Lung cancer metabolomics: a pooled analysis in the Cancer Prevention Studies.

BACKGROUND: A better understanding of lung cancer etiology and the development of screening biomarkers have important implications for lung cancer prevention. METHODS: We included 623 matched case-control pairs from the Cancer Prevention Study (CPS) cohorts. Pre-diagnosis blood samples were collected between 1998 and 2001 in the CPS-II Nutrition cohort and 2006 and 2013 in the CPS-3 cohort and were sent for metabolomics profiling simultaneously. Cancer-free controls at the time of case diagnosis were 1:1 matched to cases on date of birth, blood draw date, sex, and race/ethnicity. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using conditional logistic regression, controlling for confounders. The Benjamini-Hochberg method was used to correct for multiple comparisons. RESULTS: Sphingomyelin (d18:0/22:0) (OR: 1.32; 95% CI: 1.15, 1.53, FDR = 0.15) and taurodeoxycholic acid 3-sulfate (OR: 1.33; 95% CI: 1.14, 1.55, FDR = 0.15) were positively associated with lung cancer risk. Participants diagnosed within 3 years of blood draw had a 55% and 48% higher risk of lung cancer per standard deviation increase in natural log-transformed sphingomyelin (d18:0/22:0) and taurodeoxycholic acid 3-sulfate level, while 26% and 28% higher risk for those diagnosed beyond 3 years, compared to matched controls. Lipid and amino acid metabolism accounted for 47% to 80% of lung cancer-associated metabolites at P < 0.05 across all participants and subgroups. Notably, ever-smokers exhibited a higher proportion of lung cancer-associated metabolites (P < 0.05) in xenobiotic- and lipid-associated pathways, whereas never-smokers showed a more pronounced involvement of amino acid- and lipid-associated metabolic pathways. CONCLUSIONS: This is the largest prospective study examining untargeted metabolic profiles regarding lung cancer risk. Sphingomyelin (d18:0/22:0), a sphingolipid, and taurodeoxycholic acid 3-sulfate, a bile salt, may be risk factors and potential screening biomarkers for lung cancer. Lipid and amino acid metabolism may contribute significantly to lung cancer etiology which varied by smoking status.

Outdoor air pollution and risk of incident adult haematologic cancer subtypes in a large US prospective cohort.

BACKGROUND: Outdoor air pollution and particulate matter (PM) are classified as Group 1 human carcinogens for lung cancer. Pollutant associations with haematologic cancers are suggestive, but these cancers are aetiologically heterogeneous and sub-type examinations are lacking. METHODS: The American Cancer Society Cancer Prevention Study-II Nutrition Cohort was used to examine associations of outdoor air pollutants with adult haematologic cancers. Census block group level annual predictions of particulate matter (PM2.5, PM10, PM10-2.5), nitrogen dioxide (NO2), ozone (O3), sulfur dioxide (SO2), and carbon monoxide (CO) were assigned with residential addresses. Hazard ratios (HR) and 95% confidence intervals (CI) between time-varying pollutants and haematologic subtypes were estimated. RESULTS: Among 108,002 participants, 2659 incident haematologic cancers were identified from 1992-2017. Higher PM10-2.5 concentrations were associated with mantle cell lymphoma (HR per 4.1 µg/m3 = 1.43, 95% CI 1.08-1.90). NO2 was associated with Hodgkin lymphoma (HR per 7.2 ppb = 1.39; 95% CI 1.01-1.92) and marginal zone lymphoma (HR per 7.2 ppb = 1.30; 95% CI 1.01-1.67). CO was associated with marginal zone (HR per 0.21 ppm = 1.30; 95% CI 1.04-1.62) and T-cell (HR per 0.21 ppm = 1.27; 95% CI 1.00-1.61) lymphomas. CONCLUSIONS: The role of air pollutants on haematologic cancers may have been underestimated previously because of sub-type heterogeneity.

Consistent and changing consumption of fast-food and full-service meals and 3-year weight change in a large population cohort study.

BACKGROUND: An average American consumes 3 meals weekly from fast-food or full-service restaurants, which contain more calories, fat, sodium, and cholesterol than meals prepared at home. OBJECTIVES: This study examined whether consistent and changing fast-food or full-service consumption was associated with weight change over a 3-y period. METHODS: Among 98,589 US adults from the American Cancer Society's Cancer Prevention Study-3, self-reported weight and fast-food and full-service consumption from 2015 and 2018 were examined using a multivariable-adjusted linear regression analysis to assess the association of consistent and changing consumption on 3-y weight change. RESULTS: Individuals who made no changes to their fast-food or full-service intake over the study period gained weight regardless of consumption frequency, although low consumers gained less weight than high consumers (low fast-food: ß = -1.08; 95% CI: -1.22, -0.93; low full-service: ß = -0.35; 95% CI: -0.50, -0.21; P < 0.001). Decreased fast-food intake during the study period (e.g., from high [>1 meal/wk] to low [≤0.5 meal/wk], high to medium [>0.5 to ≤1 meal/wk], or medium to low) and decreased full-service intake from high (≥1 meal/wk) to low (<1 meal/mo) were significantly associated with weight loss (high-low: ß = -2.77; 95% CI: -3.23, -2.31; high-medium: ß = -1.53; 95% CI: -1.72, -1.33; medium-low: ß = -0.85; 95% CI: -1.06, -0.63; high-low full-service: ß = -0.92; 95% CI: -1.36, -0.49; P < 0.001). Decreased consumption of both fast-food and full-service restaurant meals was associated with greater weight loss than decreasing fast-food alone (both: ß = -1.65; 95% CI: -1.82, -1.37; fast-food only: ß = -0.95; 95% CI: -1.12, -0.79; P < 0.001). CONCLUSIONS: Decreased consumption of fast-food and full-service meals over 3 y, particularly among high consumers at baseline, was associated with weight loss and may be an effective approach to weight loss. Moreover, decreasing both fast-food and full-service meal consumption was associated with a greater weight loss than decreasing only fast-food meal consumption.

Key risk factors for the relative and absolute 5-year risk of cancer to enhance cancer screening and prevention.

BACKGROUND: This study identifies populations who may benefit most from expanded cancer screening. METHODS: Two American Cancer Society prospective cohort studies, Cancer Prevention Study-II Nutrition Cohort and Cancer Prevention Study-3, were used to identify the risk factors associated with a > 2% absolute risk of any cancer within 5 years. In total, 429,991 participants with no prior personal history of cancer were followed for cancer for up to 5 years. Multivariable Cox proportional hazards models were used to estimate hazard ratios and 95% confidence intervals for association. By using these hazard ratios, individualized coherent absolute risk estimation was used to calculate absolute risks by age. RESULTS: Overall, 15,226 invasive cancers were diagnosed among participants within 5 years of enrollment. The multivariable-adjusted relative risk of any cancer was strongest for current smokers compared with never-smokers. In men, alcohol intake, family history of cancer, red meat consumption, and physical inactivity were also associated with risk (p < .05). In women, body mass index, type 2 diabetes, hysterectomy, parity, family history of cancer, hypertension, tubal ligation, and physical inactivity were associated (p < .05). The absolute 5-year risk exceeded 2% among nearly all participants older than 50 years and among some participants younger than 50 years, including current or former smokers (<30 years since quitting) and long-term nonsmokers with a body mass index >25 kg/m2 or a first-degree family history of cancer. The absolute 5-year risk was as high as 29% in men and 25% in women. CONCLUSIONS: Older age and smoking were the two most important risk factors associated with the relative and absolute 5-year risk of developing any cancer.

Circulating plasma phospholipid fatty acid levels and breast cancer risk in the Cancer Prevention Study-II Nutrition Cohort.

Prospective studies that objectively measure circulating levels of fatty acids are needed to clarify their role in the etiology of breast cancer. Thirty-eight phospholipid fatty acids were measured using gas chromatograph in the plasma fraction of blood samples collected prospectively from 2718 postmenopausal women (905 breast cancer cases) enrolled in the Cancer Prevention Study II Nutrition Cohort. Associations of 28 fatty acids that passed quality control metrics (modeled as per 1-SD increase) with breast cancer risk were assessed using multiple variable conditional logistic regression models to compute odds ratios (OR) and 95% confidence intervals (CI). The false discovery rate (q value) was computed to account for multiple comparisons. Myristic acid levels were positively associated with breast cancer risk (OR, 1.17, 95% CI: 1.07-1.28; q value = 0.03). Borderline associations were also found for palmitoleic acid (OR, 1.14, 95% CI: 1.04-1.24) and desaturation index16 (OR, 1.10, 95% CI: 1.01-1.20) at nominal P values (<.03) (q values>0.05). These findings suggest that higher circulating levels of myristic acid, sourced from dietary intake of palm kernel oils along with increased de novo synthesis of fatty acids, may increase breast cancer risk. Additional studies are needed to investigate de novo synthesis of fatty acid in breast cancer tissues.

Anthropometric traits and risk of multiple myeloma: a pooled prospective analysis.

BACKGROUND: Obesity is a risk factor for multiple myeloma (MM), yet results of prior studies have been mixed regarding the importance of early and/or later adult obesity; other measures of body composition have been less well studied. METHODS: We evaluated associations of early adult (ages 18-21) and usual adult body mass index (BMI), waist circumference, and predicted fat mass with MM by pooling data from six U.S. prospective cohort studies comprising 544,016 individuals and 2756 incident diagnoses over 20-37 years of follow-up. We used Cox proportional hazards models to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for associations, adjusted for age and other risk factors. RESULTS: Each 5 kg/m2 increase in usual adult BMI was associated with a 10% increased risk of MM (HR: 1.10; 95% CI: 1.05-1.15). Positive associations were also noted for early adult BMI (HR per 5 kg/m2: 1.14; 95% CI: 1.04-1.25), height (HR per 10 cm: 1.28; 95% CI: 1.20-1.37), waist circumference (HR per 15 cm: 1.09; 95% CI: 1.00-1.19), and predicted fat mass (HR per 5 kg: 1.06; 95% CI: 1.01-1.11). CONCLUSIONS: These findings highlight the importance of avoidance of overweight/obesity and excess adiposity throughout adulthood as a potential MM risk-reduction strategy.

Age-related health deficits and five-year mortality among older, long-term cancer survivors.

INTRODUCTION: Geriatric assessment evaluates multiple domains of health that, together, are superior to using chronologic age for predicting outcomes, such as hospitalization and mortality among patients with cancer. Most studies have not included comparison groups of individuals without cancer and assessed domains around the time of initial cancer diagnosis. Further, the potential for brief, self-reported measures to capture deficits that similarly predict mortality has not been well examined. This study compared age-related health deficit prevalence between older, long-term cancer survivors and individuals without a cancer history, and estimated associations between deficits and mortality risk among survivors. MATERIALS AND METHODS: Analyses included participants in the Cancer Prevention Study (CPS)-II Nutrition Cohort who were cancer-free at enrollment in 1992/1993 and completed the Patient Reported Outcome Measurement Information System® (PROMIS®) global health questionnaire in 2011. Age-related deficits in five domains (comorbidities, functional status, mental health, malnutrition/weight loss, and social support) were self-reported. Cancer information was self-reported and confirmed via medical records or state cancer registries. Vital status through 2016 and cause of death was ascertained by linkage with the National Death Index. RESULTS: Analyses included 9979 participants (median age = 80) diagnosed with invasive cancer 5-20 years prior to completing the 2011 survey and 63,578 participants without a cancer history (median age = 79). Overall deficits in the five domains were similar among long-term cancer survivors and controls. However, survivors of specific cancer types - non-Hodgkin lymphoma (NHL), lung, and kidney cancer - were more likely to report deficits in mental health and functional status than the control group. Among all survivors, each domain was independently associated with all-cause mortality, particularly functional status (hazard ratio [HR] = 2.02; 95% confidence interval [CI]: 1.80-2.27) and mental health (HR = 1.84; 95% CI: 1.65-2.04). Mortality risk increased with the number of deficits. DISCUSSION: These results suggest that, several years after treatment, NHL, lung, and kidney cancer survivors are still more likely to experience age-related deficits compared to other similarly-aged individuals. Furthermore, results show that shorter, self-reported physical and mental health assessments, such as the PROMIS® global health questions, are predictive of mortality among older, long-term cancer survivors and, therefore, may be useful in clinical and research settings.

Body size and risk of non-Hodgkin lymphoma by subtype: A pooled analysis from six prospective cohorts in the United States.

In 2022, more than 100 000 non-Hodgkin lymphoma (NHL) diagnoses are expected, yet few risk factors are confirmed. In this study, data from six US-based cohorts (568 717 individuals) were used to examine body size and risk of NHL. Over more than 20 years of follow-up, 11 263 NHLs were identified. Hazard ratios (HRs) and 95% confidence intervals (CI) estimated associations with NHLs for adult body mass index (BMI), height, weight change, waist circumference and predicted fat mass. Adult height was broadly associated with NHL, but most strongly with B-cell NHLs among non-White participants (e.g. HRBLACK  = 2.06, 95% CI: 1.62-2.62). However, the strongest association among the anthropometric traits examined was for young adult BMI and risk of diffuse large B-cell lymphoma (DLBCL), particularly those who maintained a higher BMI into later adulthood. Individuals with BMI over 30 kg/m2 throughout adulthood had more than double the DLBCL risk (HR = 2.67, 95% CI: 1.71-4.17) compared to BMI 18.5-22.9 kg/m2 . Other anthropometric traits were not associated with NHL after controlling for BMI. These results suggest that sustained high BMI is a major driver of DLBCL risk. If confirmed, we estimate that up to 23.5% of all DLBCLs (and 11.1% of all NHLs) may be prevented with avoidance of young adult obesity.

The Role of Individual-Level Factors in Rural Mortality Disparities.

Introduction: The role of individual risk factors in the rural‒urban mortality disparity is poorly understood. The purpose of this study was to explore the role of individual-level demographics and health behaviors on the association between rural residence and the risk of mortality. Methods: Cancer Prevention Study-II participants provided updated addresses throughout the study period. Rural‒Urban Commuting Area codes were assigned to participants' geocoded addresses as a time-varying exposure. Cox proportional hazards regression was used to estimate hazard ratios and 95% CIs for mortality associated with Rural‒Urban Commuting Area groups. Results: After adjustment for age and sex, residents of rural areas/small towns had a small but statistically significant elevated risk of all-cause mortality compared with metropolitan residents (hazard ratio=1.04; 95% CI=1.01, 1.06). Adjustment for additional covariates attenuated the association entirely (hazard ratio=0.99; 95% CI=0.97, 1.01). Individually, adjustment for education (hazard ratio=0.99; 95% CI=0.97, 1.01), alcohol use (hazard ratio=1.01; 95% CI=0.99, 1.04), and moderate-to-vigorous intensity aerobic physical activity (hazard ratio=1.00; 95% CI=0.97, 1.02) eliminated the elevated risk. Conclusions: The elevated risk of death for rural compared with that for metropolitan residents appeared to be largely explained by individual-level demographics and health behaviors. If replicated in other subpopulations, these results suggest that modifiable factors may play an important role in reducing the rural mortality disparity.

Breast cancer risk factors by mode of detection among screened women in the Cancer Prevention Study-II.

BACKGROUND: Identifying risk factors for women at high risk of symptom-detected breast cancers that were missed by screening would enable targeting of enhanced screening regimens. To this end, we examined associations of breast cancer risk factors by mode of detection in screened women from the Cancer Prevention Study (CPS)-II Nutrition Cohort. METHODS: Among 77,206 women followed for a median of 14.8 years, 2711 screen-detected and 1281 symptom-detected breast cancer cases were diagnosed. Multivariable-adjusted associations were estimated using joint Cox proportional hazards regression models with person-time calculated contingent on screening. RESULTS: Factors associated with higher risks of symptom-detected and screen-detected breast cancer included current combined hormone therapy (HT) use (HR 2.07, 95% CI 1.72-2.48 and 1.45, 1.27-1.65, respectively) and history of benign breast disease (1.85, 1.64-2.08 and 1.43, 1.31-1.55, respectively). Current estrogen-only HT use was associated with symptom-detected (1.40, 1.15-1.71) but not screen-detected (0.95, 0.83-1.09) breast cancer. Higher risk of screen-detected but not symptom-detected breast cancer was observed for obese vs. normal body mass index (1.22, 1.01-1.48 and 0.76, 0.56-1.01, respectively), per 3 h/day sitting time (1.10, 1.04-1.16 and 0.97, 0.89-1.06, respectively), and ≥ 2 drinks per day vs. nondrinker (1.40, 1.16-1.69 and 1.27, 0.97-1.66, respectively). CONCLUSIONS: Differences in risk factors for symptom-detected vs. screen-detected breast cancer were observed and most notably, use of combined and estrogen-only HT and a history of benign breast disease were associated with increased risk of symptomatic detected breast cancer. IMPACT: If confirmed, these data suggest that such women may benefit from more intensive screening to facilitate early detection.

Erythrocyte levels of cadmium and lead and risk of B-cell non-Hodgkin lymphoma and multiple myeloma.

Cadmium and lead are persistent environmental toxins that are known or probable carcinogens, based on evidence for causality for nonhematologic cancers. Associations of these metals with risk of non-Hodgkin lymphoma (NHL) and multiple myeloma (MM) are unknown but biologically plausible. To examine the associations of circulating levels of lead and cadmium exposure with risk of B-cell NHL (B-NHL) and multiple myeloma, we conducted a nested case-control study among 299 incident B-cell NHLs and 76 MM cases within the Cancer Prevention Study-II Nutrition Cohort (CPS-II NC). Each case was incidence-density matched to two eligible controls on age, race, sex and blood draw date. Conditional logistic regression was used to estimate relative risks (RR) and 95% confidence intervals (CI) for lymphoid malignancies overall and stratified by subtype. We observed a significant positive association between high erythrocyte lead concentration and risk of lymphoid malignancies overall (RR = 1.16, 95% CI: 1.02-1.33 per 17.6 µg/L (1 standard deviation [SD])) and follicular lymphoma in particular (RR = 1.80, 95% CI: 1.15-2.80 per SD). In contrast, there was no association between erythrocyte cadmium and risk of B-NHL (RR = 0.89, 95% CI: 0.75-1.06 per 0.37 µg/L [1 SD]), or any B-NHL subtypes; but a strong inverse association with MM risk (RR = 0.59, 95% CI: 0.38-0.89, per SD). Results from our study suggest a positive association between erythrocyte lead level and risk of lymphoid malignancies and a possible inverse association between cadmium and myeloma. Additional research is needed to confirm and further explore these findings.

Light-Intensity Physical Activity in a Large Prospective Cohort of Older US Adults: A 21-Year Follow-Up of Mortality.

BACKGROUND: Studies show that regular moderate to vigorous physical activity is associated with a lower risk of cardiovascular disease, certain cancers, and premature death, but few studies have examined associations of light-intensity physical activity (LPA) and mortality, especially among older adults. OBJECTIVES: The aim of this study was to investigate the association of LPA with the risks of death from all causes, cancer, cardiovascular diseases, and respiratory diseases among older adults in the Cancer Prevention Study-II Nutrition Cohort (CPS-II NC). METHODS: Analyses included 123,232 participants in CPS-II NC, among whom 46,829 died during follow-up (1993-2014). Cox proportional hazards regression models were used to estimate hazard ratios (HR) and 95% confidence intervals (95% CI) for self-reported leisure time LPA associated with mortality. RESULTS: Engaging in little or no LPA (<3 metabolic equivalent [MET]-h/week) was associated with a 16% higher risk of all-cause mortality (HR 1.16, 95% CI 1.12-1.20) compared to engaging in some LPA (3 to <9 MET-h/week) after adjusting for moderate to vigorous physical activity. However, there was no evidence of a dose-response relationship. A statistically significant interaction with age suggested that more LPA was associated with a lower risk of respiratory disease mortality only among participants aged ≥70 years (21+ vs. 3 to <9 MET-h/week, HR 0.78, 95% CI 0.66-0.91; pint = 0.003). CONCLUSIONS: In this prospective study of older adults, accumulating little/no leisure time LPA was associated with a higher risk of mortality. It is of substantial public health value to demonstrate the potential benefits of engaging in any activity, even if light in intensity, among older adults given the aging US population.

Residential ambient benzene exposure in the United States and subsequent risk of hematologic malignancies.

Benzene is considered a carcinogen, mostly based on evidence of causality for myeloid leukemia from high levels of exposure in occupational studies. We used United States Environmental Protection Agency National Ambient Toxics Assessment (NATA) estimates of low-level ambient benzene to examine potential associations for the general public between benzene exposure and risk of hematologic cancers. Exposure was estimated by linking participants' residential address to the NATA benzene estimates for that census tract. Among 115,996 American Cancer Society Cancer Prevention Study-II Nutrition cohort participants (52,554 men, 63,442 women), 2,595 were diagnosed with incident hematologic cancer between 1997 and 2013. Extended Cox regression modeling was used to estimate hazard ratios (HR) and 95% confidence intervals (CI). Among all participants, ambient benzene was positively associated with myelodysplastic syndromes (HR = 1.16, 95% CI: 1.01-1.33 per µg/m3 ) and T-cell lymphoma (HR = 1.29, 95% CI: 1.08-1.53 per µg/m3 ). Among men, ambient benzene was also positively associated with any hematologic malignancy (HR = 1.07, 95% CI: 1.01-1.15 per µg/m3 ) and follicular lymphoma (HR = 1.28, 95% CI: 1.09-1.50 per µg/m3 ). No significant associations were observed for women only, but associations were suggestive for MDS and T-cell lymphoma. It is possible that the NATA ambient benzene estimates are a better proxy for benzene exposure for men than women in this cohort. The results of this study support an association between ambient benzene and risk of hematologic malignancies, particularly MDS, T-cell lymphoma and follicular lymphoma. More research in large scale or pooled studies is needed to further explore these associations.

Blood levels of cadmium and lead in relation to breast cancer risk in three prospective cohorts.

Cadmium and lead have been classified as carcinogens by the International Agency for Research on Cancer. However, their associations with breast cancer risk are unknown despite their persistence in the environment and ubiquitous human exposure. We examined associations of circulating levels of cadmium and lead with breast cancer risk in three case-control studies nested within the Cancer Prevention Study-II (CPS-II) LifeLink Cohort, European Prospective Investigation into Cancer and Nutrition - Italy (EPIC-Italy) and the Northern Sweden Health and Disease Study (NSHDS) cohorts. Metal levels were measured in stored erythrocytes from 1,435 cases and 1,433 controls using inductively coupled plasma-mass spectrometry. Summary relative risks (RR) and 95% confidence intervals (CI) were calculated using random-effects models with each study result weighted by the within- and between-study variances. I2 values were calculated to estimate proportion of between study variation. Using common cut-points, cadmium levels were not associated with breast cancer risk in the CPS-II cohort (continuous RR = 1.01, 95% CI 0.76-1.34), but were inversely associated with risk in the EPIC- Italy (continuous RR = 0.80, 95% CI 0.61-1.03) and NSHDS cohorts (continuous RR = 0.73, 95% CI 0.54-0.97). The inverse association was also evident in the meta-analysis (continuous RR = 0.84, 95% CI 0.69-1.01) with low between-study heterogeneity. Large differences in lead level distributions precluded a meta-analysis of their association with breast cancer risk; no associations were found in the three studies. Adult cadmium and lead levels were not associated with higher risk of breast cancer in our large meta-analysis.

Randomized Trial of an Integrated Behavioral Health Home: The Health Outcomes Management and Evaluation (HOME) Study.

OBJECTIVE: Behavioral health homes provide primary care health services to patients with serious mental illness treated in community mental health settings. The objective of this study was to compare quality and outcomes of care between an integrated behavioral health home and usual care. METHOD: The study was a randomized trial of a behavioral health home developed as a partnership between a community mental health center and a Federally Qualified Health Center. A total of 447 patients with a serious mental illness and one or more cardiometabolic risk factors were randomly assigned to either the behavioral health home or usual care for 12 months. Participants in the behavioral health home received integrated medical care on-site from a nurse practitioner and a full-time nurse care manager subcontracted through the health center. RESULTS: Compared with usual care, the behavioral health home was associated with significant improvements in quality of cardiometabolic care, concordance of treatment with the chronic care model, and use of preventive services. For most cardiometabolic and general medical outcomes, both groups demonstrated improvement, although there were no statistically significant differences between the two groups over time. CONCLUSIONS: The results suggest that it is possible, even under challenging real-world conditions, to improve quality of care for patients with serious mental illness and cardiovascular risk factors. Improving quality of medical care may be necessary, but not sufficient, to improve the full range of medical outcomes in this vulnerable population.