Cancer Prevention Study-II Nutrition Cohort Research Articles

Educational Attainment and Cancer Incidence in a Large Nationwide Prospective Cohort.

Educational attainment is a social determinant of health and frequently used as an indicator of socioeconomic status. Educational attainment is a predictor of cancer mortality, but associations with site-specific cancer incidence are variable. The aim of this study was to evaluate the association of educational attainment and site-specific cancer incidence adjusting for known risk factors in a large prospective cohort. Men and women enrolled in the American Cancer Society's Cancer Prevention Study-II Nutrition Cohort who were cancer free at baseline were included in this study (n = 148,965). Between 1992 and 2017, 22,810 men and 17,556 women were diagnosed with incident cancer. Cox proportional hazards regression models were used to estimate age- and multivariable-adjusted risk and 95% confidence intervals of total and site-specific cancer incidence in persons with lower versus higher educational attainment. Educational attainment was inversely associated with age-adjusted cancer incidence among men but not women. For specific cancer sites, the multivariable-adjusted risk of cancer in the least versus most educated individuals remained significant for colon, rectum, and lung cancer among men and lung and breast cancer among women. Educational attainment is associated with overall and site-specific cancer risk though adjusting for cancer risk factors attenuates the association for most cancer sites. This study provides further evidence that educational attainment is an important social determinant of cancer but that its effects are driven by associated behavioral risk factors suggesting that targeting interventions toward those with lower educational attainment is an important policy consideration.

Physical activity, obesity, and bladder cancer incidence.

Cigarette smoking is an established risk factor for bladder cancer (BC), but evidence for physical inactivity and obesity is limited. This analysis included 146,027 participants from the Cancer Prevention Study-II (CPS-II) Nutrition Cohort, a large prospective cohort of cancer incidence established in 1992. Multivariable-adjusted Cox proportional hazards models were used to examine associations between body mass index (BMI), moderate-to-vigorous intensity aerobic physical activity (MVPA), leisure-time spent sitting, and BC risk. Effect modification by stage, smoking status, and sex was examined. Only participants accumulating 15.0- < 30.0 MET-hrs/wk of MVPA had a lower risk of BC overall (RR 0.88, 95% CI 0.78, 0.99, compared to > 0-7.5 MET-hrs/wk) in the fully adjusted models. When stratifying on BC stage, MVPA (15- < 30 MET-hrs/wk vs. > 0- < 7.5 MET-hrs/wk, RR 0.83, 95% CI 0.70-0.99) and excess sitting time (≥ 6h/day vs. 0- < 3h/day RR 1.22, 95% CI 1.02, 1.47) were associated with risk of invasive BC only. There was no consistent evidence for effect modification by smoking status or sex. This study supports that MVPA and sitting time may play a role in BC incidence, but associations likely differ by stage at diagnosis. While additional studies are needed to confirm associations by stage, this study adds to the evidence of the importance of being physically active for cancer prevention.

Abstract 6494: Postdiagnosis adherence to American Cancer Society cancer prevention guidelines and mortality among survivors of obesity-related cancers

Abstract Purpose: To examine the combined and individual associations of postdiagnosis body mass index (BMI), physical activity, diet quality and alcohol consumption with all-cause mortality, cardiovascular disease mortality (CVDM) and cancer-specific mortality (CSM) among survivors of obesity-related cancers. Methods: American Cancer Society (ACS) Cancer Prevention Study-II Nutrition Cohort participants diagnosed with one of 13 invasive (but non-metastatic) obesity-related cancers between 1992 and 2003 were followed for mortality until 2018. Postdiagnosis lifestyle exposures were assessed at least one year after cancer diagnosis between 1999 and 2003. A lifestyle score ranging 0-8 was created according to adherence to the American Cancer Society (ACS) 2020 cancer prevention guidelines on BMI, physical activity, diet, and alcohol, with a score of 8 representing optimal behaviors for cancer prevention. Associations of the overall and individual component scores with mortality were estimated using multivariable-adjusted Cox proportional hazards regression models. Results: Among 7,945 cancer survivors, 4,862 died between 1992 and 2018. Higher ACS guideline score was associated with 6-8% lower risk of mortality per 1 point score increase (all-cause: HR: 0.94, 95% CI: 0.92-0.95; CVDM: HR:0.92, 95% CI:0.89-0.95; CSM: HR: 0.93, 95% CI 0.90-0.97) among cancer survivors. Individual scores of BMI, physical activity, and diet were inversely associated with overall mortality; however, alcohol score was positively associated with all-cause mortality, only among female survivors. Compared with participants who had low scores both before and after cancer diagnosis, those with high scores after diagnosis had lower risk of all-cause mortality, CVDM, and possibly CSM. Conclusion: Following ACS guidelines on diet and physical activity for cancer prevention after a cancer diagnosis is associated with better survival outcomes among survivors of obesity-related cancers. Citation Format: Ying Wang, Christina Newton, Marjorie L. McCullough, Lauren R. Teras, Erika Rees-Punia, Caroline Um, Alpa V. Patel. Postdiagnosis adherence to American Cancer Society cancer prevention guidelines and mortality among survivors of obesity-related cancers. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6494.

Using High-Resolution Metabolomics for Identifying Metabolic Profiles Associated with Ambient Air Pollution in the Cancer Prevention Study-II Nutrition Cohort

Background. Mechanisms underlying ambient air pollution toxicity remains largely unknown despite the established links between air pollution and numerous adverse health effects. There is growing interest in applying high-resolution metabolomics (HRM) to study air pollution and health. Broad application of HRM is limited, however, due to concerns over statistical power and study generalizability. Methods. Using previously collected data, we conducted a cross-sectional metabolomics wide association study among 1,263 postmenopausal women within the American Cancer Society Cancer Prevention Study-II Nutrition Cohort. Modeled estimates of PM2.5 (1999-2004), NO2 (2006), and O3 (2002-2004) concentrations were linked to the participant residence at enrollment. Metabolic profiling on serum samples collected between 1998-2001 was measured by mass spectrometry-based platforms. We followed an untargeted metabolome-wide association study framework to evaluate metabolite and metabolic pathway perturbations associated with chronic exposures to air pollution. Results. We detected and analyzed 1,186 metabolites in serum samples, with an average technical intraclass correlation coefficient of 87% and coefficient of variance of 23%. Sixty-five unique metabolites were significantly associated with at least one air pollutant (false positive discovery rate &amp;#x3c;0.05), after controlling for covariates, including sociodemographic, smoking status, and year of blood draw. We observed perturbations in several inflammatory and oxidative stress related metabolic pathways associated with lipid, xenobiotic, amino acid, and vitamin metabolism. We subsequently confirmed the chemical identity of 43 unique metabolites with level 1 evidence, including diacylglycerol, taurine, docosapentaenoate, alpha- carboxyethylhydroxychroman, and palmitoyl ethanolamide. Conclusions. In this large cross-sectional analysis of air pollution and serum metabolites in postmenopausal women, we identified several novel metabolic markers and pathways associated with long-term exposures to air pollution and replicated others. These results support future development of sensitive metabolic markers of air exposures, as well as corresponding investigation into the specific molecular mechanisms and disease etiologies indicated by these markers. Keywords: Air Pollution, Metabolomics

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

BACKGROUND AND AIM: Outdoor air pollution and airborne particulate matter (PM) have been classified as Group 1 carcinogens for lung cancer. Previous research on childhood leukemias and adult cancer mortality suggest associations of outdoor air pollutants with blood cancers, which are etiologically diverse. However, detailed examinations of major air pollutants by histologic subtypes of incident adult hematologic cancers are lacking. METHODS: The American Cancer Society Cancer Prevention Study-II Nutrition Cohort was used to examine associations of outdoor air pollutants with risk of incident hematologic cancers. Residential address at enrollment was used to assign census block-group level annual predictions of PM10, PM2.5, NO2, O3, SO2, and CO concentrations. Cox proportional hazard regression was used to estimate multivariable-adjusted hazard ratios (HR) and 95% confidence intervals (CI) for associations per each fifth percentile-mean difference in 1992-2015 average pollutant concentrations with risk of incident Hodgkin lymphoma (HL), non-Hodgkin lymphoma (NHL), myeloid leukemia and eleven specific histologic subtypes. RESULTS: There were 2,659 total incident hematologic cancer cases identified among 108,002 participants followed from 1992-2017. Positive HRs were observed for several residential outdoor air pollutants and incident HL (n=54), with statistically significant elevated HRs observed for both NO2 (HR per 6.4 ppb=1.42; 95% CI=1.05-1.90) and SO2 (HR per 1.6 ppb=1.41, 95% CI 1.07-1.85). There were no clear positive associations observed for either NHL (n=2,276) or myeloid leukemias (n=329) and there was an inverse association observed for the chronic lymphocytic leukemia/small lymphocyte lymphoma subtype. In analyses by gender, the positive associations observed with incident HL strengthened among women. CONCLUSIONS: Overall, there were few positive associations of outdoor particulate or gas residential air pollution concentrations and incident adult hematologic cancers observed. However, subtype analyses revealed some evidence for positive associations with HL, particularly among women, which require further investigation. KEYWORDS: outdoor air pollution, particulate matter, lymphoma, leukemia

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

BackgroundThis study identifies populations who may benefit most from expanded cancer screening.MethodsTwo 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.ResultsOverall, 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.ConclusionsOlder age and smoking were the two most important risk factors associated with the relative and absolute 5‐year risk of developing any cancer.

Prospective associations of hemoglobin A1c and c-peptide with risk of diabetes-related cancers in the Cancer Prevention Study-II Nutrition Cohort.

Self-reported type 2 diabetes mellitus (T2DM) is a risk factor for many cancers, suggesting its pathology relates to carcinogenesis. We conducted a case-cohort study to examine associations of hemoglobin A1c (HbA1c) and c-peptide with cancers associated with self-reported T2DM. This study was drawn from a prospective cohort of 32,383 women and men who provided blood specimens at baseline: c-peptide and HbA1c were assessed in 3,000 randomly selected participants who were cancer-free-at-baseline and an additional 2,281 participants who were cancer-free-at-baseline and subsequently diagnosed with incident colorectal, liver, pancreatic, female breast, endometrial, ovarian, bladder, or kidney cancers. Weighted-Cox regression models estimated hazards ratios (HRs) and 95% confidence intervals (CI), adjusted for covariates. C-peptide was associated with higher risk of liver cancer (per standard deviation (SD) HR: 1.80; 95%CI: 1.32-2.46). HbA1c was associated with higher risk of pancreatic cancer (per SD HR: 1.21 95%CI 1.05-1.40) and with some suggestion of higher risks for all-cancers-of-interest (per SD HR: 1.05; 95%CI: 0.99-1.11) and colorectal (per SD HR: 1.09; 95%CI: 0.98-1.20), ovarian (per SD HR: 1.18; 95%CI 0.96-1.45) and bladder (per SD HR: 1.08; 95%CI 0.96-1.21) cancers. Compared to no self-reported T2DM and HbA1c <6.5% (reference group), self-reported T2DM and HbA1c <6.5% (i.e., T2DM in good glycemic control) was not associated with risk of colorectal cancer, whereas it was associated with higher risks of all-cancers-of-interest combined (HR: 1.28; 95%CI: 1.01-1.62), especially for breast and endometrial cancers. Additional large, prospective studies are needed to further explore the roles of hyperglycemia, hyperinsulinemia, and related metabolic traits with T2DM-associated cancers to better understand the mechanisms underlying the self-reported T2DM-cancer association and to identify persons at higher cancer risk.

Abstract 2235: Identifying populations at elevated risk of cancer outside those traditionally targeted for screening and prevention

Abstract Introduction: Currently, populations are identified for cancer screening interventions one cancer type at a time. With new developments in cancer screening, including multi-cancer early detection tests, it is important and timely to understand the overall cancer burden in populations outside those traditionally targeted for single-cancer screenings. Thus, we sought to identify the most important risk factors for developing any invasive cancer, and to calculate associated 5-year absolute risks, with a particular focus on persons under age 50 years. Methods: Two large American Cancer Society cohorts followed prospectively for cancer, the Cancer Prevention Study-II Nutrition Cohort (CPS-IINC) enrolled from 1992-1993 and Cancer Prevention Study 3 (CPS-3) enrolled from 2006-2013, were used to examine a broad range of cancer risk factors. Multivariable Cox proportional hazards models were used to estimate hazard ratios (HR) and 95% confidence intervals (CIs) for associations between potential risk factors and subsequent overall risk of any invasive cancer. The Individualized Coherent Absolute Risk Estimation tool used these HRs to estimate absolute risk in 5-year age groups. Results: 15,226 cancers were identified among 429,991 participants within 5 years of follow-up. Several risk factors including smoking history, obesity, alcohol, family history of cancer, and various chronic medical conditions (e.g., diabetes, hypertension) were associated with a higher risk of cancer. Persons above age 50 years, regardless of other risk factors considered, had at least 2% absolute risk per 5 years. Among persons under age 50 years, smoking status was the most important factor differentiating risk. For men under age 50, absolute risk of any cancer did not exceed 2% except for men ages 45-49 years who currently smoke or recently quit (within 30 years). For women under age 50, absolute risk exceeded 2% starting at age 35-39 years for current or recent former smokers, and all women, even long-term nonsmokers, at age 45-49 had over 2% absolute risk. Conclusions: Smoking history is important in differentiating absolute risk of any cancer in adults under age 50 years. More research to understand the extent to which other cancer risk factors influence risk for specific populations aged &amp;lt;50 years should be carried out. Citation Format: Alpa V. Patel, Emily Deubler, Lauren R. Teras, Graham A. Colditz, Cari J. Lichtman, William G. Cance, Christina A. Clarke. Identifying populations at elevated risk of cancer outside those traditionally targeted for screening and prevention [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2235.

The Associations of Multivitamin and Antioxidant Use With Mortality Among Women and Men Diagnosed With Colorectal Cancer.

BackgroundColorectal cancer survivors often use multivitamins and other over-the-counter dietary supplements, but evidence is limited regarding their potential associations with mortality.MethodsThis prospective analysis included women and men from the Cancer Prevention Study-II Nutrition Cohort who were cancer-free at baseline (1992 or 1993) and diagnosed with colorectal cancer through June 2015. Detailed information on multivitamin use, vitamin C supplements, and vitamin E supplements was self-reported on questionnaires at baseline, in 1997, and every 2 years thereafter. Pre- and postdiagnosis data were available for 3176 and 2006 colorectal cancer survivors, respectively, among whom 2116 (648 from colorectal cancer) and 1256 (242 from colorectal cancer) died. Multivariable-adjusted Cox proportional hazards regression models examined associations. All statistical tests were 2-sided.ResultsAmong colorectal cancer survivors, 49.7% and 58.5% reported multivitamin use before and after diagnosis, respectively (vitamin C use before and after diagnosis: 27.8% and 28.1%; vitamin E use before and after diagnosis: 27.5% and 29.4%, respectively). There were no statistically significant associations of pre- or postdiagnosis multivitamin use with all-cause, colorectal cancer-specific, or noncolorectal cancer mortality. Vitamin C was also not associated with any mortality outcomes. However, prediagnosis vitamin E use was associated with a non-statistically significant increased risk of all-cause mortality (multivariable adjusted hazard ratio = 1.08, 95% confidence intervals = 0.96 to 1.23) and all other noncolorectal cancer mortality (multivariable adjusted hazard ratio = 1.13, 95% confidence intervals = 0.97 to 1.31).ConclusionsThese results suggest that multivitamin use before or after diagnosis is not associated with mortality in colorectal cancer survivors. However, vitamin E use may be associated with increased risk of mortality and merits further investigation.

Abstract P2-11-01: Breast cancer (BC) risk among patients with benign breast disease (BBD) by NSAID use

Abstract Background: Approximately one million U.S women are diagnosed with benign breast disease (BBD) annually, which increases breast cancer (BC) risk between 1.5- and four-fold, depending on the pathologic characteristics of the lesion and other factors. BBD lesions are associated with inflammation and fibrosis, suggesting that inflammatory pathways may play a role in progression of BBD to BC. Aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) are well tolerated, widely used drugs that block inflammation by inhibiting cyclooxygenase enzymes, which lowers prostaglandin synthesis, and by exerting numerous additional anti-inflammatory effects. NSAIDs are inversely associated with several types of cancer, including BC in some, but not all studies, and have been linked to lower BC risk among BBD patients in prior publications. We examined the association between NSAID use and BC risk, overall and by self-reported history of BBD, using data from the American Cancer Society Cancer Prevention Study II (CPS-II). Methods: The Cancer Prevention Study-II (CPS-II) Nutrition Cohort is a study of approximately 189,000 U.S. men and women followed prospectively for cancer incidence and mortality. Study participants filled out a detailed questionnaire at baseline in 1992/1993 and follow-up surveys in 1997 and every two years until 2017. On each follow-up survey, participants reported type, quantity, and duration of NSAID use as well as diagnoses of BBD. Incident BCs were either self-reported and validated via medical records or cancer registry linkage, or identified via National Death Index linkage. Women in the analytic cohort were followed from date of 1997 survey until diagnosis of BC, reported use of tamoxifen, report of cancer other than BC, date of death, loss to follow-up or end of follow-up. Hazard ratios (HRs) and 95% confidence intervals (CIs) assessing associations of BBD and NSAID use with BC risk were estimated using Cox proportional hazards regression analysis. Statistical interactions between BBD and NSAID were evaluated by fitting and testing the corresponding cross-product terms, along with the main effects of each. Both NSAID use and BBD were modeled as time-dependent variables, allowing exposure status to change over the course of the multiple surveys returned. Results: Of the 60,517 women included in the study, 3,899 (6.4%) developed BC. Mean follow-up time was 12.7 years. A total of 23,661 women (39%) reported a diagnosis of BBD at some point during the study period, and 54,656 (90%) reported some NSAID use. Women self-reporting BBD were 46% more likely to develop BC than those without self-reported BBD (HR 1.46, 95% CI 1.36-1.57). Overall, BC risk was not increased among NSAID users versus non-users (HR 0.95, 95% CI 0.88-1.02). In contrast, BC risk was reduced among current NSAID users with a history of BBD (HR 0.87, 95% CI 0.78-0.97), but not among NSAID users who did not report a history of BBD (HR 1.02, 95% CI 0.92-1.13, p-interaction=0.04). Risk did not differ across number of pills per month (RR=0.84 for &amp;lt;15 pills/month, 0.89 for 15-29, 0.88 for 30-44, 0.78 for 45-59, 0.88 for 60+). Conclusion: In our study, NSAID use had a statistically-significant protective effect on BC risk among women with BBD, suggesting its potential use as a chemopreventive agent in this high-risk group of women, but not among those who did not report a history of BBD. Citation Format: Robert A Vierkant, Matthew Masters, Lauren R Teras, Mark E Sherman. Breast cancer (BC) risk among patients with benign breast disease (BBD) by NSAID use [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P2-11-01.

Biomarkers of Glucose Homeostasis and Inflammation with Risk of Prostate Cancer: A Case–Cohort Study

AbstractBackground:Few prospective studies have examined biomarkers of glucose homeostasis or inflammation with prostate cancer risk by tumor stage or grade.Methods:We conducted a case–cohort study to examine associations of prediagnosis hemoglobin A1c (HbA1c), C-peptide, and C-reactive protein (CRP) with prostate cancer risk overall and stratified by tumor stage and grade. The study included 390 nonaggressive (T1–2, N0, M0, and Gleason score &amp;lt;8) and 313 aggressive cases (T3–4, or N1, or M1, or Gleason score 8–10) diagnosed after blood draw (1998–2001) and up to 2013, and a random subcohort of 1,303 cancer-free men at blood draw in the Cancer Prevention Study-II Nutrition Cohort. Prentice-weighted Cox proportional hazards regression models were used to estimate HRs and 95% confidence intervals (CI).Results:In the multivariable-adjusted model without body mass index, HbA1c was inversely associated with nonaggressive prostate cancer (HR per unit increase, 0.89; 95% CI, 0.80–1.00; P = 0.04). Analyses stratified by tumor stage and grade separately showed that HbA1c was inversely associated with low-grade prostate cancer (HR per unit increase, 0.89; 95% CI, 0.80–1.00) and positively associated with high-grade prostate cancer (HR per unit increase, 1.15; 95% CI, 1.01–1.30). C-peptide and CRP were not associated with prostate cancer overall or by stage or grade.Conclusions:The current study suggests that associations of hyperglycemia with prostate cancer may differ by tumor grade and stage.Impact:Future studies need to examine prostate cancer by tumor stage and grade, and to better understand the role of hyperglycemia in prostate cancer progression.

Abstract LB079: Circulating plasma phospholipid fatty acid levels &amp; breast cancer risk in the CPS-II Nutrition Cohort

Abstract Circulating plasma phospholipid fatty acid levels and breast cancer risk in the CPS-II Nutrition Cohort Background The association between dietary fat intake and breast cancer risk has been a source of controversy with conflicting results reported in past decades. Additional prospective studies that objectively measure circulating levels of fatty acids are now needed to better understand the associations between dietary fat and breast cancer development. MethodsWe assessed the relation between breast cancer risk and plasma levels of 60 phospholipid fatty acids in a nested case-control study of 2,718 postmenopausal women (905 breast cancer cases and 1,813 matched controls) enrolled in the Cancer Prevention Study II (CPS-II) Nutrition Cohort. Blood samples were collected at baseline (1997-1998). Multivariable-adjusted conditional logistic regression models that included established breast cancer risk factors (alcohol use, postmenopausal hormone use, smoking status, waist circumference, body mass index, and weight change from age 18 years to blood draw) were used to compute odds ratios (OR) and 95% confidence intervals (CI). The false discovery rate (FDR; q-value) was computed to control for multiple comparisons. ResultsAfter adjustment for multiple comparisons and in continuous log-transformed multivariable models, plasma levels of myristic acid (a saturated fatty acid) were positively associated with breast cancer risk (OR per log-value, 1.17, 95% CI: 1.07-1.28; q-value = 0.03), with similar magnitude associations found for estrogen receptor (ER) positive and ER negative breast cancer (p-interaction = 0.39). Positive associations were also found for plasma levels of monounsaturated fatty acid (OR per log-value, 1.09, 95% CI: 1.00-1.18; q-value = 0.24), palmitoleic acid (OR per log-value, 1.14, 95% CI: 1.04-1.24; q-value = 0.09), palmitic acid (OR per log-value, 1.12, 95% CI: 1.01-1.24; q-value = 0.17), dihomo-γ-linolenic acid (OR per log-value, 1.14, 95% CI: 1.04-1.25; q-value = 0.09), and adrenic acid (OR per log-value, 1.13, 95% CI: 1.03-1.24; q-value = 0.11) with breast cancer risk; however, after adjustment for multiple comparisons these associations did not reach the threshold of statistical significance. Similarly, inverse associations between plasma levels of trans α-linolenic acid (OR per log-value, 0.85, 95% CI: 0.76-0.96; q-value = 0.09), heptadecanoic acid (OR per log-value, 0.90, 95% CI: 0.82-0.99; q-value = 0.17), and vaccenic acid (OR per log-value, 0.88, 95% CI: 0.80-0.97; q-value = 0.11) with breast cancer risk were not statistically significant after adjustment for multiple comparisons. ConclusionThese findings suggest that higher circulating levels of myristic acid, that can be sourced from dietary intake of dairy foods or via de novo synthesis, may increase breast cancer risk. Additional studies are needed to replicate this finding and provide mechanistic insights. Citation Format: Michele Matta, Emily Deubler, Veronique Chajès, Marc Gunter, Neil Murphy, Mia M. Gaudet. Circulating plasma phospholipid fatty acid levels &amp; breast cancer risk in the CPS-II Nutrition Cohort [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB079.

Pre-Diagnostic Circulating Metabolites and Colorectal Cancer Risk in the Cancer Prevention Study-II Nutrition Cohort.

Untargeted metabolomic studies have identified potential biomarkers of colorectal cancer risk, but evidence is still limited and broadly inconsistent. Among 39,239 Cancer Prevention Study II Nutrition cohort participants who provided a blood sample between 1998–2001, 517 newly diagnosed colorectal cancers were identified through 30 June 2015. In this nested case–control study, controls were matched 1:1 to cases on age, sex, race and date of blood draw. Mass spectroscopy-based metabolomic analyses of pre-diagnostic plasma identified 886 named metabolites, after quality control exclusions. Conditional logistic regression models estimated multivariable-adjusted odds ratios (OR) and 95% confidence intervals (CI) for 1 standard deviation (SD) increase in each metabolite with risk of colorectal cancer. Six metabolites were associated with colorectal cancer risk at a false discovery rate < 0.20. These metabolites were of several classes, including cofactors and vitamins, nucleotides, xenobiotics, lipids and amino acids. Five metabolites (guanidinoacetate, 2’-O-methylcytidine, vanillylmandelate, bilirubin (E,E) and N-palmitoylglycine) were positively associated (OR per 1 SD = 1.29 to 1.32), and one (3-methylxanthine) was inversely associated with CRC risk (OR = 0.79, 95% CI, 0.69–0.89). We did not replicate findings from two earlier prospective studies of 250 cases each after adjusting for multiple comparisons. Large pooled prospective analyses are warranted to confirm or refute these findings and to discover and replicate metabolites associated with colorectal cancer risk.

Associations of Aspirin and Non-Aspirin Non-Steroidal Anti-Inflammatory Drugs With Colorectal Cancer Mortality After Diagnosis.

Aspirin use reduces colorectal cancer (CRC) incidence, but there is limited evidence regarding associations of aspirin and non-aspirin non-steroidal anti-inflammatory drugs (NSAIDs) with CRC-specific survival. This prospective analysis includes women and men from the Cancer Prevention Study-II Nutrition Cohort who were cancer free at baseline (1992 or 1993) and diagnosed with CRC during incidence follow-up through 2015. Detailed information on aspirin and non-aspirin NSAID use was self-reported on questionnaires at baseline, in 1997, and every 2 years thereafter. Pre- and postdiagnosis data were available for 2686 and 1931 participants without distant metastases, respectively, among whom 512 and 251 died from CRC during mortality follow-up through 2016. Secondary analyses examined associations between prediagnosis aspirin use and stage at diagnosis (distant metastatic vs localized or regional). All statistical tests were 2-sided. Long-term regular use of aspirin (>15 times per month) before diagnosis was associated with lower CRC-specific mortality (multivariable-adjusted hazard ratio [HR] = 0.69, 95% confidence interval [CI] = 0.52 to 0.92). Postdiagnosis regular aspirin use was not statistically significantly associated with risk of CRC-specific mortality overall (HR = 0.82, 95% CI = 0.62 to 1.09), although participants who began regular aspirin use only after their diagnosis were at lower risk than participants who did not use aspirin at both the pre- and postdiagnosis periods (HR = 0.60, 95% CI = 0.36 to 0.98). Long-term aspirin use before diagnosis was also associated with lower odds of diagnosis with distant metastases (multivariable-adjusted odds ratio = 0.73, 95% CI = 0.53 to 0.99). Our results suggest that long-term aspirin use before a diagnosis of nonmetastatic colorectal cancer may be associated with lower CRC-specific mortality after diagnosis, consistent with possible inhibition of micrometastases before diagnosis.

Toxoplasma gondii infection and the risk of adult glioma in two prospective studies.

Toxoplasma gondii (T gondii) is a common parasite that shows affinity to neural tissue and may lead to the formation of cysts in the brain. Previous epidemiologic studies have suggested an association between glioma and increased prevalence of T gondii infection, but prospective studies are lacking. Therefore, we examined the association between prediagnostic T gondii antibodies and risk of glioma in two prospective cohorts using a nested case-control study design. Cases and matched controls were selected from the American Cancer Society's Cancer Prevention Study-II Nutrition Cohort (CPSII-NC) (n = 37 cases and 74 controls) and the Norwegian Cancer Registry's Janus Serum Bank (Janus) (n = 323 cases and 323 controls). Blood samples collected prior to diagnosis were analyzed for antibodies to two T gondii surface antigens (p22 and sag-1), with individuals considered seropositive if antibodies to either antigen were detected. Conditional logistic regression was used to calculate odds ratios (OR) and 95% confidence intervals (95% CI) for each cohort. In both cohorts, a suggestive increase in glioma risk was observed among those infected with T gondii (OR: 2.70; 95% CI: 0.96-7.62 for CPSII-NC; OR: 1.32, 95% CI: 0.85-2.07 for Janus), particularly among participants with high antibody titers specific to the sag-1 antigen (CPSII-NC OR: 3.35, 95% CI: 0.99-11.38; Janus OR: 1.79, 95% CI: 1.02-3.14). Our findings provide the first prospective evidence of an association between T gondii infection and risk of glioma. Further studies with larger case numbers are needed to confirm a potential etiologic role for T gondii in glioma.

Coffee Consumption and Invasive Breast Cancer Incidence among Postmenopausal Women in the Cancer Prevention Study-II Nutrition Cohort

There is limited evidence of a potential inverse association between coffee, particularly caffeinated coffee, consumption and postmenopausal breast cancer risk, and few studies have examined this association by tumor hormone receptor status. To provide further evidence, we examined total, caffeinated, and decaffeinated coffee consumption in relation to postmenopausal invasive breast cancer incidence overall, and by tumor estrogen receptor (ER) and/or progesterone receptor (PR) subtype. Among 57,075 postmenopausal women in the Cancer Prevention Study-II Nutrition Cohort who were cancer free and reported coffee intake in 1999, we identified 2,980 women diagnosed with invasive breast cancer during follow-up through June 2015. Multivariable-adjusted Cox proportional hazards regression was used to compute hazard ratios (HR) and 95% confidence intervals (CI). Neither total, caffeinated, nor decaffeinated coffee consumption was associated with invasive breast cancer risk; HRs (95% CIs) comparing consumption of ≥2 cups per day with <1 cup per month were 0.99 (0.89-1.11), 0.96 (0.87-1.06), and 1.06 (0.95-1.19), respectively. Similarly, coffee consumption was not associated with risk of hormone receptor-positive (ER+ or PR+) or hormone receptor-negative (ER- and PR-) breast tumors. These findings do not support an association between coffee consumption and invasive breast cancer risk among postmenopausal women. This large prospective study contributes to the limited evidence on coffee consumption and breast cancer risk, finding no association overall or by tumor receptor subtype.

Relationship Between Muscle-Strengthening Activity and Cause-Specific Mortality in a Large US Cohort.

IntroductionMuscle-strengthening activity (MSA) has beneficial effects on hypertension, glucose homeostasis, and other health conditions; however, its association with mortality is not as well understood.MethodsWe analyzed data from the Cancer Prevention Study-II Nutrition Cohort (data collection 1982–2014), a prospective US cohort that consisted of 72,462 men and women who were free of major chronic diseases; 18,034 of the cohort died during 13 years of follow-up (2001–2014). We used Cox proportional hazards modeling, controlling for various potential confounding factors, to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for MSA (none, >0 to <1 h/wk, 1 to <2 h/wk, and ≥2 h/wk) in relation to mortality risk, independent of and in combination with aerobic physical activity.ResultsThe association between MSA and mortality appeared to be nonlinear (quadratic trend P value, <.001). After multivariable adjustment and comparison with no MSA, engaging in less than 2 hours per week of MSA was associated with lowered all-cause mortality (>0 to <1 h/wk: HR = 0.88, 95% CI, 0.82–0.94; 1 to <2 h/wk: HR = 0.90, 95% CI, 0.84–0.97), but engaging in 2 or more hours per week was not associated with reduced risk (HR = 1.01; 95% CI, 0.92–1.09). Associations were similar but not significant for cancer mortality. Engaging in >0 to <1 hr/wk of MSA was associated with a 19% lower risk (HR = 0.81; 95% CI, 0.71–0.92) of cardiovascular disease mortality, but more time spent in MSA was not associated with reduced risk (quadratic trend P value =.005). Associations did not vary by amount of moderate-to-vigorous aerobic physical activity.ConclusionEngaging in ≥2 hours per week of MSA was associated with lower all-cause mortality, independent of aerobic activity. Reasons for the lack of association with higher amounts of MSA are unclear. Our findings support recommending muscle-strengthening activities for overall health.

Late Adulthood Physical Activity Trajectories In Relation To All-cause Mortality

PURPOSE: Despite the known benefits of being physically active, about half of U.S. adults (and nearly two-thirds of adults age 65+ years) do not meet current U.S. Physical Activity Guidelines for Americans of 150-300 minutes of moderate (75-150 minutes of vigorous) physical activity (MVPA) per week. Given the aging U.S. population and rising healthcare costs, identifying factors associated with healthy aging is critical. There is limited epidemiologic evidence examining whether increasing or initiating MVPA in later adulthood can increase longevity. This study examined the association between late adulthood MVPA trajectories and all-cause mortality in a large U.S. prospective cohort. METHODS: This analysis included 71,862 Cancer Prevention Study-II Nutrition Cohort participants (mean age 74.1 years; range 52-89 years) who were free of major chronic diseases. Participants self-reported MVPA at two time points approximately 5-years apart and were categorized based on their level of adherence to MVPA guidelines at each time point (inactive, “insufficiently active”, “sufficient”, and “>double minimum recommended”). 12 trajectories were defined (4 each for consistent, increasing, or decreasing MVPA); participants who were consistently “insufficiently active” served as the reference category. Multivariable Cox proportional hazards regression modeling was used to estimate hazard ratios (HR) and 95% confidence intervals (CI). RESULTS: After an average of 9.9 years of follow-up, 22,736 deaths occurred. The most active participants (>double recommended) at both time points had a 24% lower mortality risk compared to insufficiently active participants (95% CI 0.73-0.79). Those who increased MVPA over time (insufficient to sufficient) also had a lower mortality risk (HR=0.85, 95% CI 0.80-0.91). Conversely, those who decreased activity (sufficient to inactive) had a higher mortality risk (HR=1.18, 95% CI 1.10-1.26). Associations were similar for men and women, and for cardiovascular disease and cancer-specific mortality. CONCLUSIONS: Maintaining a physically active lifestyle at older ages is optimal for longevity. Public health messaging should encourage active individuals to maintain their physical activity level as they age and reinforce that it is never too late to start being active.

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.

Coffee consumption and risk of colorectal cancer in the Cancer Prevention Study-II Nutrition Cohort

BackgroundThe association between coffee consumption and colorectal cancer risk generally appears null, but recent evidence suggests that risk may vary by coffee type. We examined associations of caffeinated and decaffeinated coffee intake with colorectal cancer risk overall and with colon and rectum separately, among older U.S. men and women. MethodsIn 1999, 47,010 men and 60,051 women with no previous diagnosis of cancer, aged 47–96 years, in the Cancer Prevention Study-II Nutrition Cohort completed a food frequency questionnaire that assessed caffeinated and decaffeinated coffee intake; consumption was updated in 2003. A total of 1829 colorectal cancer cases were verified through June 2015. Cox proportional hazards regression was used to estimate multivariable-adjusted hazard rate ratios (HRs) and 95% confidence intervals (CIs), adjusting for smoking history, alcohol, caffeinated/decaffeinated coffee intake (depending on the model), and other colorectal cancer risk factors. ResultsConsumption of ≥2 cups/day of decaffeinated coffee, compared to no decaffeinated coffee, was associated with lower risk of overall colorectal cancer (HR = 0.82, 95% CI: 0.69−0.96, P-trend = 0.04), colon cancer (HR = 0.82, 95% CI: 0.69−0.99, P-trend = 0.05) and rectal cancer (HR = 0.63, 95% CI: 0.40−0.99, P-trend = 0.17). Consumption of ≥2 cups/day of caffeinated coffee was associated with higher risk of rectal cancer (HR = 1.37, 95% CI: 0.99–1.89, P-trend = 0.04), but not with colorectal or colon cancer. ConclusionIn this prospective study, higher intake of decaffeinated coffee was associated with lower risk of colorectal, colon, and rectal cancers. Further study on associations of caffeinated and decaffeinated coffee with colorectal cancer risk by subsite is needed.