Faculty Bibliography

We examined adults with untreated Burkitt lymphoma (BL) from 2009 to 2018 across 30 US cancer centers. Factors associated with progression-free survival (PFS) and overall survival (OS) were evaluated in univariate and multivariate Cox models. Among 641 BL patients, baseline features included the following: median age, 47 years; HIV+, 22%; Eastern Cooperative Oncology Group (ECOG) performance status (PS) 2 to 4, 23%; >1 extranodal site, 43%; advanced stage, 78%; and central nervous system (CNS) involvement, 19%. Treatment-related mortality was 10%, with most common causes being sepsis, gastrointestinal bleed/perforation, and respiratory failure. With 45-month median follow-up, 3-year PFS and OS rates were 64% and 70%, respectively, without differences by HIV status. Survival was better for patients who received rituximab vs not (3-year PFS, 67% vs 38%; OS, 72% vs 44%; P < .001) and without difference based on setting of administration (ie, inpatient vs outpatient). Outcomes were also improved at an academic vs community cancer center (3-year PFS, 67% vs 46%, P = .006; OS, 72% vs 53%, P = .01). In multivariate models, age ≥ 40 years (PFS, hazard ratio [HR] = 1.70, P = .001; OS, HR = 2.09, P < .001), ECOG PS 2 to 4 (PFS, HR = 1.60, P < .001; OS, HR = 1.74, P = .003), lactate dehydrogenase > 3× normal (PFS, HR = 1.83, P < .001; OS, HR = 1.63, P = .009), and CNS involvement (PFS, HR = 1.52, P = .017; OS, HR = 1.67, P = .014) predicted inferior survival. Furthermore, survival varied based on number of factors present (0, 1, 2 to 4 factors) yielding 3-year PFS rates of 91%, 73%, and 50%, respectively; and 3-year OS rates of 95%, 77%, and 56%, respectively. Collectively, outcomes for adult BL in this real-world analysis appeared more modest compared with results of clinical trials and smaller series. In addition, clinical prognostic factors at diagnosis identified patients with divergent survival rates.

Existing studies addressing alcohol consumption have not captured the multidimensionality of drinking patterns, including drinking frequency, binge drinking, beverage preference and changes in these measures across the adult life course. We examined longitudinal trends in drinking patterns and their association with diet over four decades in ageing US adults from the Framingham Offspring Study (n 4956; baseline mean age 36·2 years). Alcohol intake (drinks/week, drinking frequency, beverage-specific consumption, drinks/occasion) was assessed quadrennially from examinations 1 to 8. Participants were classified as binge drinkers, moderate drinkers or heavy drinkers (4+ and 5+ drinks/occasion; ≤1 and ≤2 drinks/d and >7 and >14 drinks/week for women and men, respectively). Dietary data were collected by a FFQ from examinations 5 to 8 (1991-2008). We evaluated trends in drinking patterns using linear mixed effect models and compared dietary intake across drinking patterns using heterogeneous variance models. Alcohol consumption decreased from 1971 to 2008 (3·7 v. 2·2 oz/week; P < 0·05). The proportion of moderate (66 v. 59·3 %), heavy (18·4 v. 10·5 %) and binge drinkers (40·0 v. 12·3 %) declined (P < 0·05). While average wine consumption increased (1·4 v. 2·2 drinks/week), beer (3·4 v. 1·5 drinks/week) and cocktail intake (2·8 v. 1·2 drinks/week) decreased. Non-binge drinkers consumed less sugary drinks and more whole grains than binge drinkers, and the latter consumed more total fat across all examinations (P < 0·05). There was a significant difference in consumption trends of total grains by drinking level (P < 0·05). In conclusion, alcohol drinking patterns are unstable throughout adulthood. Higher intakes were generally associated with poorer diets. These analyses support the nuanced characterisation of alcohol consumption in epidemiological studies.

BACKGROUND:The molecular mechanisms underlying the association between increased adiposity and aggressive breast cancer phenotypes remain unclear, but likely involve the adipokines, leptin (LEP) and adiponectin (ADIPOQ), and their receptors (LEPR, ADIPOR1, ADIPOR2). METHODS:We used immunohistochemistry (IHC) to assess LEP, LEPR, ADIPOQ, ADIPOR1, and ADIPOR2 expression in breast tumor tissue microarrays among a sample of 720 women recently diagnosed with breast cancer (540 of whom self-identified as Black). We scored IHC expression quantitatively, using digital pathology analysis. We abstracted data on tumor grade, tumor size, tumor stage, lymph node status, Ki67, estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) from pathology records, and used ER, PR, and HER2 expression data to classify breast cancer subtype. We used multivariable mixed effects models to estimate associations of IHC expression with tumor clinicopathology, in the overall sample and separately among Blacks. RESULTS:Larger proportions of Black than White women were overweight or obese and had more aggressive tumor features. Older age, Black race, postmenopausal status, and higher body mass index were associated with higher LEPR IHC expression. In multivariable models, lower LEPR IHC expression was associated with ER-negative status and triple-negative subtype (P < 0.0001) in the overall sample and among Black women only. LEP, ADIPOQ, ADIPOR1, and ADIPOR2 IHC expression were not significantly associated with breast tumor clinicopathology. CONCLUSIONS:Lower LEPR IHC expression within the breast tumor microenvironment might contribute mechanistically to inter-individual variation in aggressive breast cancer clinicopathology, particularly ER-negative status and triple-negative subtype.

OBJECTIVE:Shared reading is believed to enhance parent-child relationships, but the extent to which it reduces harsh parenting is understudied. Associations between early shared reading and subsequent harsh parenting were investigated. METHODS:Data from a national urban birth cohort were used to estimate associations between mother-reported shared reading at ages 1 and 3 years and harsh parenting-based on a composite of psychological and physical aggression subscales of a validated self-report instrument-when the children were at ages 3 and 5 years. The authors used multivariable linear regression and generalized estimating equations to account for repeated observations. Given potential inverse associations between shared reading and child disruptive behaviors, which can trigger harsh parenting, the authors investigated the extent to which children's behavior at age 3 years mediated the association between shared reading at age 1 year and harsh parenting at age 5 years. RESULTS:This study included 2165 mother-child dyads. Thirty-four percent and 52% of mothers reported daily reading at ages 1 and 3 years. In adjusted models, shared reading at age 1 year was associated with less harsh parenting at age 3 years. Similarly, shared reading at age 3 years was associated with less harsh parenting at age 5 years. These associations remained significant in lagged repeated-measures models. Decreased disruptive behaviors partially mediated the association between shared reading at age 1 year and harsh parenting at age 5 years. CONCLUSION/CONCLUSIONS:Shared reading predicted less harsh parenting in a national urban sample. These findings suggest that shared reading contributes to an important aspect of the parent-child relationship and that some of the association operates through enhanced child behaviors.

OBJECTIVE/UNASSIGNED:To examine adherence to a Mediterranean-like diet at age 9-10 years in relation to onset of breast development (thelarche) and first menstruation (menarche). DESIGN/UNASSIGNED:We evaluated the associations of adherence to a Mediterranean-like diet (measured by an adapted Mediterranean-like Diet Score, range 0-9) with thelarche at baseline, age at thelarche and time to menarche. Data were collected at baseline during a clinic visit, complemented with a mailed questionnaire and three 24 hour telephone dietary recalls, followed by annual follow-up questionnaires. Multivariable Poisson regression, linear regression and Cox proportional hazards regression were used to evaluate timing of pubertal development in relation to diet adherence. SETTING/UNASSIGNED:New Jersey, USA. PARTICIPANTS/UNASSIGNED:Girls aged 9 or 10 years at baseline (2006-2014, n 202). RESULTS/UNASSIGNED:High Mediterranean-like diet adherence (score 6-9) was associated with a lower prevalence of thelarche at baseline compared with low adherence (score 0-3; prevalence ratio = 0·65, 95 % CI 0·48, 0·90). This may have been driven by consumption of fish and non-fat/low-fat dairy. Our models also suggested a later age at thelarche with higher Mediterranean-like diet adherence. Girls with higher Mediterranean-like diet adherence had significantly longer time to menarche (hazard ratio = 0·45, 95 % CI 0·28, 0·71 for high v. low adherence). Further analysis suggested this may have been driven by vegetable and non-fat/low-fat dairy consumption. CONCLUSIONS/UNASSIGNED:Consuming a Mediterranean-like diet may be associated with older age at thelarche and menarche. Further research is necessary to confirm our findings in other US paediatric populations and elucidate the mechanism through which Mediterranean-like diet may influence puberty timing.

Triple negative breast cancer (TNBC) is an aggressive subset for which effective therapeutic approaches are needed. A significant proportion of TNBC patients harbor either germline or somatic mutations in BRCA1, or epigenetic silencing of BRCA1, which renders them deficient in DNA repair. Virtually all BRCA1 deficient breast cancers harbor mutations in TP53 suggesting that inactivation of p53 is a requirement for tumor progression in the setting of BRCA1 deficiency. Due to this dependency, we hypothesized that restoring wild type p53 function in BRCA1 deficient breast cancer would be therapeutic. The majority of TP53 mutations are missense, which generate a defective protein that potentially can be targeted with small molecules. Zinc metallochaperones (ZMCs) are a new class of anti-cancer drugs that specifically reactivate zinc-deficient mutant p53 by restoring zinc binding. Using ZMC1 in human breast cancer cell lines expressing the zinc deficient p53^R175H, we demonstrate that loss of BRCA1 sensitizes cells to mutant p53 reactivation. Using murine breast cancer models with Brca1 deficiency, we demonstrate that ZMC1 significantly improves survival of mice bearing tumors harboring the zinc-deficient Trp53

Estrogen plays an important role in breast cancer development. While the mechanism of the estrogen effects is not fully elucidated, one possible route is by increasing the stem cell-like properties in the tumors. Tocopherols are known to reduce breast cancer development and progression. The aim of the present study is to investigate the effects of tocopherols on the regulation of breast cancer stemness mediated by estrogen. To determine the effects of tocopherols on estrogen-influenced breast cancer stem cells, the MCF-7 tumorsphere culture system, which enriches for mammary progenitor cells and putative breast cancer stem cells, was utilized. Treatment with estrogen resulted in an increase in the CD44+/CD24- subpopulation and ALDH activity in tumorspheres as well as the number and size of tumorspheres. Tocopherols inhibited the estrogen-induced expansion of the breast cancer stem population. Tocopherols decreased the levels of stem cell markers, including OCT4, CD44 and SOX-2, as well as estrogen-related markers, such as TFF/pS2, CTSD, PGR and SERPINA1, in estrogen-stimulated tumorspheres. Overexpression of OCT4 increased CD44 and SOX2 levels and significantly increased cell invasion and expression of the invasion markers, matrix metalloproteinases, tissue inhibitors of metalloproteinase and urokinase plasminogen activator, and tocopherols inhibited these OCT4-mediated effects. These results suggest a potential inhibitory mechanism of tocopherols in estrogen-induced stemness and cell invasion in breast cancer.

Case-control studies suggest that higher whole grain and lower refined grain intakes are associated with reduced cancer risk, but longitudinal evidence is limited. The objective of this prospective cohort study is to evaluate associations between whole and refined grains and their food sources in relation to adiposity-related cancer risk. Participants were adults from the Framingham Offspring cohort (N = 3,184; ≥18 yr). Diet, measured using a food frequency questionnaire, medical and lifestyle data were collected at exam 5 (1991-95). Between 1991 and 2013, 565 adiposity-related cancers were ascertained using pathology reports. Cox proportional hazards models were used to estimate adjusted hazard ratios and 95% confidence intervals for associations of whole and refined grains with risk of adiposity-related cancers combined and with risk of breast and prostate cancers in exploratory site-specific analyses. Null associations between whole and refined grains and combined incidence of adiposity-related cancers were observed in multivariable-adjusted models (HR: 0.94; 95% CI: 0.71-1.23 and HR: 0.98; 95% CI: 0.70-1.38, respectively). In exploratory analyses, higher intakes of whole grains (oz eq/day) and whole grain food sources (servings/day) were associated with 39% and 47% lower breast cancer risk (HR: 0.61; 95% CI: 0.38-0.98 and HR: 0.53; 95% CI: 0.33-0.86, respectively). In conclusion, whole and refined grains were not associated with adiposity-related cancer risk. Whole grains may protect against breast cancer, but findings require confirmation within a larger sample and in other ethnic groups.

BACKGROUND:Higher sugar consumption may increase cancer risk by promoting insulin-glucose dysregulation, oxidative stress, hormonal imbalances, and excess adiposity. This prospective study investigates the association between dietary sugars(fructose and sucrose) and sugary foods and beverages in relation to combined and site-specific (breast, prostate, colorectal) adiposity-associated cancers. METHODS:The analytic sample consisted of 3,184 adults, aged 26-84y, from the Framingham Offspring cohort. Diet data was first collected between 1991-1995 using a food frequency questionnaire. Intakes of fructose, sucrose, sugary foods and sugary beverages (fruit juice and sugar-sweetened beverages) were derived. Participants were followed up until 2013 to ascertain cancer incidence; 565 doctor-diagnosed adiposity-related cancers, including 124 breast, 157 prostate and 68 colorectal cancers occurred. Multivariable-adjusted Cox proportional hazards models were used to evaluate associations. Tests for interaction with BMI and waist circumference were conducted. RESULTS:No associations were observed between fructose, sucrose, sugary food consumption and combined incidence of adiposity-related cancers or the examined site-specific cancers. While total consumption of sugary beverages was not associated with site-specific cancer risk, higher intakes of fruit juice were associated with 58% increased prostate cancer risk(HR:1.58;95%CI:1.04-2.41) in multivariable-adjusted models. In exploratory stratified analyses, higher sugary beverage intakes increased overall adiposity-related cancer risk by 59% in participants with excessive central adiposity(HR:1.59;95%CI:1.01-2.50)(p-trend=0.057). CONCLUSIONS:In this cohort of American adults, higher sugary beverage consumption was associated with increased cancer risk among participants with central adiposity. IMPACT/CONCLUSIONS:These analyses suggest that avoiding sugary beverages represents a simple dietary modification that may be used as an effective cancer control strategy.

Higher carbohydrate intake, glycaemic index (GI), and glycaemic load (GL) are hypothesised to increase cancer risk through metabolic dysregulation of the glucose-insulin axis and adiposity-related mechanisms, but epidemiological evidence is inconsistent. This prospective cohort study investigates carbohydrate quantity and quality in relation to risk of adiposity-related cancers, which represent the most commonly diagnosed preventable cancers in the USA. In exploratory analyses, associations with three site-specific cancers: breast, prostate and colorectal cancers were also examined. The study sample consisted of 3184 adults from the Framingham Offspring cohort. Dietary data were collected in 1991-1995 using a FFQ along with lifestyle and medical information. From 1991 to 2013, 565 incident adiposity-related cancers, including 124 breast, 157 prostate and sixty-eight colorectal cancers, were identified. Cox proportional hazards models were used to evaluate the role of carbohydrate nutrition in cancer risk. GI and GL were not associated with risk of adiposity-related cancers or any of the site-specific cancers. Total carbohydrate intake was not associated with risk of adiposity-related cancers combined or prostate and colorectal cancers. However, carbohydrate consumption in the highest v. lowest quintile was associated with 41 % lower breast cancer risk (hazard ratio (HR) 0.59; 95 % CI 0.36, 0.97). High-, medium- and low-GI foods were not associated with risk of adiposity-related cancers or prostate and colorectal cancers. In exploratory analyses, low-GI foods, were associated with 49 % lower breast cancer risk (HR 0.51; 95 % CI 0.32, 0.83). In this cohort of Caucasian American adults, associations between carbohydrate nutrition and cancer varied by cancer site. Healthier low-GI carbohydrate foods may prevent adiposity-related cancers among women, but these findings require confirmation in a larger sample.