Supplemental Figure 2: Associations of ASB consumption and cancer mortality stratified by 10-year follow-up period (≥2 drinks/day vs never, HR and 95% CI) among men and women in the CPS-II cohort (1982-2016)

Supplemental Figure 1: Associations of SSB consumption and cancer mortality stratified by 10-year follow-up period (≥2 drinks/day vs never, HR and 95% CI) among men and women in the CPS-II cohort (1982-2016)

Supplemental Table 1. Associations (HR, 95% CI) of sugar-sweetened beverage consumption and all-cancer and site-specific cancer mortality in CPS II, controlling for BMI, 1982-2016; Supplemental Table 2. Associations (HR, 95% CI) of sugar-sweetened beverage consumption and all-cancer and site-specific mortality in CPS II among never smokers, 1982-2016; Supplemental Table 3. Associations (HR, 95% CI) of sugar-sweetened beverage consumption and site-specific cancer mortality in CPS II among never smokers, controlling for BMI, 1982-2016; Supplemental Table 4. Associations (HR, 95% CI) of sugar-sweetened beverage consumption and all-cancer and site-specific cancer mortality in CPS-II by BMI status (kg/m2) at baseline, 1982-2016; Supplemental Table 5. Associations (HR, 95% CI) of artificially-sweetened beverage consumption and all-cancer and site-specific cancer mortality in CPS II, controlling for BMI, 1982-2016; Supplemental Table 6. Associations (HR, 95% CI) of artificially-sweetened beverage consumption and all-cancer and site-specific cancer mortality in CPS II among never smokers, 1982-2016; Supplemental Table 7. Associations (HR, 95% CI) of artificially-sweetened beverage consumption and site-specific cancer mortality in CPS II among never smokers, controlling for BMI, 1982-2016; Supplemental Table 8. Associations (HR, 95% CI) of artificially-sweetened beverage consumption and all-cancer and site-specific cancer mortality in CPS-II by BMI status (kg/m2) at baseline, 1982-2016

Supplemental Table 1 - Association of self-reported T2DM at blood draw with risk of all-cancers combined and separately in CPS-II LifeLink participants; Supplemental Table 2 - Association BMI per 5 kg/m2 at blood draw with risk of all-cancers combined and separately in CPS-II LifeLink participants. Excludes those with BMI <18.5 kg/m2; Supplementary Table 3 - Associations of c-peptide with risk of all cancers combined and for the specific cancers of interest by sex in the CPS-II LifeLink cohort; Supplementary Table 4 - Associations of HbA1c with risk of all cancers combined and for the specific cancers of interest by sex in the CPS-II LifeLink cohort.

Abstract Background: Sugar-sweetened beverage (SSB) consumption may be associated with cancer mortality independent of, or indirectly through, established influences on increased body adiposity. Methods: We examined the associations of SSBs and artificially-sweetened beverages (ASB) with mortality from all-cancers combined, obesity-related cancers combined, and 20 cancer types, among men and women in the Cancer Prevention Study-II (CPS-II) prospective cohort. In 1982, 934,777 cancer-free participants provided information on usual SSB and ASB consumption. Deaths were identified through 2016. Multivariable Cox proportional hazards regression models examined associations of beverage types with cancer mortality, without and with BMI adjustment. Results: During follow-up, 135,093 CPS-II participants died from cancer. Consumption of ≥2 SSB drinks/day vs. never was not associated with all-cancer mortality, but was associated with increased risk of obesity-related cancers [HR, 1.05; 95% confidence intervals (CI), 1.01–1.08; Ptrend = 0.057], which became null after adjustment for BMI. SSBs were associated with increased mortality from colorectal (HR, 1.09; 95% CI, 1.02–1.17; Ptrend = 0.011), and kidney (HR, 1.17; 95% CI, 1.03–1.34; Ptrend = 0.056) cancers, which remained after BMI adjustment. A positive association of ASB consumption with obesity-related cancers (HR, 1.05; 95% CI, 1.01–1.08; Ptrend = 0.001) was null after controlling for BMI; however, an increased risk of pancreatic cancer was robust to BMI adjustment (HR, 1.11; 95% CI, 1.02–1.20; Ptrend < 0.008). Conclusions: SSB consumption was associated with higher mortality from certain cancers, partially mediated through obesity. Associations of ASB consumption and increased pancreatic cancer risk merit further study. Impact: Future research should consider the role of BMI in studies of sweetened beverages and cancer risk. These results should inform policy regarding sweetened beverage consumption.

Background Accurate assessment of eating-occasion behaviors, such as timing, frequency, and consumption intervals, is important for evaluating associations with obesity and other chronic diseases. Objectives The main objective of this study was to assess the relative validity of a 24-hour grid approach to assess eating-occasion timing and frequency in comparison to data derived from repeated 24-hour dietary recalls (DRs). A second objective was to assess the 1-year test-retest reproducibility of the 24-hour grid. Methods Between 2015 and 2016, 626 participants in the Cancer Prevention Study-3 (CPS-3) Diet Assessment Substudy (mean age, 52 years; age range, 31-70 years; 64% female; 64% non-Hispanic white, 22% non-Hispanic black, 14% Hispanic) completed 2 grids and up to 6 unannounced, telephone, interviewer-administered DRs over 1 year. Spearman correlations (rho; 95% CIs) were calculated to assess reproducibility between the repeated eating-occasion grid-derived variables (e.g., numbers of snacks and meals per day, timing of eating occasions) and to assess relative validity by comparing the meal grid and DR-derived summary data separately for weekdays and weekend days. Results Reproducibility correlations for eating-occasion variables derived from the eating-occasion grids completed 1 year apart were >= 0.5 for the majority of variables analyzed for both weekdays and weekend days, including numbers of snacks and meals per day and timing of the first and last eating occasions of the day. Relative validity was highest among weekday variables and was >= 0.5 for the majority of variables, with correlations ranging from rho values of 0.32 (number of meals per day) to 0.68 (hour of the first eating occasion). Conclusions These findings suggest the eating-occasion grid used in CPS-3 has good reproducibility over 1 year and yields estimates comparable to those from a more detailed method of assessment of eating timing and frequency.

Background: Colorectal cancer survivors often use multivitamins and other over-the-counter dietary supplements, but evidence is limited regarding their potential associations with mortality. Methods: This 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. Results: Among 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). Conclusions: These 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.

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 HRs and 95% confidence intervals (CI), adjusted for covariates. c-peptide was associated with higher risk of liver cancer [per 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 with 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.Significance:The results from this study suggest that HbA1c and c-peptide, markers of hyperglycemia and hyperinsulinemia respectively, are associated with certain cancers, though people with diabetes may be at increased risk of these cancers, perhaps other than colorectal, even when their glucose is well controlled.

BACKGROUND:The relationship between time-use behaviors and prospective weight change is poorly understood.METHODS:A subset of Cancer Prevention Study-3 participants (n = 549, 58% women, 66% non-Latinx white) self-reported weight in 2015 and 2018 and completed an accelerometer protocol for seven days. Sedentary time, sleep, light, moderate, and vigorous intensity physical activity (PA) were treated as a compositional variable and multiple linear regression was used to examine associations between activity composition and weight change stratified by sex and race/ethnicity. Compositional isotemporal substitution analysis was used to quantify change in weight associated with reallocating 30 min./day.RESULTS:Activity composition was associated with weight change among women (p = 0.007), but not men (p = 0.356), and among Latinx (p = 0.032) and white participants (p = 0.001), but not Black participants (p = 0.903). Replacement of 30 min./day sedentary time with moderate-vigorous PA was associated with 3.49 lbs. loss (-6.76, -0.22) in Latinx participants and replacement with sleep was associated with 1.52 (0.25, 2.79) and 1.31 (0.40, 2.21) lbs. gain in white women and men.CONCLUSION:The distribution of time spent in daily behaviors was associated with three-year weight change in women, Latinx, and white participants. This was the first longitudinal compositional study of weight change; thus, more studies are needed.

BACKGROUND Aspirin-use reduces colorectal cancer (CRC) incidence, but there is limited evidence regarding associations of aspirin and non-aspirin nonsteroidal anti-inflammatory drugs (NSAIDs) with CRC-specific survival. METHODS 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 post-diagnosis data were available for 2,686 and 1,931 participants without distant-metastases, respectively, among whom 512 and 251 died from CRC during mortality follow-up through 2016. Secondary analyses examined associations between pre-diagnosis aspirin-use and stage at diagnosis (distant-metastatic versus localized or regional). All statistical tests were two-sided. RESULTS 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% CI = 0.52-0.92). Post-diagnosis regular aspirin use was not statistically significantly associated with risk of CRC-specific mortality overall (HR = 0.82; 95% CI = 0.62-1.09), 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 post-diagnosis periods (HR = 0.60; 95% CI = 0.36-0.98). 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 = 0.53-0.99). CONCLUSIONS Our results suggest that long-term aspirin use before a diagnosis of non-metastatic colorectal cancer may be associated with lower CRC-specific mortality after diagnosis, consistent with possible inhibition of micro-metastases before diagnosis.

Background: Response in acute myeloid leukemia (AML) is based on morphologic evaluation of bone marrow (BM) and peripheral blood lab-based assessments. Electronic health records (EHRs) hold structured information on peripheral blood assessments, but it may be incomplete; unstructured documents containing BM morphologic evaluations can be abstracted to derive data on morphologic leukemia-free state (MLFS). The objective of this analysis was to assess the feasibility of capturing MLFS using EHR with enough completeness for analytic use. The association of MLFS status with real-world time to next treatment (rwTTNT) and real-world overall survival (rwOS) was evaluated.

BACKGROUND:Body mass index (BMI) is a complex phenotype that may interact with genetic variants to influence colorectal cancer risk. METHODS:We tested multiplicative statistical interactions between BMI (per 5 kg/m2) and approximately 2.7 million single nucleotide polymorphisms with colorectal cancer risk among 14 059 colorectal cancer case (53.2% women) and 14 416 control (53.8% women) participants. All analyses were stratified by sex a priori. Statistical methods included 2-step (ie, Cocktail method) and single-step (ie, case-control logistic regression and a joint 2-degree of freedom test) procedures. All statistical tests were two-sided. RESULTS:Each 5 kg/m2 increase in BMI was associated with higher risks of colorectal cancer, less so for women (odds ratio [OR] = 1.14, 95% confidence intervals [CI] = 1.11 to 1.18; P = 9.75 × 10-17) than for men (OR = 1.26, 95% CI = 1.20 to 1.32; P = 2.13 × 10-24). The 2-step Cocktail method identified an interaction for women, but not men, between BMI and a SMAD7 intronic variant at 18q21.1 (rs4939827; Pobserved = .0009; Pthreshold = .005). A joint 2-degree of freedom test was consistent with this finding for women (joint P = 2.43 × 10-10). Each 5 kg/m2 increase in BMI was more strongly associated with colorectal cancer risk for women with the rs4939827-CC genotype (OR = 1.24, 95% CI = 1.16 to 1.32; P = 2.60 × 10-10) than for women with the CT (OR = 1.14, 95% CI = 1.09 to 1.19; P = 1.04 × 10-8) or TT (OR = 1.07, 95% CI = 1.01 to 1.14; P = .02) genotypes. CONCLUSION:These results provide novel insights on a potential mechanism through which a SMAD7 variant, previously identified as a susceptibility locus for colorectal cancer, and BMI may influence colorectal cancer risk for women.