Jo L. Freudenheim

Background: Processed meat and unprocessed red meat are considered carcinogenic and ‘probably carcinogenic’ to humans, respectively, but findings for bladder cancer remain inconsistent. Objectives: We assessed associations between processed meat and unprocessed red meat intake and bladder cancer risk using data from the Pooling Project of Prospective Studies of Diet and Cancer. Methods: Associations with bladder cancer risk were assessed using individual-level data from 30 cohort studies from North America, Europe, Australia and Asia. Diet was assessed at enrolment using validated food frequency questionnaires or diet histories. Following a pre-specified analysis plan, study- and sex-specific hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox regression, adjusted for smoking status and duration and other potential confounders, and pooled using inverse-variance-weighted random-effects meta-analysis. Results: During median follow-up across cohorts of 8–29 years, among 2,575,971 participants, 20,780 were diagnosed with bladder cancer. Processed meat intake was associated with increased bladder cancer risk (HR comparing ≥40 with <5 g/day = 1.08; 95% CI: 1.02–1.15; HR per 20 g/day = 1.02; 95% CI: 1.00–1.03). Weaker evidence of association with increased risk was also observed for unprocessed red meat (HR comparing ≥100 with <20 g/day = 1.06; 95% CI: 1.00–1.13; HR per 50 g/day = 1.01; 95% CI: 0.99–1.03). There was no evidence of heterogeneity by study, sex, or region. Conclusions: Higher intakes of processed meat and unprocessed red meat were associated with a small increase in risk of bladder cancer. These findings are consistent with existing public health recommendations to limit consumption of red and processed meat.

Background: This study aimed to investigate the association between alcohol consumption and squamous cell cancers of the upper aerodigestive tract (UADT), using data from 28 cohorts within the Pooling Project of Prospective Studies of Diet and Cancer (DCPP). Methods: Individual-level data from 2 365 437 participants were pooled. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox models to quantify the association between alcohol consumption (g/day) and UADT cancer risk, adjusting for potential confounders. Analyses were conducted by sex, smoking status, geographic region, and alcoholic beverages. Results: Over a median follow-up of 15.5 years, 6903 UADT cancer cases were identified. Alcohol consumption was positively associated with UADT cancer risk overall. Even at intakes as low as 5–<15 g/day, the HR estimate was 1.12 (95% CI = 1.03 to 1.21) compared with the reference group (0.1-<5 g/day). The HR10 g/day (95% CI) was 1.16 (1.14 to 1.18) for women and 1.12 (1.11 to 1.13) for men (Pheterogeneity < .0001). HR10 g/day estimates were 1.14 (1.13 to 1.15) in current, 1.10 (1.09 to 1.12) in former, and 1.15 (1.12 to 1.18) in never smokers. Consistent UADT HR10 g/day estimates were observed across all beverage types. HR10 g/day estimates varied across geographic regions, with HR10 g/day (95% CI) equal to 1.15 (1.14 to 1.17) in Europe–Australia, 1.13 (1.11 to 1.15) in Asia, and 1.11 (1.09 to 1.12) in North America (Pheterogeneity < .0001). Conclusion: Alcohol consumption was associated with UADT cancer risk, irrespective of smoking status or beverage type. However, due to differential baseline risks, alcohol is expected to impact the UADT cancer burden more in smokers than never smokers. These findings support public health strategies to reduce alcohol consumption.

Supplemental Figure S1. Log-transformed CD8+ T-cell density per mm2 by ACKR1/DARC genotype. Figure displays box plot distribution of CD8+ T-cell density per mm2 according to ACKR1/DARC genotype (N=428).

Supplemental Figure S2. Meta-analysis full forest plots from AABCG for rs2814778 in relation to risk of breast cancer overall, ER- and TNBC. Figure shows non-significant odds ratio (OR) estimates for breast cancer risk overall, ER- and TNBC for ACKR1/DARC variant, rs2814778 in reference to controls.

Background: Immune response in blood varies by ancestry, linked to an African-specific variant (rs2814778) in the Duffy Antigen Receptor for Chemokines (DARC/ACKR1) gene. We examined associations between rs2814778, CD8+ T-cell density in breast tumors, and breast cancer risk in African-American/Black women. Methods: CD8+ T-cell density in tumors from 428 Black women were examined in relation to the rs2814778 variant. In the African Ancestry Breast Cancer Genetics (AABCG) Consortium with 16,886 cases and 18,044 controls, rs2814778 was evaluated in relation to risk of overall breast cancer and to more aggressive subtypes [estrogen receptor-negative (ER−) and triple-negative breast cancer (TNBC)]. Results: Women with the African-specific CC genotype had lower tumor CD8+ T-cell density (87.0 per mm2) than those with TT genotypes (146.6 per mm2; P < 0.05). Each T allele was significantly associated with an increase in T-cell density (P = 0.04). In the largest analysis, to date, there were no associations between rs2814778 and risk of overall breast cancer [OR = 0.90 (95% confidence interval (CI), 0.66–1.22)] or with ER− breast cancer [OR = 0.86 (95% CI, 0.68–1.08)] or TNBC [OR = 0.77 (95% CI, 0.56–1.05)]. Conclusions: Although breast tumors from women with the African-specific DARCC allele had lower CD8+ T-cell density levels than those with T alleles, in a large breast cancer consortium with adequate statistical power, the variant was not associated with breast cancer risk overall, nor with risk of ER− breast cancer or TNBC, as previously hypothesized. Impact: Although the “Duffy-null” allele has been the focus of research as a contributor to aggressive breast cancer in Black women, this study with 34,930 cases and controls found no associations with risk.

Background: The American Cancer Society recommends physicians inform average-risk women about endometrial cancer risk on reaching menopause, but new diagnoses are rising fastest in women aged younger than 50 years. Educating these younger women about endometrial cancer risks requires knowledge of risk factors. However, endometrial cancer in young women is rare and challenging to study in single study populations. Methods: We included 13 846 incident endometrial cancer patients (1639 aged younger than 50 years) and 30 569 matched control individuals from the Epidemiology of Endometrial Cancer Consortium. We used generalized linear models to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for 6 risk factors and endometrial cancer risk. We created a risk score to evaluate the combined associations and population attributable fractions for these factors. Results: In younger and older women, we observed positive associations with body mass index and diabetes and inverse associations with age at menarche, oral contraceptive use, and parity. Current smoking was associated with reduced risk only in women aged 50 years and older (Phet < .01). Body mass index was the strongest risk factor (OR≥35 vs<25 kg/m2 = 5.57, 95% CI = 4.33 to 7.16, for ages younger than 50 years; OR≥35 vs<25 kg/m2 = 4.68, 95% CI = 4.30 to 5.09, for ages 50 years and older; Phet = .14). Possessing at least 4 risk factors was associated with approximately ninefold increased risk in women aged younger than 50 years and approximately fourfold increased risk in women aged 50 years and older (Phet < .01). Together, 59.1% of endometrial cancer in women aged younger than 50 years and 55.6% in women aged 50 years and older were attributable to these factors. Conclusions: Our data confirm younger and older women share common endometrial cancer risk factors. Early educational efforts centered on these factors may help mitigate the rising endometrial cancer burden in young women.

Background: There are few studies of social support and other social determinants of health after breast cancer diagnosis and their associations with mortality; results have been inconclusive. Further, it is not known if observed associations are specific to women with breast cancer diagnosis or if associations would be similar among healthy women. Methods: Women with incident, pathologically confirmed invasive breast cancer, stage I-IV (n = 1012), and healthy frequency age-matched participants (n = 2036) answered a social support questionnaire in prospective follow-up of a population-based case-control study, the Western New York Exposures and Breast Cancer Study. At interview, all participants were aged 35-79 years and resident of 2 counties in Western New York State. Mortality status was ascertained from the National Death Index. Participants were queried regarding the number of their close friends, frequency of seeing them, household size, household income, and marital status. Hazard ratios (HRs) and 95% confidence intervals (CIs) for breast cancer–specific mortality (breast cancer women only) and all-cause mortality were estimated. Results: Lower household income was associated with higher all-cause mortality among women diagnosed with breast cancer (HR = 2.48, 95% CI = 1.24 to 4.97) and similarly among the healthy women (HR = 2.63, 95% CI = 1.25 to 5.53). Number and frequency of seeing friends, marital status, and household size were not associated with mortality, either among breast cancer patients or among healthy women. Conclusion: Among those diagnosed with breast cancer and healthy women, lower income was associated with more than twice the mortality. Marital status, household size, and number or frequency of meeting friends were not associated with survival.

Figure S1 shows the study flowchart for the inclusion of participants. It depicts how we arrived at our final analytic population.

Figure S2 is a forest plot of the association between hypertension and endometrial cancer by study site. It displays the associations between hypertension and endometrial cancer for each study site included grouped by study type (case-control, cohort)

Association of Hypertension Status with Endometrial Cancer by Histologic Subtype