2792 PDAC patients who had participated in 3 PDAC case-control studies in the Pancreatic Cancer Case-Control Consortium. There were 300 patients with long-term diabetes of more than 3 years' duration (11%) and 418 patients with recently diagnosed diabetes of 3-year duration or less (15%). We performed Cox regression to determine the association of long-term diabetes and recently diagnosed diabetes with overall survival, adjusting for study site, age, sex, race, stage of disease, surgery, chemotherapy, smoking history, and body mass index at diagnosis. Results In the overall population, neither long-term diabetes (hazard ratio [HR], 1.10; 95% confidence interval [CI], 0.97-1.26) nor recently diagnosed diabetes (HR, 1.06; 95% CI, 0.94-1.18) was associated with shorter survival. When stratified by stage of disease, long-term diabetes was associated with 42% increase in rate of death in persons with resectable PDAC (HR, 1.42; 95% CI, 1.13-1.78), whereas it was not associated with survival in PDAC patients with more advanced disease. Conclusion Long-term diabetes was associated with increased rate of death in patients with resectable PDAC.

Although childhood adiposity is inversely associated with breast cancer risk, the association of childhood adiposity with mammographic density in premenopausal women has not been adequately studied. We analyzed data from 365 premenopausal women who came in for screening mammography at Washington University (St. Louis, MO) from 2015 to 2016. Body size at age 10 was self-reported using somatotype pictogram. Body mass index (BMI) at age 10 was imputed using data from Growing Up Today Study. Volpara software was used to evaluate volumetric percent density (VPD), dense volume (DV), and nondense volume (NDV). Adjusted multivariable linear regression models were used to evaluate the associations between adiposity at age 10 and mammographic density measures. Adiposity at age 10 was inversely associated with VPD and positively associated with NDV. A 1 kg/m2 increase in BMI at age 10 was associated with a 6.4% decrease in VPD, and a 6.9% increase in NDV (P < 0.001). Compared with women whose age 10 body size was 1 or 2, women with body size 3 or 4 had a 16.8% decrease in VPD and a 26.6% increase in NDV, women with body size 5 had a 32.2% decrease in VPD and a 58.5% increase in NDV, and women with body sizes ≥6 had a 47.8% decrease in VPD and a 80.9% increase in NDV (P < 0.05). The associations were attenuated, but still significant after adjusting for current BMI. Mechanistic studies to understand how childhood adiposity influences breast development, mammographic density, and breast cancer in premenopausal women are needed. Cancer Prev Res; 11(5); 287–94. ©2018 AACR.

Objectives Circulating 25-hydroxyvitamin D (25-OHD) is associated with improved cancer prognosis in some studies, yet it may be a surrogate marker for physical activity. We investigated the associations of leisure-time physical activity (LTPA) with circulating 25-OHD levels in cancer survivors, and determined whether associations differ by indoor and outdoor activity. Design Cross-sectional study. Setting The US National Health and Nutrition Examination Survey (NHANES). Participants Cancer survivors with available data on demographic information, measures of adiposity, smoking history, self-reported LTPA and circulating 25-OHD levels in five waves of NHANES (2001–2010). Main outcomes measures Circulating 25-OHD levels. Results Multivariable linear regression and logistic regression models were used to evaluate the associations of self-reported LTPA with 25-OHD, adjusting for potential confounders. Due to the differences in LTPA measure, the analyses were conducted separately for 2001–2006 and 2007–2010 data. We further estimated associations by indoor and outdoor activity in the 2001–2006 data. There were 1530 cancer survivors (mean age=60.5 years, mean body mass index=28.6 kg/m 2 ). The prevalent cancer sites were breast (19.3%), prostate (18.8%), cervix (10.4%) and colon (8.6%). Compared with inactive cancer survivors, being physically active was associated with higher circulating 25-OHD levels (8.07 nmol/L, 95% CI 4.63 to 11.52) for 2001–2006 data. In the mutually adjusted model, higher outdoor activity (5.83 nmol/L, 95% CI 1.64 to 10.01), but not indoor activity (2.93 nmol/L, 95% CI −1.80 to 7.66), was associated with statistically significantly higher 25-OHD levels. The interaction between indoor and outdoor activities was, however, not significant (p=0.29). The only statistically significant association seen in the 2007–2010 data was among obese cancer survivors. Conclusion Physical activity, particularly outdoor activity, is associated with higher 25-OHD levels in cancer survivors. In view of the possible beneficial effects of vitamin D on cancer prognosis, engaging in outdoor physical activity could provide clinically meaningful increases in 25-OHD levels among cancer survivors.

We investigated the associations of adolescent adiposity, changes in adiposity during adulthood, and attained adiposity with volumetric mammographic density measures.We recruited 383 premenopausal women who had a routine screening mammogram at the Breast Health Center, Washington University in St. Louis, MO from December 2015 to October 2016. Trained research personnel assessed current adiposity measures. Weight at ages 18 and 30 were self-reported. We evaluated mammographic density measures: volumetric percent density (VPD), dense volume (DV), and non-dense volume (NDV) using Volpara. Multivariable linear regression models were used to evaluate the associations of adiposity measures with volumetric mammographic density measures.All attained adiposity measures, BMI at age 18, age 30, and weight change were significantly inversely associated with VPD, and positively associated with DV and NDV. One unit increase in body fat % was associated with a 4.9% decrease in VPD and a 6.5% increase in NDV (p-values0.001). For each kilogram increase in weight change from age 18 to attained, VPD decreased by 16.3%, 47.1%, and 58.8% for women who gained 5.1-15, 15.1-25 and25 kg, respectively, compared to women who gained less than 5 kg during this time period (p-values0.001). Irrespective of BMI at age 18, VPD significantly decreased and NDV increased among women who were currently obese.There is a need for mechanistic studies focusing on early adulthood to provide a better understanding of how adiposity in early life relates to mammographic density, and possibly breast cancer development in premenopausal women.

BACKGROUND: Pre-diagnosis obesity and diabetes are associated with survival from pancreatic cancer, but the underlying mechanisms have not been characterized. Since both are associated with dysregulation in circulating insulin-like growth factor (IGF) levels, we evaluated the associations of pre-diagnosis IGF levels (IGF-I, IGF-II), and IGF binding protein 3 (IGFBP-3) with pancreatic cancer survival. METHODS: Participants were subjects enrolled in the intervention arm of the PLCO Cancer Screening Trial who developed exocrine pancreatic cancer during follow-up (N=178, 116 men and 67 women). Participants provided blood samples at enrollment, before cancer diagnosis. Cox proportional hazards regression model, adjusted for confounders was used to investigate associations of IGF biomarkers with pancreatic cancer survival. Because of the well-documented gender-specific differences in circulating IGF biomarkers, and differential associations of IGF biomarkers with mortality, we evaluated associations separately among males and females. RESULTS: Median survival was 172 days. Higher IGF-II, and IGFBP-3 levels were associated with pancreatic cancer survival among males, but not among females. The hazard ratios of death among men in the highest tertiles of IGF-II and IGFBP-3 compared to men in the lowest tertiles were HR=0.40 (95%CI 0.23–0.71, p-trend

A situational analysis of breast cancer (BC) early detection services was carried out to investigate whether Trinidad and Tobago (T&T) has the framework for successful organized national screening. An online survey was designed to assess the availability, accessibility, quality control and assurance (QC&A), and monitoring and evaluation (M&E) mechanisms for public and private BC early detection. A focus group with local radiologists (n = 3) was held to identify unaddressed challenges and make recommendations for improvement. Major public hospitals offer free detection services with wait times of 1–6 months for an appointment. Private institutions offer mammograms for TTD$240 (USD$37) at minimum with same day service. Both sectors report a lack of trained staff. Using 1.2 mammograms per 10,000 women ≥40 years as sufficient, the public sector’s rate of 0.19 mammograms per 10,000 women ≥40 years for screening and diagnosis is inadequate. Program M&E mechanisms, QC&A guidelines for machinery use, delays in receipt of pathology reports, and unreliable drug access are further unaddressed challenges. T&T must first strengthen its human and physical resources, implement M&E and QC&A measures, strengthen cancer care, and address other impediments to BC early detection before investing in nationally organized BC screening.

Circulating 25-hydroxyvitamin D (25-OHD) is associated with a reduction in risk of some cancers, but its association with prognosis among patients with cancer is poorly understood. In view of the increasing number of cancer survivors in the United States and the high prevalence of vitamin D deficiency among patients with cancer, an evaluation of the role of circulating 25-OHD in prognosis among patients with cancer is essential. We conducted a systematic review of studies published in the following databases—PubMed, OvidSP, BioMed Central, EMBASE, and Scopus till September 2013 using the following search terms: “vitamin D,” “25-hydroxyvitamin D,” “calcidiol,” “cancer,” “survival,” “mortality,” and “prognosis.” Our search yielded 1,397 articles. From the 1,397 articles, we identified 26 studies that evaluated the associations of circulating 25-OHD with prognosis among patients with cancer. Evidence suggests that circulating 25-OHD levels may be associated with better prognosis in patients with breast and colorectal cancer, but there is a paucity of information on its association with prognosis in other cancers. This review highlights the need for further studies evaluating the role of vitamin D in prognosis among patients with cancer. Cancer Epidemiol Biomarkers Prev; 23(6); 917–33. ©2014 AACR.

Background: Diabetes is a risk factor for pancreatic cancer but its association with survival from pancreatic cancer is poorly understood. Our objective was to investigate the association of diabetes with survival among pancreatic cancer patients in a prospective cohort-based study where diabetes history was ascertained before pancreatic cancer diagnosis. Methods: We evaluated survival by baseline (1993–2001) self-reported diabetes history (n ¼62) among 504 participants that developed exocrine pancreatic cancer within the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial. Hazard ratios (HRs) and 95% confidence intervals (CIs) for mortality were estimated using Cox proportional hazards model, adjusted for age, sex, body mass index, race, smoking, and tumour stage (local, locally advanced, and metastatic). Results: The multivariable-adjusted HR for mortality comparing participants with diabetes to those without was 1.52 (95% CI ¼1.14–2.04, P-value o0.01). After excluding those diagnosed with pancreatic cancer within 3 years of study enrolment, HR for mortality among those with diabetes was 1.45 (95% CI ¼1.06–2.00, P-value ¼0.02). Conclusions: Using prospectively collected data, our findings indicate that diabetes is associated with worse survival among patients with pancreatic cancer.

ABSTRACT: Background: We investigated whether the free β-human chorionic gonadotropin (free β-hCG) would provide additional information to that provided by total hCG alone and thus be useful in future epidemiological studies relating hCG to maternal breast cancer risk. Materials & methods: Cases (n = 159) and controls (n = 286) were a subset of our previous study within the Northern Sweden Maternity Cohort on total hCG during primiparous pregnancy and breast cancer risk. Results: The associations between total hCG (hazard ratio: 0.79; 95% CI: 0.49–1.27), free β-hCG (hazard ratio: 0.85; 95% CI: 0.33–2.18) and maternal risk of breast cancer were very similar in all analyses and mutual adjustment for either one had minor effects on the risk estimates. Conclusion: In the absence of a reliable assay on intact hCG, total hCG alone can be used in epidemiological studies investigating hCG and breast cancer risk, as free β-hCG does not appear to provide any additional information.

Body size, from birth throughout adulthood, is associated with breast cancer risk, but few studies have investigated early-life body size and benign breast disease (BBD), a well-established breast cancer risk factor. We consider whether prenatal factors and size at birth, 10, 18 year, and intervening growth, are related to BBD risk. The Growing Up Today Study includes 9032 females who completed questionnaires annually from 1996 to 2001, then 2003, 2005, 2007, 2010, and 2013. In 1996, their mothers provided pregnancy-related data. From 2005 to 2013, participants (18 year+) reported whether they had ever been diagnosed with biopsy-confirmed BBD (N = 142 cases). Girls had greater adiposity (BMI; kg/m2) at 10 year if they were larger at birth, if mother’s pre-pregnancy BMI was higher, or if gestational weight gain was greater (all p

Both bone mineral density (BMD) and breast density are related to reproductive hormone levels. This suggests that BMD and breast density could be meaningfully associated, and serve as surrogate markers for breast cancer risk. However, few studies have investigated the association of BMD with percent mammographic density, making it difficult to draw meaningful conclusions.We conducted a systematic review of studies published in electronic databases till April 2016 using the following search terms: "bone density," "bone mineral density," "mammographic breast density," "breast density," and "mammographic density." We identified 203 articles, of which 8 met the inclusion criteria for this review.BMD does not appear to be associated with percent mammographic density. BMD at the spine was weakly positively associated with percent mammographic density among postmenopausal women who were not hormone users, while BMD at the hip and legs was positively associated with percent mammographic density among premenopausal women. On the other hand, one study reported an inverse association of BMD at the spine and hip with percent mammographic density among perimenopausal women.In this review, we found no evidence of an association between BMD and percent mammographic density.

Background Excess body weight and a sedentary lifestyle are associated with the development of several diseases, including cardiovascular disease, diabetes and cancer in women. One proposed mechanism linking obesity to chronic diseases is an alteration in adipose-derived adiponectin and leptin levels. We investigated the effects of 12-month reduced calorie, weight loss and exercise interventions on adiponectin and leptin concentrations. Methods Overweight/obese postmenopausal women (n = 439) were randomized as follows: (i) a reduced calorie, weight-loss diet (diet; N = 118), (ii) moderate-to-vigorous intensity aerobic exercise (exercise; N = 117), (iii) a combination of a reduced calorie, weight-loss diet and moderate-to-vigorous intensity aerobic exercise (diet + exercise; N = 117), and (iv) control (N = 87). The reduced calorie diet had a 10% weight-loss goal. The exercise intervention consisted of 45 min of moderate-to-vigorous aerobic activity 5 days per week. Adiponectin and leptin levels were measured at baseline and after 12 months of intervention using a radioimmunoassay. Results Adiponectin increased by 9.5% in the diet group and 6.6% in the diet + exercise group (both P ≤ 0.0001 vs. control). Compared with controls, leptin decreased with all interventions (diet + exercise, −40.1%, P

Initial studies have investigated the association between inflammation and colorectal cancer (CRC) using C-reactive protein (CRP) as a proinflammatory biomarker and have noted inconsistent results among women. We here report the findings from a large prospective study with repeat measurements of CRP, as well as serum amyloid A (SAA), an additional biomarker of inflammation, and risk of CRC. In the Women's Health Initiative Observational Study, we examined associations of CRP and SAA with CRC using repeat assessments (baseline and 3-year follow-up) among 953 matched case-control pairs for CRP and 966 pairs for SAA. Multivariate-adjusted conditional-logistic regression models were used with two-sided tests of significance. Receiver operating characteristic (ROC) curve analysis assessed their utility as early detection markers. Colon cancer risk (odds ratio [OR] and 95% confidence intervals) among women in the highest quintiles of CRP or SAA compared to those in the lowest quintiles was ORcolon/CRP = 1.37 (0.95-1.97, p-trend = 0.04) and ORcolon/SAA = 1.26 (0.88-1.80, p-trend = 0.10), respectively. Women with elevated concentrations of both CRP and SAA had an increased risk of ORcolon = 1.50 (1.12-2.00, p-value = 0.006) compared to those with low concentrations. No positive associations were observed with rectal cancer and weaker associations for CRC overall. Temporal changes in biomarkers more than 3 years did not predict risk. The area under the 6-month ROC curve for CRP+SAA was 0.62 (95% confidence interval = 0.55-0.68). Elevated inflammatory biomarkers are associated with an increased risk of CRC, mainly colon cancer. Nevertheless, changes in the biomarkers over time do not suggest that they merit consideration as early detection markers for CRC.

Obesity is a well-established cause of postmenopausal breast cancer. However, early life adiposity is inversely associated with breast cancer incidence. To understand these conflicting relations, we use validated measures to assess adiposity in childhood and late adolescence, as well as weight change, in relation to total invasive breast cancer incidence and receptor subtypes. We conducted a prospective observational study among 74,177 women from the Nurses' Health Study from 1980-2012, with updated risk factors every 2 years during which 4,965 incident invasive breast cancers occurred. Overall, weight at age 18 was inversely associated with both premenopausal (HR per 30 kg = 0.52, 95% CI = 0.39-0.71) and postmenopausal (HR per 30 kg = 0.81, 95% CI = 0.72-0.92) breast cancer which was largely explained by adiposity at age 10. Long-term weight gain from age 18 both during premenopause and postmenopause were positively associated with postmenopausal breast cancer risk. However, premenopausal weight gain was not related to premenopausal breast cancer risk. Furthermore, weight gain since age 18 was positively associated with ER+/PR+ postmenopausal breast cancer (HR per 30 kg = 1.50, 95% CI = 1.36-1.65) but not ER+/PR- (HR per 30 kg = 0.96, 95% CI = 0.78-1.19) or ER-/PR- (HR per 30 kg = 1.16, 95% CI = 0.95-1.42) postmenopausal breast cancer. Overall, 17% of ER+/PR+ postmenopausal breast cancer and 14% of total postmenopausal breast cancer are attributable to weight gain of 5 kg since age 18.

Human chorionic gonadotropin (hCG) is necessary for the maintenance of early pregnancy and promotes normal breast cell differentiation. Administered hCG reduces risk of carcinogen-induced breast cancer in animal models, and higher circulating hCG concentrations were associated with significantly lower long-term risk of breast cancer in a prior nested case–control study. In this study, we investigated early-pregnancy hCG concentrations and subsequent breast cancer risk. We conducted a nested case–control study with 1,191 cases and 2,257 controls (matched on age and date at blood collection) in the Finnish Maternity Cohort, a cohort with serum samples from 98% of pregnancies registered in Finland since 1983. This study included women with a serum sample collected early (

Background Inflammation is associated with cancer but there are conflicting reports on associations of biomarkers of inflammation with cancer risk and mortality. We investigated the associations of C-reactive protein (CRP) and leukocyte count with cancer risk and mortality using individual biomarkers, and an inflammatory score derived from both biomarkers. Methods We conducted this analysis among 2,570 men enrolled in the population-based, prospective Kuopio Ischemic Heart Disease Risk Factor Study in Finland. During an average follow-up period of 26 years, 653 cancer cases and 287 cancer deaths occurred. We computed a z-score for each participant, with the combined z-score being the sum of each individual’s CRP and leukocyte z-scores. Multivariable-adjusted Cox proportional hazard model was used to evaluate associations with cancer risk and mortality. Results Using individual biomarkers, elevated leukocyte count was associated with an increased risk of cancer (RR = 1.31, 95 % CI 1.04-1.66), and cancer mortality (RR=, 95 % CI 1.39, 0.98-1.97). The corresponding results for CRP were (RR = 1.23, 95 % CI 0.97-1.55) for risk and (RR = 1.15, 95 % CI 0.81-1.64) for cancer mortality. Associations of the biomarkers with cancer appeared to be more robust using the combined z-score. HRs comparing men within the highest z-score quartile to those within the lowest z-score quartiles were 1.47 (95 % CI 1.16-1.88, p-trend